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  • CLASSES

    Compounding Kits Miscellaneous
    Nonsteroidal Antiinflammatory Drugs/NSAIDs
    Nonsteroidal Antiinflammatory Drugs/NSAIDs with Gastroprotectants
    Ophthalmological Non-steroidal Anti-inflammatories
    Other Anti-migraine Drugs
    Topical Anti-inflammatory

    BOXED WARNING

    Alcoholism, anticoagulant therapy, chemotherapy, corticosteroid therapy, GI bleeding, GI disease, GI perforation, peptic ulcer disease, tobacco smoking, ulcerative colitis

    Chronic use of diclofenac can result in gastritis, ulceration with or without GI perforation, and/or GI bleeding, which can occur at any time, often without preceding symptoms. Therefore, intravenous, oral, or topical diclofenac should be used with caution in patients with a history of or active GI disease including peptic ulcer disease, ulcerative colitis, or GI bleeding. Patients with a prior history of peptic ulcer disease or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. It is recommended not to initiate therapy with maximum doses in these patients due to the likely increase frequency of adverse reactions. Patients at increased risk for NSAID-induced GI bleeding include those receiving concurrent myelosuppressive chemotherapy, corticosteroid therapy, or anticoagulant therapy, tobacco smoking patients, elderly patients, and patients with alcoholism. All patients receiving prolonged treatment should be routinely monitored for potential GI ulceration and bleeding. Consider alternative therapies to NSAIDs for high risk patients.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, myocardial infarction or stroke, peripheral vascular disease, tachycardia

    Diclofenac, like all nonsteroidal anti-inflammatory drugs (NSAIDs), may exacerbate hypertension and congestive heart failure and may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. The FDA has warned that the risk of myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. Data demonstrate that patients treated with NSAIDs were more likely to die in the first year following a myocardial infarction compared to those not treated with NSAIDs. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event following NSAID use, likely due to a higher baseline risk. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is an increased risk of heart failure with NSAID use. Caution is recommended when administering diclofenac to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing renal disease, or fluid retention. In addition, clinical practice guidelines state NSAIDs should not be administered to patients presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use. Closely monitor blood pressure during diclofenac receipt. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event. Inform patients to seek immediate medical attention if they experience any signs or symptoms of a cardiovascular thrombotic event.

    DEA CLASS

    Rx

    DESCRIPTION

    NSAID available in intravenous, oral, topical, and ophthalmic formulations
    Analgesic and antipyretic properties
    Increases risk of serious GI events and may increase risk of serious CV events; use lowest dose for shortest time

    COMMON BRAND NAMES

    Cambia, Cataflam, DSG Pak, Dyloject, Flector, INFLAMMA-K, PENNSAID, REXAPHENAC, Solaraze, Voltaren, Voltaren Gel, Voltaren-XR, VOPAC MDS, Zipsor, Zorvolex

    HOW SUPPLIED

    Cambia Oral Pwd F/Recon: 50mg
    Cataflam/Diclofenac/Diclofenac Potassium Oral Tab: 50mg
    Diclofenac Sodium/DSG Pak/Solaraze/Voltaren Gel Topical Gel: 1%, 3%
    Diclofenac Sodium/INFLAMMA-K/PENNSAID/VOPAC MDS Topical Sol: 1.5%, 2%
    Diclofenac Sodium/Voltaren Ophthalmic Sol: 0.1%
    Diclofenac Sodium/Voltaren Oral Tab DR: 25mg, 50mg, 75mg
    Diclofenac Sodium/Voltaren-XR Oral Tab ER: 100mg
    Dyloject Intravenous Inj Sol: 1mL, 37.5mg
    Flector Topical Film: 1.3%
    REXAPHENAC Topical Pwd: 1%
    Zipsor/Zorvolex Oral Cap: 18mg, 25mg, 35mg

    DOSAGE & INDICATIONS

    For the treatment of osteoarthritis.
    NOTE: Different oral formulations of diclofenac are not bioequivalent even if of equivalent milligram strength.
    Oral dosage (immediate-release tablets only, Cataflam)
    Adults

    50 mg PO 2 to 3 times daily. Dosages greater than 150 mg/day PO are not recommended.

    Oral dosage (immediate-release capsules only, Zorvolex)
    Adults

    35 mg PO 3 times daily. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

    Oral dosage (delayed-release tablets only, Voltaren)
    Adults

    50 mg PO 2 to 3 times daily or 75 mg PO twice daily. Dosages greater than 150 mg/day PO are not recommended.

    Oral dosage (extended-release tablets only, Voltaren XR)
    Adults

    100 mg PO once daily for chronic therapy. Dosages greater than 150 mg/day PO are not recommended. Voltaren-XR is not indicated for the management of acute exacerbations and should only be used as chronic maintenance therapy.

    Topical dosage (Voltaren 1% gel)

    NOTE: The gel is only indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment such as the knees and hands. The gel was not evaluated for use on joints of the spine, hip, or shoulder.

    Adults

    4 g for each knee, ankle, or foot 4 times daily. Do not apply more than 16 g daily to any 1 affected joint of the lower extremities. Apply 2 g for each elbow, wrist, or hand 4 times daily. Do not apply more than 8 g daily to any 1 affected joint of the upper extremities. Do not exceed a total dose of 32 g per day over all affected joints.

    Topical dosage (Pennsaid 1.5% Topical Solution)

    NOTE: Pennsaid is indicated for the relief of the signs and symptoms of osteoarthritis of the knee(s) and was not evaluated for use on other joints.

    Adults

    Apply 40 drops to each affected knee 4 times daily. The entire dose of 40 drops should be applied 10 drops at a time, directly on the knee or first into the hand and then onto the knee; spread the 10 drops around the knee, and repeat this procedure until the entire dose of 40 drops has been applied.

    Topical dosage (Inflamma-K kit; diclofenac 1.5% topical solution with Salonpas patch)
    Adults

    Apply 40 drops to each affected knee 4 times daily. The entire dose of 40 drops should be applied 10 drops at a time, directly on the knee or first into the hand and then onto the knee; spread the 10 drops around the knee, and repeat this procedure until the entire dose of 40 drops has been applied. Cover affected area with the Salonpas patch for up to 8 hours after an application.

    Topical dosage (Pennsaid 2% Topical Solution)
    Adults

    Apply 40 mg (2 pump actuations) to each affected knee twice daily. Deliver the entire dose directly into the palm of the hand then apply evenly around the front, back, and sides of the knee.

    For the treatment of rheumatoid arthritis.
    NOTE: Different oral formulations of diclofenac are not bioequivalent even if of equivalent milligram strength.
    Oral dosage (immediate-release tablets only, Cataflam)
    Adults

    50 mg PO 3 to 4 times daily. Dosages greater than 200 mg/day PO are not recommended.

    Oral dosage (delayed-release tablets only, Voltaren)
    Adults

    50 mg PO 3 to 4 times daily, or 75 mg PO twice daily. Dosages greater than 200 mg/day PO are not recommended.

    Oral dosage (extended-release tablets only, Voltaren XR)
    Adults

    100 mg PO once daily for chronic therapy. In the rare cases where 100 mg/day is unsatisfactory, the dose may be increased to 100 mg PO twice daily if the benefits outweigh the risks. Dosages greater than 200 mg/day PO are not recommended. Voltaren-XR is not indicated for the management of acute exacerbations and should only be used as chronic maintenance therapy.

    For the treatment of ankylosing spondylitis.
    NOTE: Different oral formulations of diclofenac are not bioequivalent even if of equivalent milligram strength.
    Oral dosage (delayed-release tablets only, Voltaren)
    Adults

    100 to 125 mg/day PO in 4 to 5 divided doses. Usually 25 mg PO 4 times daily with an additional 25-mg dose at bedtime, if needed. When a satisfactory response is achieved the dosage should be reduced to the minimum required to provide relief of symptoms. The safe and effective use of doses exceeding 125 mg/day PO has not been established for ankylosing spondylitis.

    For the acute treatment of migraine with or without aura.
    NOTE: Different oral formulations of diclofenac are not bioequivalent even if of equivalent milligram strength.
    NOTE: Diclofenac is not indicated for migraine prophylaxis.
    Oral dosage (powder for oral solution only, Cambia)
    Adults

    50 mg PO as a single dose per migraine; repeat doses are not recommended. Mix contents of one packet into a cup of 1 to 2 oz of water and drink immediately; do not use liquids other than water.

    For the treatment of mild pain or moderate pain.
    NOTE: Different oral formulations of diclofenac are not bioequivalent even if of equivalent milligram strength.
    For primary dysmenorrhea or for mild or moderate pain associated with nonrheumatic inflammatory conditions, bone pain†, arthralgia†, myalgia†, and vascular or migraine headache†.
    NOTE: Voltaren XR is not indicated for the management of acute painful conditions.
    Oral dosage (immediate-release tablets only, e.g., Cataflam)
    Adults

    50 mg PO 3 times daily. For better relief, give 100 mg PO initially, then follow with 50 mg doses. After the first day of therapy with a maximum dose of 200 mg, total doses should generally not exceed 150 mg/day.

    For the treatment of acute mild or moderate pain.
    Oral dosage (immediate-release capsules only, Zipsor)
    Adults

    25 mg PO 4 times daily.

    Oral dosage (immediate-release capsules only, Zorvolex)
    Adults

    18 or 35 mg PO 3 times daily. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

    Intravenous dosage

    NOTE: For use alone or in combination with opioid analgesics.

    Adults

    37.5 mg IV every 6 hours as needed. Do not exceed 150 mg/day.

    For the topical treatment of acute mild pain or moderate pain due to minor strains, sprains, and contusions.
    NOTE: Carefully consider the potential benefits and risks of the diclofenac patch. If the patch will be used, use the lowest effective dose for the shortest possible duration.
    Topical dosage (Flector only)
    Adults

    Apply 1 patch to the most painful area twice a day.

    For the treatment of postoperative ocular inflammation following cataract extraction.
    For the reduction of photophobia and ocular pain following corneal refractive surgery.
    Ophthalmic dosage
    Adults

    1 to 2 drops to the affected eye(s) within 1 hour prior to surgery, then 1 to 2 drops 15 minutes after surgery and then 4 times daily beginning 4 to 6 hours after surgery and continue for up to 3 days as needed.

    Ophthalmic dosage
    Adults

    1 drop to the affected eye(s) 4 times daily, starting 24 hours after cataract surgery and continue for 2 weeks.

    For the treatment of moderate to severe pain alone or in combination with opioid analgesics.
    Intravenous dosage
    Adults

    37.5 mg IV every 6 hours as needed. Do not exceed 150 mg/day.

    For the treatment of actinic keratosis.
    Topical dosage (Solaraze 3% gel)
    Adults

    Gently apply to affected areas twice daily. The amount needed depends upon the size of the lesion. Assure that enough topical diclofenac is applied to adequately cover each lesion (usually 0.5 g gel is used on each 5 x 5 cm lesion site). The recommended duration of therapy is from 60 to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following the cessation of therapy. Therapy may be interrupted for severe dermal reactions until the condition subsides.

    For the prevention of heterotopic ossification†.
    Oral dosage

    Salt form and manufacturer of oral drug used in the study was unstated.

    Adults

    50 mg PO 3 times daily for the first 3 weeks after an initial or revision of a total hip endoprosthesis led to heterotopic ossification degree 1 or 2 according to Brooker in 18.6% of 497 patients; only 1.4% of the patients had degree 3 and none had degree 4 (connective ossification).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    150 mg/day IV; 200 mg/day PO in rheumatoid arthritis; 150 mg/day PO in osteoarthritis, dysmenorrhea, or mild-to-moderate pain; 125 mg/day PO in ankylosing spondylitis; 32 g/day of the 1% topical gel over all affected joints; 160 drops/knee/day of the topical solution; 2 patches/day topically.

    Geriatric

    150 mg/day IV; 200 mg/day PO in rheumatoid arthritis; 150 mg/day PO in osteoarthritis, dysmenorrhea, or mild-to-moderate pain; 125 mg/day PO in ankylosing spondylitis; 32 g/day of the 1% topical gel over all affected joints; 160 drops/knee/day of the topical solution; 2 patches/day topically.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with hepatic impairment may require reduced doses of diclofenac compared to patients with normal hepatic function. Initiate therapy at the lowest dose and discontinue if not effective. Immediately discontinue diclofenac if signs and symptoms consistent with hepatic disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and abnormal liver tests are detected, persist, or worsen.

    Renal Impairment

    Intravenous diclofenac is contraindicated in patients with moderate to severe renal insufficiency in the perioperative period and who are at risk for volume depletion. Specific guidelines for dosage adjustments in renal impairment are not available; dosage reduction or initiation of diclofenac therapy at the lower end of the usual dosage range is prudent in patients with renal impairment. According to the manufacturers, use of diclofenac intravenous solution, topical gel, patch, or solution, oral tablet or capsule, or diclofenac potassium oral tablet, capsule, or powder for solution is not recommended in patients with advanced renal disease. Patients must be well hydrated prior to the use of the intravenous formulation, and caution should be used when initiating intravenous diclofenac therapy in patients with considerable dehydration.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Tablets and capsules:
    Do not crush delayed-release or extended-release formulations (e.g., Voltaren or Voltaren XR).
    Administration of Zorvolex capsules with food may reduce efficacy.
    Administer with food to minimize GI irritation. Extended-release forms (e.g., Voltaren or Voltaren XR) may be administered with food to ensure more consistent blood concentrations.

    Oral Liquid Formulations

    Powder for oral solution:
    Empty the contents of one packet into a cup containing 1 to 2 ounces (30 to 60 mL) of water, mix well, and drink immediately. Do not use liquids other than water.
    Administration with food may reduce efficacy.

    Injectable Administration

    Diclofenac is administered intravenously.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. If visibly opaque particles, discoloration, or other foreign particles are observed, the solution should not be used.

    Intravenous Administration

    Adequately hydrate patients before administering intravenous diclofenac to reduce the risk of renal adverse reactions.
    Inject by IV bolus over no less than 15 seconds.

    Topical Administration

    Wash hands before and after applying or handling diclofenac topical products unless hands are a treated area.
    Do not apply to open skin wounds, infections, or exfoliative dermatitis.
    Avoid contact with eyes and mucous membranes. If eye contact occurs, immediately wash out the eye with water or saline, and consult a physician if irritation persists.

    Cream/Ointment/Lotion Formulations

    Topical gel, Solaraze 3% Gel:
    Avoid application of cosmetics, sunscreens, and other topical medications on the area being treated with topical diclofenac.
    The effect of the gel under occlusive dressings has not been evaluated.
    Protect the treated area from natural and artificial sunlight.
     
    Topical gel, Voltaren 1% Gel:
    Use 1 dosing card for each application of drug product. Apply the gel within the oblong area of the dosing card up to the 2 gram or 4 gram line. The dosing card can be used to apply the gel.
    Gently massage the gel into the skin to ensure application to the entire affected area. The entire foot includes the sole, top of the foot, and the toes. The entire hand includes the palm, back of the hands, and the fingers. If Voltaren gel is used to treat hand osteoarthritis, do not wash the hand for at least 1 hour after application.
    Do not apply occlusive dressings to treated areas.
    Avoid application of cosmetics, sunscreens, lotions, moisturizers, insect repellants, and other topical medications on the area being treated with topical diclofenac. Concomitant administration has not been tested and should be avoided because of the potential to alter local tolerability and absorption.
    Avoid covering a treated area with clothes or gloves for at least 10 minutes after applying the gel, and avoid showering or bathing for at least 1 hour after the application.
    Avoid exposure of the treated joint(s) to sunlight.
    Application of a heat patch for 15 minutes before gel application or gel application followed by a 20-minute treadmill exercise did not lead to clinically relevant differences of systemic absorption and tolerability. Pharmacokinetics of the gel were not tested under the condition of heat application following gel application; therefore, concurrent use of the gel and external heat is not recommended.
     
    Topical solution, Pennsaid Topical Solution:
    Apply to clean, dry skin.
    Do not apply external heat or occlusive dressings to treated areas.
    Wait until the treated area is dry before covering with clothing or applying lotions, cosmetics, sunscreens, and other topical medications.
    Wait at least 30 minutes after application of diclofenac topical solution before bathing.
    Protect the treated area from natural and artificial sunlight.
    Pennsaid 1.5% topical solution: Utilizing 10 drops at a time to minimize spills, spread solution over the front, back, and sides of the knee; repeat until full dose is applied. May apply directly to treatment area or into the hand for application.
    Pennsaid 2% topical solution: Prime pump before first use by fully depressing the pump 4 times while holding the bottle upright. Discard this portion to ensure proper priming. No further priming should be necessary. Fully depress the pump twice to dispense the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and apply evenly around the front, back and sides of the knee.
     
    Topical solution, Inflamma-K kit (diclofenac 1.5% topical solution with Salonpas patch):
    Apply to clean, dry skin. 
    Dispense 10 drops of solution at a time either directly onto the knee or first into the hand and then onto the knee. Spread the solution evenly around front, back, and sides of the knee. Rub into skin until completely absorbed. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution.
    Remove the Salonpas patch from the film and apply to the affected area. The patch may be applied for up to 8 hours. Do not apply other occlusive dressings to the affected area.
    Wait until the treated area is dry before covering or applying lotions, cosmetics, sunscreens, and other topical medications.
    Protect the treated area from natural and artificial sunlight.
    Do not apply external sources of heat to the treated area.

    Transdermal Patch Formulations

    Topical patch, Flector:
    NOTE: Each patch contains 180 mg of diclofenac epolamine and 13 mg of diclofenac epolamine per gram of adhesive.
    Remove the release liner before applying the patch to skin.
    Only apply a patch to normal, intact skin. Do not apply to damaged skin such as wounds or burns.
    Only one patch should be worn at a time.
    Do not cover patch with occlusive dressing.
    If patch begins to peel off edges may be secured with adhesive tape. A mesh netting sleeve may also be used to secure patch if needed, particularly if patch is applied over ankles, knees, or elbows.
    Remove a patch before the patient bathes or showers.
    Once removed, discard a used patch in a waste receptacle out of the reach of children and pets. A used patch may contain as much as 170 mg of diclofenac eoplamine. Serious adverse effects may occur if a patch is chewed or ingested.

    Ophthalmic Administration

    Instruct patient on proper instillation of eye solution.
    Do not to touch the tip of the dropper to the eye, fingertips, or other surface.
    When used after surgery, using the same bottle for both eyes is not recommended.

    STORAGE

    Cambia:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Cataflam:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    DSG Pak:
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Dyloject:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Flector:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    INFLAMMA-K :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    PENNSAID:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    REXAPHENAC:
    - Storage information not provided in labeling
    Solaraze:
    - Avoid exposure to heat
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Voltaren:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Voltaren Gel:
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Voltaren-XR:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    VOPAC MDS:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zipsor:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zorvolex:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Acute bronchospasm, asthma, bovine protein hypersensitivity, gelatin hypersensitivity, nasal polyps, NSAID hypersensitivity, polysorbate 80 hypersensitivity, salicylate hypersensitivity, urticaria

    Intravenous, oral, or topical diclofenac is contraindicated in patients with salicylate hypersensitivity or NSAID hypersensitivity who have experienced asthma, urticaria, or other allergic reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactoid reactions to diclofenac have been reported in such patients. In addition, the use of immediate-release gel capsules is contraindicated in patients with bovine protein hypersensitivity. Cautious use of diclofenac is recommended for patients with asthma, and diclofenac should not be used in asthma patients with aspirin-sensitive asthma or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who experience severe, potentially fatal, acute bronchospasm after taking aspirin or other NSAIDs. The use of NSAIDs, including diclofenac, may cause serious and potentially fatal skin reactions. Patients should be instructed to discontinue the medication and to contact their health care provider if erythema, rash, blisters, or related skin reactions develop. The patch contains polysorbate 80 and gelatin and may be inappropriate for use by patients with either gelatin hypersensitivity or polysorbate 80 hypersensitivity.

    Alcoholism, anticoagulant therapy, chemotherapy, corticosteroid therapy, GI bleeding, GI disease, GI perforation, peptic ulcer disease, tobacco smoking, ulcerative colitis

    Chronic use of diclofenac can result in gastritis, ulceration with or without GI perforation, and/or GI bleeding, which can occur at any time, often without preceding symptoms. Therefore, intravenous, oral, or topical diclofenac should be used with caution in patients with a history of or active GI disease including peptic ulcer disease, ulcerative colitis, or GI bleeding. Patients with a prior history of peptic ulcer disease or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. It is recommended not to initiate therapy with maximum doses in these patients due to the likely increase frequency of adverse reactions. Patients at increased risk for NSAID-induced GI bleeding include those receiving concurrent myelosuppressive chemotherapy, corticosteroid therapy, or anticoagulant therapy, tobacco smoking patients, elderly patients, and patients with alcoholism. All patients receiving prolonged treatment should be routinely monitored for potential GI ulceration and bleeding. Consider alternative therapies to NSAIDs for high risk patients.

    Bone marrow suppression, coagulopathy, hematological disease, hemophilia, immunosuppression, neutropenia, surgery, thrombocytopenia

    All forms of diclofenac should be used cautiously in patients with preexisting hematological disease (e.g., coagulopathy or hemophilia) or thrombocytopenia because of its effect on platelet function and vascular response to bleeding. Like other NSAIDs, diclofenac can prolong bleeding time. Diclofenac should be used with caution in patients undergoing surgery when a high degree of hemostasis is required. Diclofenac should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. NSAIDs may mask the signs of infection such as fever and pain in patients with bone marrow suppression.

    Contact lenses, ocular surgery, rheumatoid arthritis

    There have been reports that ophthalmic administration of diclofenac may cause increased bleeding of ocular tissues (including hyphema) in conjunction with ocular surgery. Therefore, diclofenac ophthalmic solution should be used with caution in ocular surgery patients with known bleeding tendencies or who are receiving other medications that may prolong bleeding time. Ocular diclofenac is recommended to be used with caution in patients with diabetes, corneal denervation, corneal epithelial defects, xerophthalmia, rheumatoid arthritis, or repeat ocular surgery within a short time period, as they may be at greater risk for corneal adverse events. Some ocular adverse effects may be sight-threatening. Patients who are wearers of hydrogel soft contact lenses should use the diclofenac ophthalmic preparation with caution; use of ophthalmic diclofenac has caused ocular irritation, erythema, and burning in this patient population.

    Anemia

    Anemia may be exacerbated with the use of NSAIDs, including orally administered and systemically absorbed topical diclofenac. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythrogenesis. Patients who have initial hemoglobin values of 10 g/dl or less and who are to receive long-term NSAID therapy should have hemoglobin values determined periodically. Anemia has not been reported after the use of ophthalmic diclofenac products.

    Dental disease, dental work

    The use of intravenous, oral, and systemically absorbed topical diclofenac may cause increased bleeding in patients with dental disease. Patients should inform their dentist that they are taking diclofenac prior to any dental work due to a potential increased risk of bleeding. Patients should be instructed on proper oral hygiene. Increased bleeding has not been specifically reported after the use of ophthalmic diclofenac products; however, the manufacturer of Voltaren Ophthalmic solution cautions that use may exacerbate bleeding tendencies.

    Hepatic disease, jaundice, porphyria

    As oral diclofenac has been associated with serious hepatic adverse reactions in patients with and without a previous history of hepatic disease, such reactions may be possible in patients who receive any diclofenac product with systemic absorption, including intravenous, oral, and topical gel, patch, and solution formulations. Post-marketing experience has shown that severe hepatic reactions may occur at any time during systemic diclofenac therapy. Hepatic transaminases should be monitored within 4 to 8 weeks of beginning chronic diclofenac therapy and then at regular intervals thereafter. If signs and symptoms consistent with hepatic disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and abnormal liver tests are detected, persist, or worsen, diclofenac should be discontinued immediately. Patients should be informed of the warning signs and symptoms of hepatic toxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and 'flu-like' symptoms), and the appropriate action to take if they notice these symptoms. In rare instances, diclofenac has exacerbated hepatic porphyria; therefore, diclofenac should be avoided in this patient population.

    Dehydration, diabetes mellitus, edema, heart failure, hypertension, hypovolemia, renal disease, renal failure, renal impairment, systemic lupus erythematosus (SLE)

    The intravenous formulation of diclofenac is contraindicated in patients with moderate to severe renal impairment or renal failure in the perioperative period and who are at risk for hypovolemia. Acute renal decompensation was observed in patients with renal impairment treated with intravenous diclofenac during clinical trials in the perioperative period. Use intravenous diclofenac with caution when initiating treatment in patients with considerable hypovolemia. Intravenous diclofenac use is not recommended in patients with moderate to severe renal insufficiency. The use of topical diclofenac gel, solution, patch, and/or diclofenac oral products is not recommended in patients with advanced renal disease because of a lack of data. Due to the role of prostaglandins in renal function and hemodynamics, patients with renal disease should be closely observed (monitor the patient's renal function) during therapy with diclofenac due to an increased risk for adverse reactions during treatment. Dosage adjustment of oral therapy may be necessary. Conditions such as congestive heart failure or hypertension can be exacerbated with diclofenac therapy. Meta-analysis have demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. In addition, normotensive patients receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy. Patients with renal impairment, renal failure, hepatic disease, diabetes mellitus, systemic lupus erythematosus (SLE), congestive heart failure, rheumatoid arthritis, edema, extracellular volume depletion (i.e., hypovolemia or dehydration), or sepsis; those taking diuretics or nephrotoxic drugs; and the elderly are at the highest risk for complications related to suboptimal renal perfusion. It is recommended not to initiate therapy with maximum doses in these patients due to the likely increased frequency of adverse reactions. Closely monitor the patient's blood pressure, renal function, and fluid status during intravenous, oral or topical diclofenac receipt. Such precautions do not apply to the use of diclofenac ophthalmic products; minimal systemic absorption and a short duration of therapy is associated with ophthalmic use of diclofenac.

    Acute myocardial infarction, angina, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, myocardial infarction or stroke, peripheral vascular disease, tachycardia

    Diclofenac, like all nonsteroidal anti-inflammatory drugs (NSAIDs), may exacerbate hypertension and congestive heart failure and may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. The FDA has warned that the risk of myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. Data demonstrate that patients treated with NSAIDs were more likely to die in the first year following a myocardial infarction compared to those not treated with NSAIDs. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event following NSAID use, likely due to a higher baseline risk. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is an increased risk of heart failure with NSAID use. Caution is recommended when administering diclofenac to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing renal disease, or fluid retention. In addition, clinical practice guidelines state NSAIDs should not be administered to patients presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use. Closely monitor blood pressure during diclofenac receipt. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event. Inform patients to seek immediate medical attention if they experience any signs or symptoms of a cardiovascular thrombotic event.

    Children, infants, neonates

    The safety and efficacy of diclofenac has not been established in pediatric patients; use is not recommended in adolescents, children, infants, or neonates.

    Labor, pregnancy

    Diclofenac tablets, delayed-release tablets, extended-release tablets, topical gel (Voltaren), and ophthalmic solution are classified as FDA pregnancy risk category C. Diclofenac topical gel (Solaraze) is classified as FDA category B. Some diclofenac products including the topical patch, topical solution, capsule, powder for oral solution, and intravenous solution are classified as FDA category C prior to 30 weeks gestation and category D if used after 30 weeks gestation due to the potential for prostaglandin synthetase inhibitors to cause in utero constriction of the fetal ductus arteriosus. Adequate and well-controlled studies of diclofenac in pregnant women do not exist; use of diclofenac should be avoided unless the potential therapeutic benefits justify its use during pregnancy. Of 40 babies born with persistent pulmonary hypertension of the newborn (PPHN), 87.5% had the presence of an NSAID in their meconium versus 24.6% of 61 children born without PPHN; the presence of only 4 NSAIDs was examined. In addition to meconium aspiration, asphyxia, respiratory distress syndrome, and group B streptococcal pneumonia, ductus arteriosus constriction by an NSAID appears to be another predisposing factor for PPHN development, as a patent ductus arteriosus was absent in 18 of the 40 infants. Some systemic NSAIDs have been shown to prolong pregnancy and inhibit labor if taken during the third trimester. Intravenous diclofenac should not be used during labor and delivery due to the inhibitory effects on prostaglandin synthesis that may adversely affect fetal circulation, inhibit uterine contractions, and increase risk of uterine bleeding.

    Breast-feeding

    According to the manufacturers, the amount, if any, of diclofenac excreted in human milk is uncertain; however, limited data indicate that low levels of diclofenac are detectable after oral diclofenac use. Diclofenac may cause serious adverse reactions in nursing infants. The manufacturer recommends that women taking diclofenac who are breast-feeding should either discontinue breast-feeding or diclofenac. It should be noted that the American Academy of Pediatrics has not assessed the compatibility of diclofenac use in breast-feeding women. Alternative analgesic and antiinflammatory drugs considered to be usually compatible with breast-feeding by the American Academy of Pediatrics include acetaminophen, ibuprofen, indomethacin, naproxen, and piroxicam. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Burns, eczema, exfoliative dermatitis, heating pad, occlusive dressing, ocular exposure, skin abrasion

    The use of diclofenac epolamine patch is contraindicated on non-intact skin or damaged skin such as open wounds (skin abrasion), skin infections, burns, or exfoliative dermatitis; additionally, do not apply the patch to skin with exudative dermatitis, eczema, or infected lesion or apply the topical solution to open wounds, skin infections, inflammations, or exfoliative dermatitis. Do not use occlusive dressing over topical applications of diclofenac; such use has not been studied with diclofenac gel formulation and is specifically prohibited with topical solution. Diclofenac topical patch my be covered with non-occlusive mesh netting or the edges tapped if needed to secure the application. Further, advise patients prescribed diclofenac topical solution to avoid use of a heating pad over area of product application ; similar caution may be reasonable with other topical formulations. Avoid ocular exposure of the topical gel, solution, and patch. If eye contact occurs, immediately wash out the eye with water or saline. Evaluate the patient if irritation persists for more than an hour.

    Benzyl alcohol hypersensitivity, sunlight (UV) exposure

    Avoid artifical and natural sunlight (UV) exposure including sunlamps while using topical diclofenac gel or solution; photosensitivity has been reported with use. Also, in animal studies, topical diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. Do not use Solaraze gel in patients with benzyl alcohol hypersensitivity.

    Coronary artery bypass graft surgery (CABG)

    The intravenous, oral, topical gel, topical solution, and patch formulations of diclofenac are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft surgery (CABG); the package labeling for diclofenac ophthalmic products does not contain this contraindication. An increased incidence of myocardial infarction and stroke was found through analysis of data regarding the use of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery.

    Accidental exposure

    Physicians and dispensing pharmacists are encouraged to question patients or caregivers about the presence of children and pets in the home, either full time or temporary, and to counsel patients regarding the dangers to children and pets from accidental exposure to the diclofenac epolamine patch. Used diclofenac epolamine patches contain up to 170 mg of diclofenac epolamine. Children or pets could suffer serious side effects from chewing or ingesting a new or used patch. Instruct patients to store and dispose the patches out of the reach of children and pets.

    Phenylketonuria

    Diclofenac powder for oral solution (Cambia) contains phenylalanine; do not prescribe this dosage form for patients with phenylketonuria or other phenylketone-related sensitivity.

    Geriatric

    As with any systemic NSAID, use of diclofenac in the geriatric patient should be approached with caution. The elderly and debilitated are typically at the highest risk for developing complications related to NSAID therapy, such as GI ulceration, fluid retention, cardiovascular side effects, and reduced renal perfusion. Ophthalmic NSAIDs such as diclofenac do not warrant these same precautions. According to the Beers Criteria, systemic NSAIDs are considered potentially inappropriate medications (PIMs) for use in geriatric patients. NSAIDs may cause new or worsening gastric and duodenal ulcers, and there is an increased risk of GI bleeding and peptic ulcer disease in high risk groups including those above 75 years of age, or those taking oral or parenteral corticosteroids, anticoagulants, or antiplatelet medications. Therefore, the Beers expert panel recommends avoiding chronic use of NSAIDs in high risk patients, unless other alternatives are not effective and the patient can take a gastro-protective agent. In addition, NSAIDs should be avoided in patients with a history of gastric or duodenal ulcers, unless other alternatives are not effective and the patient can take a gastro-protective agent. It should be noted that the use of a gastro-protective agent, like a proton pump inhibitor or misoprostol reduces, but does not eliminate, GI risks. The Panel also recommends avoiding NSAIDs in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: heart failure (potential to promote fluid retention and exacerbate the condition) or chronic kidney disease Stage IV or less (CrCl less than 30 mL/minute) (may increase the risk of acute kidney injury and cause a further decline of renal function). The risk of ulcers, gross bleeding, or perforation is cumulative with continued use (i.e., 1% of patients treated for 3 to 6 months and 2% to 4% of patients treated for 1 year); these trends continue with a longer duration of use. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, NSAIDs should be reserved for symptoms and/or inflammatory conditions for which lower risk analgesics (e.g., acetaminophen) have either failed, or are not clinically indicated. NSAIDs may cause GI bleeding in patients with a prior history of, or with increased risk for, GI bleeding. In addition, NSAIDs may cause or worsen renal failure, increase blood pressure, or exacerbate heart failure.

    ADVERSE REACTIONS

    Severe

    keratitis / Delayed / 0-28.0
    ocular hypertension / Delayed / 0-15.0
    GI bleeding / Delayed / 1.0-10.0
    GI perforation / Delayed / 1.0-10.0
    visual impairment / Early / 0-10.0
    corneal opacification / Delayed / 0-10.0
    skin atrophy / Delayed / 4.0-4.0
    aseptic meningitis / Delayed / 0-1.0
    peptic ulcer / Delayed / 1.0
    hematemesis / Delayed / Incidence not known
    esophageal ulceration / Delayed / Incidence not known
    esophageal stricture / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    porphyria / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    renal papillary necrosis / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    corneal erosion / Delayed / Incidence not known
    night blindness / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    edema / Delayed / 1.0-33.0
    contact dermatitis / Delayed / 0-33.0
    elevated hepatic enzymes / Delayed / 0-15.0
    anemia / Delayed / 1.0-10.0
    prolonged bleeding time / Delayed / 1.0-10.0
    conjunctivitis / Delayed / 0-10.0
    blurred vision / Early / 0-10.0
    iritis / Delayed / 0-10.0
    corneal deposits / Delayed / 0-10.0
    corneal edema / Early / 0-10.0
    erythema / Early / 4.0-9.0
    hypotension / Rapid / 5.0-5.0
    gastritis / Delayed / 3.0-3.0
    hypertension / Early / 1.0-3.0
    hyperesthesia / Delayed / 0-3.0
    hematuria / Delayed / 0-2.0
    dyspnea / Early / 2.0-2.0
    skin ulcer / Delayed / 1.0-2.0
    migraine / Early / 0-1.0
    hypercholesterolemia / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    peripheral vasodilation / Rapid / 0-1.0
    constipation / Delayed / 1.0
    fluid retention / Delayed / 1.0
    oral ulceration / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    colitis / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    memory impairment / Delayed / Incidence not known
    confusion / Early / Incidence not known
    psychosis / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    palpitations / Early / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    meningitis / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    amblyopia / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known

    Mild

    lacrimation / Early / 0-30.0
    xerophthalmia / Early / 30.0-30.0
    ocular pain / Early / 0-15.0
    xerosis / Delayed / 7.0-11.0
    vomiting / Early / 0-10.0
    dyspepsia / Early / 1.0-10.0
    infection / Delayed / 1.0-10.0
    ocular irritation / Rapid / 0-10.0
    ocular discharge / Delayed / 0-10.0
    ocular pruritus / Rapid / 0-10.0
    injection site reaction / Rapid / 3.0-10.0
    insomnia / Early / 0-6.0
    pharyngitis / Delayed / 2.0-6.0
    sinusitis / Delayed / 0-5.0
    cough / Delayed / 4.0-4.0
    skin discoloration / Delayed / 4.0-4.0
    vesicular rash / Delayed / 0-4.0
    skin irritation / Early / 4.0-4.0
    asthenia / Delayed / 0-3.0
    chills / Rapid / 0-3.0
    rhinitis / Early / 0-3.0
    fever / Early / 0-3.0
    influenza / Delayed / 3.0-3.0
    arthralgia / Delayed / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    myalgia / Early / 2.0-3.0
    photosensitivity / Delayed / 0-3.0
    drowsiness / Early / 1.0-2.6
    dysgeusia / Early / 2.0-2.0
    ecchymosis / Delayed / 2.0-2.0
    paresthesias / Delayed / 0-2.0
    alopecia / Delayed / 1.0-2.0
    halitosis / Early / 1.0-1.0
    hyperkinesis / Delayed / 1.0-1.0
    hypoesthesia / Delayed / 1.0-1.0
    seborrhea / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    acneiform rash / Delayed / 0-1.0
    flatulence / Early / 1.0
    pyrosis (heartburn) / Early / 1.0
    nausea / Early / 1.0
    diarrhea / Early / 1.0
    abdominal pain / Early / 1.0
    dizziness / Early / 1.0
    headache / Early / 1.0
    rash (unspecified) / Early / 1.0
    pruritus / Rapid / 1.0
    tinnitus / Delayed / 1.0
    xerostomia / Early / Incidence not known
    eructation / Early / Incidence not known
    purpura / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    malaise / Early / Incidence not known
    vertigo / Early / Incidence not known
    tremor / Early / Incidence not known
    abnormal dreams / Early / Incidence not known
    nightmares / Early / Incidence not known
    lethargy / Early / Incidence not known
    irritability / Delayed / Incidence not known
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known
    nocturia / Early / Incidence not known
    polyuria / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    hyperventilation / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    diplopia / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Acebutolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Acetaminophen; Butalbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Acetohexamide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Adefovir: (Moderate) Chronic coadministration of adefovir with nephrotoxic drugs, such as nonsteroidal antiinflammatory drugs may increase the risk of developing nephrotoxicity even in patients who have normal renal function. The use of adefovir with NSAIDs may be done cautiously. As stated in the current adefovir prescribing information, 'Ibuprofen (800 mg PO three times daily), when given concomitantly with adefovir dipivoxil, increased the adefovir Cmax by 33% and AUC by 23%, as well as urinary recovery. The increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.' In an in vitro investigation, the antiviral effect of adefovir was unaltered and the renal proximal tubule accumulation of adefovir was inhibited by the presence of a NSAID. Adefovir is efficiently transported by the human renal organic anion transporter 1, and the presence of this transporter appears to mediate the accumulation of the drug in renal proximal tubules. The in vitro study suggests that the use of a NSAID with adefovir may potentially reduce the nephrotoxic potential of adefovir. Of course, NSAIDs are associated with nephrotoxicity of their own; therefore, further data on the interaction between NSAIDs and adefovir in humans are needed.
    Aldesleukin, IL-2: (Major) Aldesleukin, IL-2 may cause nephrotoxicity. Concurrent administration of drugs possessing nephrotoxic effects, such as nonsteroidal antiinflammatory agents (NSAIDs), with Aldesleukin, IL-2 may increase the risk of kidney dysfunction. In addition, reduced kidney function secondary to Aldesleukin, IL-2 treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Aliskiren: (Moderate) NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Aliskiren; Amlodipine: (Moderate) NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Aliskiren; Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible. (Moderate) NSAIDs may attenuate the antihypertensive effects of aliskiren by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of aliskiren may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking aliskiren.
    Alpha-blockers: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Alteplase, tPA: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Altretamine: (Major) Altretamine causes mild to moderate dose-related myelosuppression. Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ambenonium Chloride: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Amikacin: (Moderate) It is possible that additive nephrotoxicity may occur in patients who receive nonsteroidal antiinflammatory drugs (NSAIDs) concurrently with other nephrotoxic agents, such as amikacin.
    Amiloride: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Amiodarone: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as amiodarone; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Amlodipine; Benazepril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Amlodipine; Olmesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Amlodipine; Telmisartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Amlodipine; Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Amobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as lansoprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Minor) Concurrent use of amphotericin B and other nephrotoxic medications, including nonsteroidal antiinflammatory drugs (NSAIDs), may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B lipid complex (ABLC): (Minor) Concurrent use of amphotericin B and other nephrotoxic medications, including nonsteroidal antiinflammatory drugs (NSAIDs), may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B liposomal (LAmB): (Minor) Concurrent use of amphotericin B and other nephrotoxic medications, including nonsteroidal antiinflammatory drugs (NSAIDs), may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Amphotericin B: (Minor) Concurrent use of amphotericin B and other nephrotoxic medications, including nonsteroidal antiinflammatory drugs (NSAIDs), may enhance the potential for drug-induced renal toxicity. Monitor renal function carefully during concurrent therapy. Amphotericin B dosage reduction may be necessary if renal impairment occurs.
    Anagrelide: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Angiotensin II receptor antagonists: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Angiotensin-converting enzyme inhibitors: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Antithrombin III: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Patients receiving these drugs together should be monitored closely for bleeding.
    Apixaban: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if diclofenac and aprepitant, fosaprepitant are used concurrently, and monitor for an increase in diclofenac-related adverse effects for several days after administration of a multi-day aprepitant regimen. In vitro, diclofenac is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of diclofenac. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and diclofenac is a CYP2C9 substrate in vitro. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as NSAIDs, as the risk of renal impairment may be increased.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Arsenic Trioxide: (Minor) A theoretical increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia including myelosuppressive antineoplastic agents.
    Aspirin, ASA: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Aspirin, ASA; Carisoprodol: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Aspirin, ASA; Dipyridamole: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Aspirin, ASA; Omeprazole: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Aspirin, ASA; Oxycodone: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Aspirin, ASA; Pravastatin: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4.
    Atenolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Atenolol; Chlorthalidone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Atropine; Edrophonium: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Azathioprine: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Azelastine; Fluticasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Azilsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Azilsartan; Chlorthalidone: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Barbiturates: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Basiliximab: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents, Monitor closely for bleeding.
    Beclomethasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Benazepril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Bendamustine: (Moderate) A theoretical increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia including myelosuppressive antineoplastic agents.
    Bendroflumethiazide; Nadolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Beta-blockers: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Betamethasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Betaxolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and nonsteroidal antiinflammatory drugs (NSAIDs) are used concomitantly. Coadministration of betrixaban and NSAIDs may increase the risk of bleeding.
    Bevacizumab: (Minor) A theoretical increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia including myelosuppressive antineoplastic agents.
    Bismuth Subsalicylate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Bisoprolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Bisphosphonates: (Moderate) Exercise caution when administering an NSAID with a bisphosphonate. Monitor for the presence of GI complaints, including potential GI ulceration and bleeding, as well as renal function, during combined use. Nonsteroidal antiinflammatory drugs (NSAIDs) are associated with esophageal and/or gastric irritation, GI ulceration. a risk of nephrotoxicity, and decreased bone mineral density. Bisphosphonates may cause GI adverse events and occasionally, renal dysfunction. Though patients receiving intravenously administered bisphosphonates have a decreased incidence of GI adverse effects as compared to those taking orally administered bisphosphonates, nephrotoxicity is possible, and GI events are rarely reported.
    Bivalirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Bleomycin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering diclofenac with boceprevir due to an increased potential for diclofenac-related adverse events. If diclofenac dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of diclofenac. Diclofenac is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated diclofenac plasma concentrations.
    Brimonidine; Timolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Budesonide: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Budesonide; Formoterol: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Bumetanide: (Moderate) If a nonsteroidal anti-inflammatory drug (NSAID) and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Patients taking diuretics and NSAIDs concurrently are at higher risk of developing renal insufficiency. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDs have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Busulfan: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Butabarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Cabozantinib: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as cabozantinib; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Calcium-channel blockers: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Candesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with diclofenac is necessary, and monitor for an increase in diclofenac-related adverse reactions. Diclofenac is a a CYP2C9 substrate. Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%. When diclofenac was coadministered with voriconazole (an inhibitor of CYP2C9, 2C19, and 3A4), the Cmax and AUC of diclofenac increased by 114% and 78%, respectively.
    Capreomycin: (Major) Because capreomycin is primarily eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Captopril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Carbamazepine: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as carbamazepine. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed.
    Carmustine, BCNU: (Major) Due to the thrombocytopenic effects of carmustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. These additive effects may not occur for at least 6 weeks after the administration of carmustine due to the delayed myelosuppressive effects of carmustine.
    Carteolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Carvedilol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Cefotaxime: (Minor) Cefotaxime's product label states that cephalosporins may potentiate the adverse renal effects of nephrotoxic agents, such as aminoglycosides, nonsteroidal antiinflammatory drugs (NSAIDs), and loop diuretics. Carefully monitor renal function, especially during prolonged therapy or use of high aminoglycoside doses. The majority of reported cases involve the combination of aminoglycosides and cephalothin or cephaloridine, which are associated with dose-related nephrotoxicity as singular agents. Limited but conflicting data with other cephalosporins have been noted.
    Celecoxib: (Major) Avoid concomitant use of celecoxib with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Ceritinib: (Major) Avoid coadministration of ceritinib with diclofenac due to increased diclofenac exposure. If coadministration is unavoidable, monitor for diclofenac-related adverse reactions; a dosage adjustment may be necessary. Ceritinib is a CYP2C9 inhibitor; diclofenac is primarily metabolized by CYP2C9.
    Chlorambucil: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chlorpropamide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Chlorthalidone; Clonidine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Cholestyramine: (Moderate) Limited data suggest that cholestyramine can substantially reduce the bioavailability of diclofenac. In a randomized cross-over study, six healthy subjects took a single oral dose of diclofenac with water, cholestyramine (8 g), or colestipol (10 g). Diclofenac AUC was reduced by 62% or 33%, respectively, during coadministration with cholestyramine or colestipol. Although the clinical implications of this pharmacokinetic interaction are uncertain, clinicians should be alert to loss of antiinflammatory or analgesic effect with diclofenac. Staggering the administration times may prevent this interaction.
    Choline Salicylate; Magnesium Salicylate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Cholinesterase inhibitors: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Chondroitin; Glucosamine: (Moderate) Patients taking methylsulfonylmethane, MSM have reported increased bruising or blood in the stool. These effects have not been confirmed in published medical literature or during clinical studies. Use methylsulfonylmethane, MSM with caution in patients who are taking drugs with the potential for additive bleeding, including nonsteroidal antiinflammatory drugs (NSAIDs). During an available, published clinical trials in patients with osteoarthritis, patients with bleeding disorders or using anticoagulants or platelet inhibiting drugs were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving NSAIDs should be observed for potential bleeding.
    Ciclesonide: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Cidofovir: (Severe) The concomitant administration of cidofovir and nonsteroidal antiinflammatory drugs (NSAIDs) is contraindicated due to the potential for increased nephrotoxicity. NSAIDs should be discontinued 7 days prior to beginning cidofovir.
    Cilostazol: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Cisplatin: (Moderate) Although the thrombocytopenic effects of cisplatin are limited, an additive risk of bleeding may be seen in patients receiving concomitant therapy with non-steroidal antiinflammatory agents (NSAIDs). Also, cisplatin may cause nephrotoxicity, and NSAIDs can be drugs with nephrotoxic potential. Long-term administration of NSAIDs has resulted in renal injury. Patients at greatest risk are the elderly, taking other nephrotoxic drugs, and those patients with renal dysfunction, liver dysfunction, or heart failure. Concurrent use can be acceptable, but monitor renal function closely and be alert for signs of bleeding.
    Citalopram: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Cladribine: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Clofarabine: (Major) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Clonidine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Clopidogrel: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with diclofenac as there is a potential for decreased diclofenac concentrations. Diclofenac is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with diclofenac as there is a potential for decreased diclofenac concentrations. Diclofenac is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer.
    Colestipol: (Moderate) Limited data suggest that colestipol can substantially reduce the bioavailability of diclofenac. In a randomized cross-over study, six healthy subjects took a single oral dose of diclofenac with water, cholestyramine (8 g), or colestipol (10 g). Diclofenac AUC was reduced by 62% or 33%, respectively, during coadministration with cholestyramine or colestipol. Although the clinical implications of this pharmacokinetic interaction are uncertain, clinicians should be alert to loss of antiinflammatory or analgesic effect with diclofenac. Staggering the administration times may prevent this interaction.
    Colistimethate, Colistin, Polymyxin E: (Major) The administration of colistimethate sodium may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Corticosteroids: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Corticotropin, ACTH: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Cortisone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Cyclosporine: (Major) Significant interactions may occur between systemic cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac. Clinical status and serum creatinine and potassium concentrations should be closely monitored when cyclosporine is given with nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, especially in a dehydrated patient. Although concomitant administration of diclofenac does not affect cyclosporine blood concentrations, a doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function have been noted. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range. The mechanism of the interaction may be inhibition of diclofenac metabolism, as diclofenac is a substrate for and cyclosporine an inhibitor of CYP3A4. NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressants such as cyclosporine. Interactions with skin and eye products containing these drugs are not expected. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
    Cytarabine, ARA-C: (Major) The main toxic effect of cytarabine, ARA-C is bone marrow suppression with leukopenia, thrombocytopenia and anemia. Due to the thrombocytopenic effects of cytarabine, an additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Dipyridamole can block membrane transport of cytarabine in tumor cells, therefore decreasing its antineoplastic activity.
    Dabigatran: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dabrafenib: (Moderate) The concomitant use of dabrafenib, a CYP29 inducer, and diclofenac, a CYP2C9 substrate, may result in decreased levels of diclofenac; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of diclofenac efficacy. In addition, an increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding.
    Dacarbazine, DTIC: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dactinomycin, Actinomycin D: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dalteparin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
    Dasatinib: (Major) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Caution should be exercised if patients are required to take medications that inhibit platelet function or anticoagulants concomitantly with dasatinib.
    Daunorubicin Liposomal: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding during concurrent use.
    Daunorubicin Liposomal; Cytarabine Liposomal: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Patients should be monitored closely for bleeding during concurrent use.
    Daunorubicin: (Major) Due to the thrombocytopenic effects of daunorubicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Decitabine: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including NSAIDs. In addition, coadministration of deferasirox with other potentially nephrotoxic drugs, including NSAIDs, may increase the acute renal failure. Monitor serum creatinine and/or creatinine clearance in patients who are receiving deferasirox and nephrotoxic drugs concomitantly
    Deferiprone: (Moderate) Avoid the concomitant use of deferiprone and diclofenac. Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and diclofenac inhibits this enzyme. The in vitro glucuronidation of deferiprone is reduced by 78% in the presence of phenylbutazone, another UGT1A6 inhibitor. Similar results may be seen when deferiprone and diclofenac are administered concomitantly.
    Deflazacort: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Delavirdine: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as delavirdine; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Denileukin Diftitox: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Desirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with hyponatremia including NSAIDs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia. A woman who took both desmopressin and ibuprofen was found in a comatose state. As her serum sodium concentration was 121 mmol/L, and her plasma osmolality was low in the presence of a high-normal urine osmolality and normal sodium excretion, she was treated with fluid restriction. Her serum sodium concentration was 124 mmol/L within a day and was 135 mmol/L by the second day. The woman had previously received desmopressin without the development of clinical symptoms of hyponatremia
    Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Patients should be monitored for signs and symptoms of bleeding while taking desvenlafaxine with NSAIDs.
    Dexamethasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Diazoxide: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diflunisal: (Major) Avoid concomitant use of diflunisal with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Digoxin: (Moderate) Increased serum digoxin concentrations have been reported in patients who received digoxin and diclofenac sodium. NSAIDs may cause a significant deterioration in renal function. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Monitor patients during concomitant treatment for possible digoxin toxicity and reduce digoxin dose as necessary.
    Diphenhydramine; Ibuprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Diphenhydramine; Naproxen: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Dipyridamole: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Docetaxel: (Major) Due to the thrombocytopenic effects of docetaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Donepezil: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Donepezil; Memantine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Dorzolamide; Timolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Doxazosin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Doxorubicin: (Major) Due to the thrombocytopenic effects of doxorubicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diclofenac is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Drospirenone; Estradiol: (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Other drugs that may have additive effects on serum potassium with drospirenone include chronic treatment with NSAIDs, and monitoring of serum potassium in the 1st month of concurrent therapy is recommended.
    Drospirenone; Ethinyl Estradiol: (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Other drugs that may have additive effects on serum potassium with drospirenone include chronic treatment with NSAIDs, and monitoring of serum potassium in the 1st month of concurrent therapy is recommended.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Other drugs that may have additive effects on serum potassium with drospirenone include chronic treatment with NSAIDs, and monitoring of serum potassium in the 1st month of concurrent therapy is recommended.
    Drotrecogin Alfa: (Moderate) Caution should be used when drotrecogin alfa is used with any other drugs that affect hemostasis, including NSAIDs. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Platelet aggregation may be impaired by duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving Nonsteroidal antiinflammatory drugs (NSAIDs). Mmonitor for signs and symptoms of bleeding when duloxetine is coadministered with NSAIDs.
    Edoxaban: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Edrophonium: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Efalizumab: (Moderate) NSAIDs, like diclofenac, should be used with caution in patients receiving immunosuppressives, such as efalizumab, as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Efavirenz: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as efavirenz; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as efavirenz; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Elbasvir; Grazoprevir: (Moderate) Administering diclofenac with elbasvir; grazoprevir may result in elevated diclofenac plasma concentrations. Diclofenac is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. NSAIDs are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the NSAID are possible. Monitor patients for adverse reactions if eltrombopag is administered with an NSAID.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with diclofenac as there is a potential for decreased diclofenac concentrations. Diclofenac is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Enalapril, Enalaprilat: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Enalapril; Felodipine: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Enoxaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Entecavir: (Moderate) The manufacturer of entecavir recommends monitoring for adverse effects when coadministered with NSAIDs. Entecavir is primarily eliminated by the kidneys; NSAIDs can affect renal function. Concurrent administration may increase the serum concentrations of entecavir and adverse events.
    Enzalutamide: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as enzalutamide. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed.
    Epirubicin: (Major) Due to the thrombocytopenic effects of epirubicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Eplerenone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Epoprostenol: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Eprosartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Eptifibatide: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Eribulin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Erlotinib: (Moderate) Use caution if erlotinib is administered with nonsteroidal antiinflammatory drugs (NSAIDs), as these patients may have an increased risk of gastrointestinal (GI) perforation. Gastrointestinal perforation, including fatal cases, has been reported in 0.2% to 0.4% of patients treated with erlotinib in clinical trials compared with 0.1% or less in control arms.
    Escitalopram: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Esmolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Esomeprazole; Naproxen: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Estramustine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ethacrynic Acid: (Moderate) If a nonsteroidal anti-inflammatory drug (NSAID) and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Patients taking diuretics and NSAIDs concurrently are at higher risk of developing renal insufficiency. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDs have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Ethanol: (Major) Concomitant ingestion of ethanol with NSAIDs increases the risk of developing gastric irritation and GI mucosal bleeding. Ethanol is a mucosal irritant and NSAIDs decrease platelet aggregation. Routine ingestion of ethanol and NSAIDs can cause significant GI bleeding, which may or may not be overt. Even occasional concomitant use of NSAIDs and ethanol should be avoided. Chronic alcoholism is often associated with hypoprothrombinemia and this condition increases the risk of bleeding. Systemic exposure of NSAIDs that are primary substrates for CYP2C9, such as diclofenac, may be increased during use of ethanol, which is a dose-dependent inhibitor of CYP2C9. The effects of ethanol may also be substrate-dependent, since in vitro data have shown varying inhibitory effects on 2C9 substrates.The manufacturer of diclofenac; misoprostol recommends that the total daily dose of diclofenac not exceed 100 mg in patients receiving a CYP2C9 inhibitor. Patients should be warned regarding the potential for increased risk of GI bleeding if alcohol-containing beverages are taken concurrently with NSAIDs.
    Etodolac: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Etravirine: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as etravirine; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Famotidine; Ibuprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as diclofenac, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diclofenac during coadministration with fenofibric acid.
    Fenoldopam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fenoprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Flavocoxid, Flavocoxid; Citrated Zinc Bisglycinate: (Major) Flavocoxid exerts similar pharmacologic characteristics to other systemic NSAIDs. Additive pharmacodynamic effects, including a potential for additive adverse cardiac and GI effects, may be seen if flavocoxid is used with NSAIDs. In general, the concurrent use of flavocoxid and NSAIDs should be avoided.
    Floxuridine: (Major) Due to the thrombocytopenic effects of floxuridine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluconazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Fludarabine: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fludrocortisone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Flunisolide: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Fluorouracil, 5-FU: (Major) Due to the thrombocytopenic effects of fluorouracil, 5-FU, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluoxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Fluoxetine; Olanzapine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Flurbiprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Fluticasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Fluticasone; Salmeterol: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Fluticasone; Vilanterol: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Fluvastatin: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as fluvastatin; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events. In addition, exposure to fluvastatin may also be increased during concurrent use.
    Fluvoxamine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Fondaparinux: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Food: (Moderate) Administering nonsteroidal antiinflammatory drugs (NSAIDs) concurrently with marijuana may limit some of marijuana's pharmacologic activities. Certain actions of marijuana require prostaglandin-mediated processes to occur; NSAIDs may interfere with these processes thereby decreasing marijuana's effect. Coadministration of indomethacin with marijuana has been shown to significantly decrease euphoria, tachycardia, and the intraocular pressure lowering activity of marijuana.
    Formoterol; Mometasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Foscarnet: (Minor) The risk of renal toxicity may be increased if foscarnet is used in conjuction with other nephrotoxic agents, such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor renal function carefully during concurrent therapy.
    Fosinopril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Furosemide: (Moderate) If a nonsteroidal anti-inflammatory drug (NSAID) and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Patients taking diuretics and NSAIDs concurrently are at higher risk of developing renal insufficiency. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDs have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Gadoterate meglumine: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Galantamine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Gallium Ga 68 Dotatate: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Ganciclovir: (Minor) Concurrent use of nephrotoxic agents, such as NSAIDs, with ganciclovir should be done cautiously to avoid additive nephrotoxicity. Monitor renal function carefully if concomitant therapy is required.
    Garlic, Allium sativum: (Minor) Garlic, Allium sativum may produce clinically-significant antiplatelet effects; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs).
    Gefitinib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Gemfibrozil: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as gemfibrozil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Gentamicin: (Moderate) It is possible that additive nephrotoxicity may occur in patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently with other nephrotoxic agents, such as gentamicin.
    Ginger, Zingiber officinale: (Minor) Patients receiving regular therapy with nonsteroidal antiinflammatory drugs (NSAIDs) should use ginger with caution, due to a theoretical risk of bleeding resulting from additive pharmacology related to the COX enzymes. However, clinical documentation of interactions is lacking. Several pungent constituents of ginger (Zingiber officinale) are reported to inhibit arachidonic acid (AA) induced platelet activation in human whole blood. The constituent (8)-paradol is the most potent inhibitor of COX-1 and exhibits the greatest anti-platelet activity versus other gingerol analogues. The mechanism of ginger-associated platelet inhibition may be related to decreased COX-1/Thomboxane synthase enzymatic activity.
    Ginkgo, Ginkgo biloba: (Moderate) Ginkgo is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Ginkgo should be used cautiously in patients receiving drugs that inhibit platelet aggregation or pose a risk for bleeding, such as NSAIDs. A case of fatal intracerebral bleeding has been reported with the combination of Ginkgo and the NSAID ibuprofen. A 71 year-old male had been taking a concentrated Ginkgo biloba extract (Gingium, Germany) 40 mg PO twice daily for a few years; 4 weeks prior to his death, he had started taking ibuprofen (600 mg daily) for osteoarthritic hip pain. The man was found comatose and CT scan revealed a massive intracerebral bleed; no other causative factors were identified.
    Glimepiride: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glimepiride; Pioglitazone: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glimepiride; Rosiglitazone: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glipizide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glipizide; Metformin: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glyburide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Glyburide; Metformin: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Gold: (Moderate) Due to the inhibition of renal prostaglandins by NSAIDs, concurrent use with other nephrotoxic agents, such as gold compounds, may lead to additive nephrotoxicity. Monitor renal function carefully during concurrent therapy.
    Guanabenz: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Guanfacine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Heparin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydralazine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Hydrocodone; Ibuprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Hydrocortisone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Ibritumomab Tiuxetan: (Major) Prolonged cytopenias, including thrombocytopenia and neutropenia, are frequently associated with the ibritumomab tiuxetan therapeutic regimen. An additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. The potential for bleeding should be considered in the concomitant use of such medications during the ibritumomab tiuxetan therapeutic regimen. Frequent laboratory monitoring of patients who must receive these therapies is recommended, with modification of clinical approaches to transfusion and other therapies if bleeding occurs due to the additive mechanisms and risks.
    Ibuprofen lysine: (Major) Because ibuprofen lysine exerts similar pharmacologic characteristics to other systemic NSAIDs, including COX-2 inhibitors, additive pharmacodynamic effects, including a potential increase for additive adverse GI effects, may be seen if ibuprofen lysine is used with other NSAIDs. In general, concurrent use of ibuprofen lysine and another NSAID should be avoided.
    Ibuprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Ibuprofen; Oxycodone: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Ibuprofen; Pseudoephedrine: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Idarubicin: (Major) Due to the thrombocytopenic effects of idarubicin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with diclofenac, a CYP3A substrate, as diclofenac toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Iloprost: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Imatinib: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. In addition, imatinib is an inhibitor of CYP2C9, and diclofenac is a CYP2C9 substrate. If coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used together the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Indapamide: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Indomethacin: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Interferon Alfa-2a: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2b: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2b; Ribavirin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Iodipamide Meglumine: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Iohexol: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Ionic Contrast Media: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Iopamidol: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Iopromide: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Ioversol: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Ioxaglate Meglumine; Ioxaglate Sodium: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Irbesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Irinotecan: (Major) Due to the thrombocytopenic effects of irinotecan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with diclofenac may result in increased serum concentrations of diclofenac. Diclofenac is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isosulfan Blue: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with diclofenac. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; diclofenac is metabolized by CYP3A and CYP2C9. Co-administration can theoretically increase diclofenac exposure leading to increased or prolonged therapeutic effects and adverse events. Do not exceed a total daily diclofenac dose of 100 mg.
    Ixabepilone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Kanamycin: (Moderate) It is possible that additive nephrotoxicity may occur in patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently with other nephrotoxic agents, such as kanamycin.
    Ketoconazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as ketoconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Ketoprofen: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Ketorolac: (Severe) Concomitant use of ketorolac with another NSAID is contraindicated. Increased adverse gastrointestinal effects are possible if ketorolac is used with other systemic nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors.
    Labetalol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Lansoprazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as lansoprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Lansoprazole; Naproxen: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers. (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as lansoprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Lapatinib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Leflunomide: (Moderate) In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide altered protein binding and thus, increased the free fraction of ibuprofen by 13% to 50%. The clinical significance of the interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis, and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Levobetaxolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Levobunolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Levomilnacipran: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Lisinopril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Lithium: (Moderate) Lithium levels should be monitored when patients initiate or discontinue nonsteroidal antiinflammatory drugs. In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to significantly increase steady-state plasma lithium concentrations. There is also evidence that other NSAIDs, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 twice daily with celecoxib 200 mg twice daily as compared to subjects receiving lithium alone. It is thought that prostaglandins are involved in the renal clearance of lithium and that NSAIDs interfere with lithium excretion. Typically, increased lithium levels develop over 5 to 10 days after adding a NSAID and return to pretreatment levels within 7 days of stopping the NSAID.
    Lomustine, CCNU: (Major) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
    Losartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of diclofenac and lumacaftor; ivacaftor may alter diclofenac exposure; monitor for diclofenac efficacy and adverse events. Diclofenac metabolism is primarily mediated by CYP2C9, with CYP3A4 and possibly CYP2C8 playing a lesser role. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9 and CYP2C8. Although induction of diclofenac's metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9- and CYP2C8-mediated metabolism is not clear.
    Lumacaftor; Ivacaftor: (Moderate) Increased monitoring is recommended if ivacaftor is administered concurrently with diclofenac. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; diclofenac is metabolized by CYP3A and CYP2C9. Co-administration can theoretically increase diclofenac exposure leading to increased or prolonged therapeutic effects and adverse events. Do not exceed a total daily diclofenac dose of 100 mg.
    Magnesium Salicylate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Magnesium Salts: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as nonsteroidal anti-inflammatory drugs (NSAIDs).
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as nonsteroidal anti-inflammatory drugs (NSAIDs).
    Mannitol: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Mechlorethamine, Nitrogen Mustard: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meclofenamate Sodium: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Mefenamic Acid: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Meloxicam: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Melphalan: (Major) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients, and includes thrombocytopenia and leukopenia. Due to the thrombocytopenic effects of melphalan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mephobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Mercaptopurine, 6-MP: (Major) Due to the thrombocytopenic effects of mercaptopurine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mesalamine, 5-ASA: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Methohexital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Methotrexate: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Methoxsalen: (Minor) Preclinical data suggest agents that inhibit prostaglandin synthesis such as diclofenac could decrease the efficacy of photosensitizing agents used in photodynamic therapy. Avoidance of diclofenac before and during photodynamic therapy may be advisable.
    Methyldopa: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Methylprednisolone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Methylsulfonylmethane, MSM: (Moderate) Patients taking methylsulfonylmethane, MSM have reported increased bruising or blood in the stool. These effects have not been confirmed in published medical literature or during clinical studies. Use methylsulfonylmethane, MSM with caution in patients who are taking drugs with the potential for additive bleeding, including nonsteroidal antiinflammatory drugs (NSAIDs). During an available, published clinical trials in patients with osteoarthritis, patients with bleeding disorders or using anticoagulants or platelet inhibiting drugs were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving NSAIDs should be observed for potential bleeding.
    Metoprolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mifepristone, RU-486: (Moderate) Mifepristone RU-486, significantly increased exposure of drugs metabolized by CYP2C8/2C9 in interaction studies. Therefore, when mifepristone is used in the treatment of Cushing's syndrome and coadministered with other CYP2C8/2C9 substrates, including NSAIDs, the lowest does of the substrate should be used and patients monitored closely for adverse reactions.
    Milnacipran: (Moderate) Platelet aggregation may be impaired by milnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking milnacipran and NSAIDs.
    Minoxidil: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mitomycin: (Major) Due to the thrombocytopenic effects of mitomycin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mitotane: (Major) Use caution if mitotane and diclofenac are used concomitantly, and monitor for decreased efficacy of diclofenac and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and diclofenac is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of diclofenac.
    Mitoxantrone: (Major) Due to the thrombocytopenic effects of mitoxantrone, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Modafinil: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as modafinil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Moexipril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Mometasone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Muromonab-CD3: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Nabumetone: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Nadolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Naproxen: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Naproxen; Pseudoephedrine: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Naproxen; Sumatriptan: (Major) Avoid concomitant use of diclofenac with any other NSAID, including COX-2 inhibitors, due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Nebivolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nebivolol; Valsartan: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Nelarabine: (Major) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Neomycin: (Minor) It is possible that additive nephrotoxicity may occur in patients who receive NSAIDs concurrently with other nephrotoxic agents, such as aminoglycosides.
    Neostigmine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Nitroprusside: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Non-Ionic Contrast Media: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when given to patients receiving a contrast agents. When possible, withhold NSAID therapy during administration of a contrast agent.
    Olmesartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and nonsteroidal antiinflammatory drugs (NSAIDs) when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
    Omeprazole: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Omeprazole; Sodium Bicarbonate: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Oritavancin: (Moderate) Coadministration of oritavancin and diclofenac may result in increases or decreases in bioactivation of diclofenac, which may increase side effects or decrease efficacy of diclofenac. Diclofenac is primarily bioactivated by CYP2C9, but also by CYP3A4. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxaprozin: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Paclitaxel: (Major) Due to the thrombocytopenic effects of paclitaxel, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Paroxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and diclofenac, a CYP3A4 substrate, may cause an increase in systemic concentrations of diclofenac. Use caution when administering these drugs concomitantly.
    Pegaspargase: (Major) Due to the thrombocytopenic effects of pegaspargase, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Penbutolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Pentamidine: (Moderate) Additive nephrotoxicity may be seen with the combination of pentamidine and other agents that cause nephrotoxicity, including non-steroidal anti-inflammatory agents (NSAIDs). Maintain adequate hydration and monitor renal function carefully during concurrent therapy.
    Pentobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Pentosan: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Pentostatin: (Major) Due to the thrombocytopenic effects of pentostatin, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Perindopril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Perindopril; Amlodipine: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Phenobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Phenoxybenzamine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phentolamine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Physostigmine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Pindolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Piroxicam: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Platelet Inhibitors: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as nonsteroidal antiinflammatory drugs (NSAIDS), may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
    Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as nonsteroidal anti-inflammatory drugs (NSAIDs).
    Polymyxin B: (Major) The chronic coadministration of systemic polymyxins may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since Polymyxin B is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Polymyxins: (Major) The administration of colistimethate sodium may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk for nephrotoxicity when used concurrently. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including nonsteroidal antiinflammatory drugs (NSAIDs), may theoretically increase serum concentrations of either drug.
    Porfimer: (Minor) Preclinical data suggest agents that inhibit prostaglandin synthesis such as diclofenac could decrease the efficacy of photosensitizing agents used in photodynamic therapy. Avoidance of diclofenac before and during photodynamic therapy may be advisable.
    Posaconazole: (Moderate) Posaconazole and diclofenac should be coadministered with caution due to an increased potential for diclofenac-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diclofenac. These drugs used in combination may result in elevated diclofenac plasma concentrations, causing an increased risk for diclofenac-related adverse events.
    Pralatrexate: (Major) Renal elimination accounts for approximately 34% of the overall clearance of pralatrexate. Concomitant administration of drugs that undergo substantial renal clearance, such as nonsteroidal antiinflammatory drugs (NSAIDs), may result in delayed clearance of pralatrexate.
    Prasugrel: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Prazosin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Prednisolone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Prednisone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Primidone: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Probenecid: (Major) Probenecid can decrease the renal clearance of nonsteroidal antiinflammatory agents (NSAIDs). Reduction of the NSAID dose may be necessary when it is used together with probenecid.
    Procarbazine: (Major) Due to the thrombocytopenic effects of procarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Propranolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Pyridostigmine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Quinapril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Quinolones: (Moderate) The concomitant administration of quinolones and nonsteroidal antiinflammatory drugs has been reported to increase the risk of CNS stimulation and convulsive seizures. Patients with CNS disorders or other risk factors that may predispose them to seizure development or patients taking drugs that lower the seizure threshold may not be appropriate candidates for NSAID usage if they are also taking a quinolone. Use a quinolone with caution in individuals who take a NSAID concomitantly.
    Ramipril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Reserpine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Reteplase, r-PA: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with diclofenac is necessary, as the systemic exposure of diclofenac may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and diclofenac is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with diclofenac is necessary, as the systemic exposure of diclofenac may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and diclofenac is a CYP3A4 substrate.
    Ritonavir: (Moderate) Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
    Rivaroxaban: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Rivastigmine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Romidepsin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Sacubitril; Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Salicylates: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Salsalate: (Major) Increased adverse gastrointestinal effects, including gastric ulceration or blood loss, are possible if diclofenac is used with salicylates. The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function.
    Secobarbital: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Selective serotonin reuptake inhibitors: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Sertraline: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Simeprevir: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diclofenac, which is a CYP3A4 substrate. Monitor patients for adverse effects of diclofenac, such as bleeding or nephrotoxicity.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with nonsteroidal antiinflammatory drugs (NSAIDs).
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as nonsteroidal anti-inflammatory drugs (NSAIDs).
    Sotalol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Spironolactone: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Streptokinase: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Streptomycin: (Moderate) It is possible that additive nephrotoxicity may occur in patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently with other nephrotoxic agents, such as streptomycin.
    Streptozocin: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Sulfinpyrazone: (Moderate) Sulfinpyrazone is an inhibitor of CYP2C9 and may lead to increased plasma levels of NSAIDs. During concurrent therapy, monitor for potential NSAID-induced toxicity, such as GI irritation or bleeding.
    Sulfonylureas: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Sulindac: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Tacrine: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering diclofenac with telaprevir due to an increased potential for diclofenac-related adverse events. If diclofenac dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of diclofenac. Diclofenac is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated diclofenac plasma concentrations.
    Telavancin: (Minor) Concurrent or sequential use of telavancin with drugs that inhibit renal prostaglandins such as nonsteroidal antiinflammatory drugs (NSAIDS) may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
    Telbivudine: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Telithromycin: (Minor) Concentrations of diclofenac may be increased with concomitant use of telithromycin. Diclofenac is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telmisartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and diclofenac is necessary, as the systemic exposure of diclofenac may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of diclofenac; consider increasing the dose of diclofenac if necessary. Diclofenac is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temozolomide: (Major) Myelosuppression, primarily neutropenia and thrombocytopenia, is the dose-limiting toxicity of temozolomide. Due to the thrombocytopenic effects of temozolomide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tenecteplase, TNK-tPA: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Teniposide: (Major) Dose-limiting bone marrow suppression is the most significant toxicity associated with teniposide, and may include thrombocytopenia. An additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Salicylates also displace protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in plasma free drug concentrations that could result in potentiation of teniposide toxicity, including bone marrow suppression.
    Tenofovir Alafenamide: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Tenofovir, PMPA: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Terazosin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Thiazide diuretics: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Thioguanine, 6-TG: (Major) Due to the thrombocytopenic effects of thioguanine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Thiopental: (Moderate) Caution is advised when administering diclofenac with inducers of CYP2C9, such as barbiturates. When used together, the systemic exposure to diclofenac (a CYP2C9 substrate) may decrease, potentially resulting in impaired efficacy. Higher diclofenac doses may be needed. In addition, phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment after diclofenac initiation.
    Thiotepa: (Major) Thiotepa is highly toxic to the hematopoietic system, and causes thrombocytopenia, leukopenia, and anemia. An additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Thrombolytic Agents: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Ticagrelor: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Ticlopidine: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Timolol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Tinzaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Tirofiban: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Tobacco: (Moderate) Concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) with tobacco smoking may enhance the risk of gastrointestinal (GI) side effects. Tobacco smoking may independently increase the risk of peptic ulcer and GI bleeding, and thus may increase the risk with NSAID usage. Patients using tobacco and NSAIDs concurrently should be monitored closely for GI adverse reactions.
    Tobramycin: (Moderate) It is possible that additive nephrotoxicity may occur in patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) concurrently with other nephrotoxic agents, such as tobramycin.
    Tolazamide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Tolbutamide: (Moderate) NSAIDs may enhance hypoglycemia in diabetic patients via inhibition of prostaglandin synthesis, which indirectly increases insulin secretion. If NSAIDs are administered or discontinued in patients receiving oral antidiabetic agents, patients should be monitored for hypoglycemia or loss of blood glucose control. No clinically significant interaction between sulindac at daily doses of 400 mg and oral hypoglycemic agents has been observed. Sulindac, its sulfide metabolite, and sulfonylureas are highly bound to protein. Sulindac could displace the sulfonylureas, altering hypoglycemic activity. Careful patient monitoring is recommended to ensure that no change in their diabetes medicine dosage is required. A sulfonylurea dose adjustment may be needed, especially if sulindac doses greater than 400 mg daily are used or if the drug combination is used in patients with renal impairment or other metabolic defects that might increase sulindac blood concentrations.
    Tolmetin: (Major) Avoid concomitant use of diclofenac with any other NSAID due to the risk of additive serious NSAID toxicities including but not limited to GI bleeding, GI perforation, or peptic ulcers.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Torsemide: (Moderate) If a nonsteroidal anti-inflammatory drug (NSAID) and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Patients taking diuretics and NSAIDs concurrently are at higher risk of developing renal insufficiency. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDs have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Tositumomab: (Major) The tositumomab therapeutic regimen frequently causes severe and prolonged thrombocytopenia. The potential benefits of medications that interfere with platelet function and/or anticoagulation should be weighed against the potential increased risk of bleeding and hemorrhage. An additive risk of bleeding may be seen in patients receiving concomitant NSAIDs. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Trandolapril: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Trandolapril; Verapamil: (Moderate) In the low-renin or volume-dependent hypertensive patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. NSAIDs may attenuate the antihypertensive effects of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors may result in a further deterioration of renal function, including acute renal failure. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. The potential clinical effects of selective or preferential COX-2 inhibitors are not known. Mean arterial blood pressure increased 3 mmHg in patients receiving ACE inhibitor (benazepril 10 to 40 mg daily for 4 weeks) with rofecoxib 25 mg once daily compared to the ACE inhibitor regimen alone.
    Trastuzumab: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with medications that impair platelet function and to promptly report any bleeding events to the practitioner.
    Treprostinil: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Tretinoin, ATRA: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Triamcinolone: (Moderate) Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Corticosteroids can have profound effects on sodium-potassium balance; NSAIDs also can affect sodium and fluid balance. Monitor serum potassium concentrations; potassium supplementation may be necessary. In addition, NSAIDs may mask fever, pain, swelling and other signs and symptoms of an infection; use NSAIDs with caution in patients receiving immunosuppressant dosages of corticosteroids. The Beers criteria recommends that this drug combination be avoided in older adults; if coadministration cannot be avoided, provide gastrointestinal protection.
    Triamterene: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Urea: (Moderate) Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain. Patients taking diuretics and NSAIDS concurrently are at higher risk of developing renal insufficiency. If an NSAID and a diuretic are used concurrently, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy.
    Urokinase: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
    Valganciclovir: (Minor) Concurrent use of nephrotoxic agents, such as NSAIDs, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Valproic Acid, Divalproex Sodium: (Moderate) Due to the high protein binding of NSAIDs, they could displace other highly protein-bound drugs such as valproic acid, divalproex sodium from albumin binding sites in the blood leading to an increase in valproic acid free drug concentrations. In such cases, a patient may experience valproic acid toxicity even if the total drug concentration is within the therapeutic range.
    Valsartan: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible.
    Vancomycin: (Minor) It is possible that additive nephrotoxicity may occur in patients who receive NSAIDs concurrently with other nephrotoxic agents, including vancomycin.
    Vasodilators: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Vemurafenib: (Minor) Concomitant use of vemurafenib and diclofenac may result in altered concentrations of diclofenac. Vemurafenib is an inhibitor of CYP2C9 and an inducer of CYP3A4. Diclofenac is a substrate of CYP2C9 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venlafaxine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor patients for signs and symptoms of bleeding when coadministering venlafaxine with NSAIDs.
    Vigabatrin: (Minor) Vigabatrin is not significantly metabolized; however, it is an inducer of CYP2C9. In theory, decreased exposure of drugs that are extensively metabolized by CYP2C9, such as diclofenac, may occur during concurrent use of vigabatrin.
    Vilazodone: (Moderate) Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with NSAIDs and to promptly report any bleeding events to the practitioner.
    Vinblastine: (Major) Due to the thrombocytopenic effects of vinblastine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Vincristine Liposomal: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Vincristine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Vinorelbine: (Major) Due to the thrombocytopenic effects of vinorelbine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Vorapaxar: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Voriconazole: (Moderate) Voriconazole is known to be an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including diclofenac. A maximum diclofenac dose of 50 mg twice daily is recommended if voriconazole is administered concurrently with diclofenac. Further, monitor for NSAID-induced toxicity such as GI irritation, GI bleeding, or renal dysfunction.
    Vorinostat: (Major) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Warfarin: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs).To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
    Zafirlukast: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as diclofenac.

    PREGNANCY AND LACTATION

    Pregnancy

    Diclofenac tablets, delayed-release tablets, extended-release tablets, topical gel (Voltaren), and ophthalmic solution are classified as FDA pregnancy risk category C. Diclofenac topical gel (Solaraze) is classified as FDA category B. Some diclofenac products including the topical patch, topical solution, capsule, powder for oral solution, and intravenous solution are classified as FDA category C prior to 30 weeks gestation and category D if used after 30 weeks gestation due to the potential for prostaglandin synthetase inhibitors to cause in utero constriction of the fetal ductus arteriosus. Adequate and well-controlled studies of diclofenac in pregnant women do not exist; use of diclofenac should be avoided unless the potential therapeutic benefits justify its use during pregnancy. Of 40 babies born with persistent pulmonary hypertension of the newborn (PPHN), 87.5% had the presence of an NSAID in their meconium versus 24.6% of 61 children born without PPHN; the presence of only 4 NSAIDs was examined. In addition to meconium aspiration, asphyxia, respiratory distress syndrome, and group B streptococcal pneumonia, ductus arteriosus constriction by an NSAID appears to be another predisposing factor for PPHN development, as a patent ductus arteriosus was absent in 18 of the 40 infants. Some systemic NSAIDs have been shown to prolong pregnancy and inhibit labor if taken during the third trimester. Intravenous diclofenac should not be used during labor and delivery due to the inhibitory effects on prostaglandin synthesis that may adversely affect fetal circulation, inhibit uterine contractions, and increase risk of uterine bleeding.

    MECHANISM OF ACTION

    Diclofenac competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
    •Anti-inflammatory Activity: The anti-inflammatory mechanism of diclofenac is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Although diclofenac is considered a non-selective NSAID, it has been shown to have preferential inhibitory activity at COX-2 when tested ex vivo.
    •Analgesic Activity: Diclofenac is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, diclofenac has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
    •Antipyretic Activity: Diclofenac promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Although not indicated for the management of fever, diclofenac may mask fever in some patients, especially with high or chronic dosing.
    •Ophthalmic Activity: Following topical application to the eye, diclofenac inhibits miosis by inhibiting the biosynthesis of ocular prostaglandins. Prostaglandins play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In the eye, prostaglandins also have been shown to disrupt the blood-aqueous humor barrier, cause vasodilation, increase vascular permeability, promote leukocytosis, and increase intraocular pressure (IOP). The degree of ocular inflammatory response is correlated with prostaglandin-induced increases in ciliary epithelium permeability. When applied topically to the eye, NSAIDs inhibit the synthesis of prostaglandins in the iris, ciliary body, and conjunctiva. Thus, NSAIDs may prevent many of the manifestations of ocular inflammation. Diclofenac does not affect intraocular pressure or tonographic aqueous outflow resistance and does not interfere with the action of acetylcholine administered during ocular surgery. Diclofenac also does not prevent increases in intraocular pressure or decreases in aqueous outflow induced by topical corticosteroids.
    •GI Effects: Gastrointestinal side effects of diclofenac are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated.
    •Platelet Effects: The inhibition of platelet aggregation seen with diclofenac is due to dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2 and an increase in bleeding time (see Adverse Reactions). The inhibition of platelet aggregation is reversible within 24 hours of discontinuation of diclofenac. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.
    •Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen in increased blood pressure, which can be significant in selected individuals.
    •Bone Effects: Nonsteroidal anti-inflammatory drugs appear to suppress bone formation via inhibition of COX-2. In vivo data from rabbits revealed a significant reduction of bone growth with both naproxen and rofecoxib as compared with placebo. Bone resorption does not appear to be a mechanism that leads to decreased net bone formation, as the number of CD51 positive osteoclast-like cells per section was decreased with either NSAID as compared with drinking water alone. As determined from in vitro data, NSAIDs appear to arrest the osteoblast cell cycle at the G(0)/G(1) phase and induce cytotoxicity and cell death of osteoblasts primarily by apoptosis rather than by necrosis.

    PHARMACOKINETICS

    Diclofenac is administered orally, intravenously, topically, and as an ophthalmic solution. It appears to be widely distributed, with significant amounts in synovial fluid. Protein binding is roughly 99%, primarily to albumin. It is unknown whether diclofenac crosses the placenta. Significant distribution into breast milk does not occur.
     
    Metabolism via hepatic cytochrome P450 2C9 and 3A4 involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in metabolism. In vitro, the biotransformation of diclofenac to 4'-hydroxy-3'-(glutathion-S-yl) diclofenac is CYP2C9-dependent, and metabolism to 5-hydroxy-4-(glutathion-S-yl) diclofenac and 5-hydroxy-6-(glutathion-S-yl) diclofenac mainly involves CYP3A4. Although both CYP2C9 and CYP3A4 catalyze the bioactivation, CYP2C9 is capable of producing the benzoquinone imine intermediate at lower drug concentrations. For example, 4'-hydroxy-3'-(glutathion-S-yl) diclofenac was the dominant metabolite over a substrate concentration range of 10 to 50 micromolar. The metabolites 5-hydroxy-4-(glutathion-S-yl) diclofenac and 5-hydroxy-6-(glutathion-S-yl) diclofenac became equally important products at diclofenac concentrations of at least 100 micromolar. The 4'-hydroxy- diclofenac metabolite, which is formed via CYP3A4, has very weak pharmacologic activity. The metabolites after administration are subsequently excreted through urinary and biliary pathways. About 65% of a dose is excreted in the urine and about 35% in the bile. Less than 1% is excreted in the urine unchanged, with the remainder as metabolites or conjugates of the drug. Conjugates of unchanged diclofenac account for 5 to 10% of the dose excreted in the urine and less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP3A4, UGT2B7, and CYP2C8
    Metabolism via hepatic CYP450 2C9 and 3A4 involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Acylglucuronidation mediated by UGT2B7 and hepatic oxidation mediated by CYP2C8 may also play a role in metabolism.

    Oral Route

    Diclofenac is available orally as immediate-release tablets and capsules, oral solution, delayed release tablets (enteric-coated), and extended release tablets. 
    Oral solid dosage forms, immediate-release: The immediate-release formulations are designed to release diclofenac in the stomach. Diclofenac is almost completely absorbed from the GI tract following oral administration, but bioavailability is only about 50% because of extensive first-pass metabolism, possibly due to intestinal cytochrome P450 CYP3A4. On the fourth day of diclofenac therapy post-surgery, a mean peak plasma concentration of 902 ng/mL at a Tmax of 1.26 hours was measured following administration of immediate-release 50 mg tablets; whereas, administration of immediate-release 25 mg liquid-filled capsules resulted in mean peak plasma concentration of 749 ng/mL at a Tmax of 0.63 hours. The effect of fed versus fasting states was not determined for either product; however, it is known that food delays the rate but not the extent of absorption of the immediate-release tablet. 
    Diclofenac oral solution, immediate-release: Following administration of diclofenac oral solution to fasting volunteers, Tmax was achieved in approximately 0.25 hours (range: 0.17 to 0.67 hours). A reduction in peak plasma concentrations of 70% was observed following administration of diclofenac oral solution after a high fat meal, which could potentially decrease efficacy.
    Delayed-release and extended-release products: The delayed-release product resists dissolution in the low pH of gastric fluids and rapidly releases the drug in the higher pH environment of the duodenum. The extended-release preparation releases diclofenac over a prolonged period. Administration of several individual diclofenac delayed-release tablets may not yield equivalent peak concentrations as one higher strength delayed-release tablet due to the staggered gastric emptying of the tablets into the duodenum. Following administration of the delayed-release diclofenac product in fasting normal volunteers, peak plasma concentrations are reached in about 2 hours (range: 1 to 4 hours). When the delayed-release products are taken with food, there is usually a delay in the onset of absorption of 1 to 4.5 hours, with delays as long as 10 hours in some patients, and a reduction in peak concentrations by approximately 40%. The extent of diclofenac absorption from the extended-release tablets is not significantly affected when the drug is taken with food; however, food significantly alters the absorption pattern as indicated by a delay of 1 to 2 hours in the Tmax and a 2-fold increase in the Cmax values. The plasma profile for the extended-release tablets under fed conditions showed a more consistent absorption pattern with a single peak usually occurring between 5 to 6 hours after the meal. Under fasting conditions, the plasma profile of the extended-release tablets is characterized by multiple peaks and high intersubject variability.

    Intravenous Route

    After IV administration to healthy volunteers, plasma concentrations of diclofenac exceeded that of immediate-release oral diclofenac for the first 45 minutes reaching a maximum of 4.8-fold 5 minutes after administration. Minimal accumulation occurred after 4 doses of 37.5 mg IV given every 6 hours. Intravenous diclofenac exhibits linear pharmacokinetics over the dose range of 18.75 to 75 mg. The reported elimination half-lives of IV diclofenac are 1.4 and 2.3 hours following single and multiple doses, respectively.

    Topical Route

    Diclofenac gel: When applied topically, diclofenac is absorbed into the epidermis resulting in a low, yet potentially clinically significant, systemic exposure. Compared to diclofenac oral bioavailability of 50 to 60%, approximately 10% of the applied dose of diclofenac 3% gel is absorbed systemically in both normal and compromised epidermis after 7 days of 4-times daily applications. The mean systemic exposure (AUC) was 9 +/- 19 ng x hour/mL, and the maximum serum diclofenac concentration (Cmax) was 4 +/- 5 ng/mL after application of 2 grams of the 3% gel three times daily for 6 days. After application of 4 grams of the 1% gel to the knee four times daily (total daily dose of 160 mg of diclofenac sodium) for 7 days, the mean Cmax was 15 +/- 7.3 ng/mL, the time to the maximum concentration was 14 hours (range, 0 to 24 hours), and the AUC over 24 hours was 233 +/- 128 ng x hour/mL. This equates to a Cmax of 0.6% and an AUC of 5.8% of the values obtained after administration of oral diclofenac sodium 50 mg three times daily. Systemic exposure after application of 4 grams of the 1% gel to each knee and 2 grams to each hand four times daily (total daily dose of 480 mg of diclofenac sodium) for 7 days equated to a Cmax of 2.2% and an AUC of 19.7% of the values obtained after administration of oral diclofenac sodium 50 mg three times daily. Use of diclofenac topical solution at recommended doses for 7 days resulted in a Cmax of 19.4 +/- 9.3 ng x hour/mL and a systemic exposure of approximately one-third that of diclofenac 3% gel use. Following diclofenac topical patch use a Cmax range of 0.7 to 6 ng/mL was obtained 10 to 20 hours after a single patch application to the upper, inner arm. Diclofenac plasma concentrations of 1.3 to 8.8 ng/mL were noted after 5 days of twice daily patch application.
    Diclofenac topical patch: The elimination half-life of diclofenac from diclofenac epolamine medicated topical patch is approximately 12 hours.

    Other Route(s)

    Ophthalmic Route
    Systemic absorption from the ophthalmic formulation is not clinically significant.