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    All Other Musculoskeletal Products
    All Other Wound Healing Agents
    Supplemental Dietary Agents

    BOXED WARNING

    Corporal rupture

    Collagenase administration is contraindicated in the treatment of Peyronie's plaques that involve the penile urethra, due to potential risk to this structure. Of note, injection of collagenase into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Care should be taken to properly administer collagenase into the plaque, avoiding other structures such as the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis. Administration of collagenase injections for the treatment of Peyronie's disease has been associated with serious penile injury, including corporal rupture. Instruct patients to immediately report signs or symptoms indicative of penile injury. Serious injury, such as corporal rupture or severe penile hematoma, may require surgical intervention.

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Collagenase enzymatically degrades collagen
    Topical enzyme ointment for the chemical debridement of acute or chronic wounds
    Injectable form for the treatment of Dupuytren's contracture with a palpable cord, and for Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees
    Due to the possible risk of serious penile injury, Xiaflex for the treatment of Peyronie's disease, will only be available through a REMS program

    COMMON BRAND NAMES

    Santyl, Xiaflex

    HOW SUPPLIED

    Santyl Topical Ointment: 1g, 250U
    Xiaflex Intralesional Inj Pwd F/Sol: 0.9mg

    DOSAGE & INDICATIONS

    For the treatment of severe partial- or full-thickness burns.
    NOTE: Removal of necrotic tissue by mechanical debridement should be considered during the initial and subsequent assessments.
    NOTE: Collagenase should only be used on wounds that have necrotic material. Antibiotic administration is paramount for infected wounds.
    NOTE: Collagenase should be discontinued as soon as the wound bed is devoid of necrotic tissue and has more than 90% granulation tissue.
    Topical dosage
    Adults, Adolescents, and Children

    Apply a thin layer to the site once daily. More frequent (e.g., twice daily) application may be needed if dressing becomes soiled.

    For the treatment of decubitus ulcer, diabetic foot ulcer, or varicose ulcer that requires debridement.
    NOTE: Removal of necrotic tissue by mechanical debridement should be considered during the initial and subsequent assessments.
    NOTE: Collagenase should only be used on wounds that have necrotic material. Stage 1 ulcers are not appropriate candidates. Antibiotic administration is paramount for infected wounds.
    NOTE: Collagenase should be discontinued as soon as the wound bed is devoid of necrotic tissue and has more than 90% granulation tissue.
    Topical dosage
    Adults, Adolescents, and Children

    Apply a thin layer to the site once daily. More frequent (e.g., twice daily) application may be needed if dressing becomes soiled. Once granulation has been firmly established, every other day application may be considered.

    For the treatment of Dupuytren's contracture with a palpable cord.
    Intralesional injection dosage
    Adults

    0.58 mg injected into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint. If a contracture persists approximately 24 hours after injection, perform a finger extension procedure to facilitate cord disruption. Injections (0.58 mg) and finger extension procedures (24 hours later) may be administered up to 3 times per cord at approximately 4-week intervals. Up to 2 injections in the same hand may be performed during a treatment visit. Two palpable cords affecting 2 joints may be injected or 1 palpable cord affecting 2 joints in the same finger may be injected at 2 locations during a treatment visit. If a patient has other palpable cords with contractures of the MP or PIP joints, these cords may be injected at other treatment visits approximately 4 weeks apart.

    For the treatment of Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy.
    Intralesional injection
    Adults males

    0.58 mg injected into a Peyronie’s plaque. If more than 1 plaque is present, inject into the plaque causing the curvature. A treatment cycle consists of 2 injection procedures and 1 penile modeling procedure. The second of 2 injection procedures is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately 6 weeks. The treatment course, consists of a maximum of 8 injection procedures and 4 modeling procedures (i.e., a maximum of 4 treatment cycles). The safety of more than 1 treatment course is unknown. If the curvature deformity is less than 15 degrees after the first, second, or third treatment cycle, or if the health care provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered. The safety and effectiveness of collagenase treatment of Peyronie's disease was established in 2 randomized, double-blind, placebo-controlled studies in adult males (n = 832) with Peyronie's disease with penile curvature deformity of at least 30 degrees. Participants were given up to 4 treatment cycles of collagenase or placebo and were then followed 52 weeks. Collagenase treatment significantly reduced penile curvature deformity and related bothersome effects compared with placebo.
    NOTE: Due to the possible risk of serious penile injury, collagenase injection for the treatment of Peyronie's disease is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Treatment should be administered by a health care professional with experience in male urological diseases. The REMS requires prescribers to be certified within the program by enrolling and completing training in the administration of collagenase injection. Participating health care facilities should also be certified to ensure appropriate product distribution.

    MAXIMUM DOSAGE

    Adults

    For topical preparations, 2 applications/day topically. For Dupuytren's contractures, 0.58 mg/dose injected into a palpable cord (only inject 1 cord at a time); for Peyronie’s disease, 0.58 mg/dose injected into penile plaque, a maximum of 8 injection procedures per treatment course.

    Geriatric

    For topical preparations, 2 applications/day topically. For Dupuytren's contractures, 0.58 mg/dose injected into a palpable cord (only inject 1 cord at a time); for Peyronie’s disease, 0.58 mg/dose injected into penile plaque, a maximum of 8 injection procedures per treatment course.

    Adolescents

    2 applications/day topically; safety and efficacy of the injectable formulation have not been established.

    Children

    2 applications/day topically; safety and efficacy of the injectable formulation have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Due to the possible risk of serious penile injury, collagenase injection for the treatment of Peyronie's disease, is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Treatment should be administered by a health care professional with experience in male urological diseases. The REMS requires prescribers to be certified within the program by enrolling and completing training in the administration of collagenase injection. Participating health care facilities should also be certified to ensure appropriate product distribution. Further information is available at (877) 313-1235.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution should be clear. Do not use if the solution contains particulates, is cloudy, or is discolored.
    Be prepared to address severe allergic reactions. Severe reactions including anaphylaxis could occur after collagenase injections.

    Other Injectable Administration

    Intralesional Injection Administration
     
    Intralesional Injection for Dupuytren's Contracture
    NOTE: Only a healthcare provider experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture should inject collagenase intralesionally.
     
    Reconstitution:
    Remove the vial containing the collagenase lyophilized powder and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for 15 to 60 minutes.
    Remove the flip-off cap from each vial and aseptically swab the rubber stopper and surrounding surface of each vial with sterile alcohol; do not use any other antiseptics.
    Only use the supplied diluent for reconstitution, as the diluent contains calcium that is required for the activity of collagenase. Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge half-inch needle, withdraw 0.39 mL of diluent for cords affecting a metacarpophalangeal (MP) joint or withdraw 0.31 mL of diluent for cords affecting a proximal interphalangeal (PIP) joint.
    Inject the diluent slowly into the sides of the lyophilized powder vial. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. Do not invert the vial or shake the solution. The reconstituted solution contains 0.9 mg of collagenase.
    Discard the syringe and needle used for reconstitution.
     
    Intralesional Injection:
    If the reconstituted solution is refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours before administration, allow this solution to return to room temperature for approximately 15 minutes before use.
    Using a new 1 mL hubless syringe that contains 0.01 ml graduations with a permanently fixed, 27-gauge, half-inch needle, withdraw 0.25 mL of reconstituted solution (containing 0.58 mg of collagenase) for cords affecting a metacarpophalangeal (MP) joint or 0.2 mL of reconstituted solution (containing 0.58 mg of collagenase) for cords affecting a proximal interphalangeal (PIP) joint. Discard any unused solution. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
    Reconfirm the cord to be injected. The chosen injection site should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord.
    Apply an antiseptic at the injection site and allow the skin to dry. 
    Administration of a local anesthetic agent before injection is not recommended, as the local anesthetic may interfere with proper placement of the collagenase injection.
    If injecting into a cord affecting the PIP joint of the fifth finger, take care to inject as close to the palmar digital crease as possible (as far proximal to the digital PIP joint crease); avoid injecting more than 4 mm distal to the palmar digital crease. Do not insert the needle more than 2 to 3 mm in depth.
    Secure the patient’s hand to be treated with your non-dominant hand and simultaneously apply tension to the cord. With your dominant hand, place the needle into the cord and use caution to keep the needle within the cord. To help minimize the potential for injection of collagenase into tissues other than the cord, do not let the needle tip pass completely through the cord. Take care to avoid injection into tendons, nerves, blood vessels, or other collagen-containing structures of the hands.
    If there is any concern that the needle is in the flexor tendon, apply a small amount of passive motion at the distal interphalangeal joint. If insertion of the needle into a tendon is suspected or if paresthesia is noted by the patient, withdraw the needle and reposition it into the cord.
    If the needle is in the proper location, some resistance noted during the injection procedure will be noted. After confirming that the needle is correctly placed in the cord, inject approximately one-third of the dose. Withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and inject another one-third of the dose. Withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord.
    Wrap the patient’s treated hand with a soft, bulky, gauze dressing. Instruct the patient to limit motion of the treated finger and to keep the injected hand elevated until bedtime. Instruct the patient not to attempt to disrupt the injected cord by self-manipulation and to return the next day for follow-up and a finger extension procedure, if needed.
    Inject only one cord at a time. If a patient has other palpable cords with contractures of MP or PIP joints, these cords may be injected with collagenase in a sequential order.
     
    Follow-up:
    If a contracture remains the day after the injection, perform a passive finger extension procedure to facilitate cord disruption. Put the patient’s wrist is in the flexed position and apply moderate stretching pressure to the injected cord by extending the finger for approximately 10 to 20 seconds. For cords affecting the proximal interphalangeal (PIP) joint, perform the finger extension procedure when the metacarpophalangeal (MP) joint is in the flexed position. Avoid direct pressure on the injection site, as it will likely be tender. Local anesthesia may be used.
    If the first finger extension procedure does not result in cord disruption, a second and third attempt can be performed at 5 to 10 minute intervals. However, no more than 3 attempts are recommended to disrupt a cord.
    If the cord has not been disrupted after 3 attempts, a follow-up visit may be scheduled in approximately 4 weeks. If, at that subsequent visit, the contracted cord persists, an additional collagenase injection with finger extension procedures may be performed.
    After the finger extension procedure(s), fit the patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension. Also, instruct the patient to perform finger extension and flexion exercises several times a day for several months.
     
    Intralesional Injection for Peyronie's Disease
    NOTE: In accordance with XIAFLEX REMS Program, prescribers must be certified with the program by enrolling and completing training in the administration of collagnase injection treatment. Healthcare sites must also be certified with the program to ensure proper distribution of product.
     
    Reconstitution:
    Remove the vial containing the collagenase lyophilized powder and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for 15 to 60 minutes.
    Remove the flip-off cap from each vial and aseptically swab the rubber stopper and surrounding surface of each vial with sterile alcohol; do not use any other antiseptics.
    Only use the supplied diluent for reconstitution, as the diluent contains calcium that is required for the activity of collagenase. Using a 1 ml syringe that contains 0.01 ml graduations with a 27-gauge half-inch needle, withdraw 0.39 ml of diluent.
    Inject the diluent slowly into the sides of the lyophilized powder vial. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. Do not invert the vial or shake the solution. The reconstituted solution contains 0.9 mg of collagenase.
    Discard the syringe and needle used for reconstitution.
     
    Intralesional Injection:
    If the reconstituted solution is refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 4 hours before administration, allow this solution to return to room temperature for approximately 15 minutes before use.
    Prior to each treatment cycle, identify the treatment area by inducing a penile erection. A single intracavernosal injection of 10 or 20 mcg alprostadil may be used for this purpose. Apply antiseptic at the site of injection and allow the skin to dry prior to the intracavernosal injection.
    Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis. Mark the point with a surgical marker. This indicates the target area in the plaque for intralesional injection.
    Before intralesional injection, apply an antiseptic at the injection site and allow the skin to dry. Administer suitable local anesthetic, if desired.
    Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge half-inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of collagenase).
    The penis should be in a flaccid state before intralesional injection. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum.
    Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger.
    With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject collagenase into the plaque
    Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque.
    Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary.
    Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent.
    The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection.
     
    Follow-up:
    Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure on the flaccid penis to stretch and elongate the treated plaque.
    Administer suitable local anesthetic, if desired.
    Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site.
    Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient’s penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release.
    After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt.
    In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle. During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds. The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain.
    Of note, injection of collagenase into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, collagenase should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.

    Topical Administration

    Collagenase is only for use on necrotic skin tissue.
     
    Site preparation:
    Assess the need for pain control during wound manipulation. Enzyme application is usually not pain-inducing because tissue is not removed mechanically as with surgical debridement or wet-to-dry dressings. The process of washing and rinsing the wound could cause discomfort.
    There is no need to remove all collagenase ointment from the wound, if it has been applied previously. Gently wash the site with a normal saline soaked sterile gauze pad. Do not scrub the site. Wash several times if povidone iodine, acidic detergents, or cleansers with heavy metal ions (e.g., mercury, silver) have been used previously on the site. Examples of such items include silver sulfadiazine, silver nitrate, aluminum acetate, Burow's solution, and povidone-iodine. Hydrogen peroxide and Dakin's solution do not interact with collagenase. After the wash, rinse the wound with normal saline.
    If appropriate, remove loose necrotic debris with forceps and scissors.
    If clinically indicated, thick eschar may be crosshatched using a #10 blade to expose more surface area to collagenase.
    If an infection is present, surgical debridement may be needed initially; systemic antibiotics are of limited value for necrotic tissue, as it is avascular. If a topical antibiotic is applied to the site, the antibiotic is applied before collagenase. Antibiotic therapy should be chosen based on culture results. If the infection does not resolve, collagenase ointment should be withheld until culture results show infection resolution.

    Cream/Ointment/Lotion Formulations

    Apply the ointment within the boundaries of the wound. Application may be direct to the site or to a sterile gauze pad that it secured to the site. Do not touch the tip of the tube to any surface, including a finger, the wound, or sterile gauze pad. Application to normal skin may cause some irritation.
    Once daily application is usually sufficient; however, if the dressing becomes soiled, wound cleansing and collagenase reapplication may be appropriate.
    Cessation of collagenase use is needed when necrotic tissue debridement is complete and granulation tissue is well-established.

    STORAGE

    Generic:
    - Avoid excessive heat (above 104 degrees F)
    - Store at room temperature (between 59 to 86 degrees F)
    Santyl:
    - Store at 77 degrees F
    Xiaflex:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Topical collagenase is contraindicated for use by patients who have shown local or systemic collagenase hypersensitivity. Injectable collagenase is contraindicated for use in patients with a history of collagenase hypersensitivity whether injectable or used in any other therapeutic application or application method.

    Bone marrow suppression, hyperglycemia, immunosuppression, infection, malnutrition

    Use of topical collagenase may increase the risk of bacteremia in at-risk patients; the presence of eschar or necrotic tissue is a good medium to support bacterial growth. Wounds of patients with immunosuppression need to be monitored vigilantly for signs and symptoms of infection. Patients who are elderly or patients with hyperglycemia, malnutrition, immunosuppressant use, bone marrow suppression, or certain cancers may be at greater risk for wound infection due to immunosuppression. Patients with malnutrition may have inadequate intake of nutrients, protein and calories necessary for proper wound repair. Infection at the wound site may lead to a systemic infection (sepsis). Patients with a fever, chills, elevated white blood count, hypotension, confusion, purulent wound exudate, or odiforous wounds may need appropriate antimicrobial therapy.

    Arteriosclerosis, diabetes mellitus, peripheral vascular disease

    Certain wounds of patients with peripheral vascular disease, diabetes mellitus, or arteriosclerosis may have insufficient vascular supply. Wound beds need adequate blood supply to facilitate nutrition delivery, infection control, and waste removal. Topical collagenase application to a wound bed with inadequate blood perfusion may be moot. Steps to optimize circulation, such as external compression, surgery, exercise, and medication optimization may be considered, as appropriate.

    Anticoagulant therapy, coagulopathy, hemophilia, thrombocytopenia, vitamin K deficiency

    Cautious use of injectable collagenase is warranted for patients with a coagulopathy,hemophilia, vitamin K deficiency, thrombocytopenia, or on anticoagulant therapy (except low-dose aspirin). In clinical trials, 70% of patients developed an ecchymosis/contusion, and 38% developed an injection site hemorrhage. The efficacy and safety of injectable collagenase in patients receiving anticoagulant medications other than aspirin up to 150 mg per day within 7 days of injectable collagenase administration is unknown.

    Children

    The safety and efficacy of injectable collagenase in children have not been established.

    Pregnancy

    Collagenase injection is classified as FDA pregnancy risk category B. Human pharmacokinetic studies showed that collagenase levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord. No well-controlled studies are available in pregnant women for use of the injectable collagenase and the injections should be given to a pregnant woman only when clearly needed. Almost all patients develop anti-AUX-I and anti-AUX-II after injectable collagenase treatment; the clinical significance of anti-product antibody formation on a developing fetus is unknown. Human collagenase also plays a role in cervical ripening during labor, and the effects on labor or obstetric delivery are not completely understood. There is no information regarding the systemic absorption of topical collagenase ointment; theoretically systemic absorption would be influenced by application site size and other factors; use as directed rarely results in systemic adverse effects to the person to whom it is applied. Case reports describe topical collagenase ointment use for wound care during pregnancy within the medical literature, and use is generally considered compatible when clearly needed for proper wound care.

    Breast-feeding

    Topical collagenase ointment has no specific precautions for use in breast-feeding women. According to the manufacturer, caution is advised in the use of injectable collagenase; however, human pharmacokinetic studies showed that collagenase concentrations were not quantifiable in the systemic circulation after injection into a Dupuytren’s cord. Consider the benefits of breast-feeding, the risk of 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Corporal rupture

    Collagenase administration is contraindicated in the treatment of Peyronie's plaques that involve the penile urethra, due to potential risk to this structure. Of note, injection of collagenase into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Care should be taken to properly administer collagenase into the plaque, avoiding other structures such as the urethra, nerves, blood vessels, corpora cavernosa, or other collagen-containing structures of the penis. Administration of collagenase injections for the treatment of Peyronie's disease has been associated with serious penile injury, including corporal rupture. Instruct patients to immediately report signs or symptoms indicative of penile injury. Serious injury, such as corporal rupture or severe penile hematoma, may require surgical intervention.

    Requires an experienced clinician

    Collagenase injection requires an experienced clinician in the treatment of patients with Dupuytren's contracture and injection procedures of the hand or in the treatment of male urological diseases, who has completed required training for use of collagenase injection in the treatment of Peyronie's disease.

    ADVERSE REACTIONS

    Severe

    penile edema / Early / 55.0-55.0
    tendon rupture / Delayed / 0-1.0
    corporal rupture / Delayed / 0.5-0.5
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    edema / Delayed / 55.0-73.0
    hematoma / Early / 3.7-65.5
    penile pain / Rapid / 45.4-45.4
    bleeding / Early / 38.0-38.0
    skin laceration / Delayed / 9.0-22.0
    lymphadenopathy / Delayed / 13.0-13.0
    erythema / Early / 6.0-6.0
    impotence (erectile dysfunction) / Delayed / 1.8-1.8
    penile irritation / Rapid / 1.1-1.1
    dyspareunia / Delayed / 1.1-1.1
    dyspnea / Early / Incidence not known
    antibody formation / Delayed / Incidence not known

    Mild

    ecchymosis / Delayed / 14.5-70.0
    pruritus / Rapid / 4.0-15.0
    skin discoloration / Delayed / 1.8-1.8
    pelvic pain / Delayed / 1.1-1.1
    urticaria / Rapid / Incidence not known
    rash (unspecified) / Early / Incidence not known
    skin irritation / Early / Incidence not known
    infection / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain either magnesium or aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
    Abciximab: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Aluminum Hydroxide: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Carbonate: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amphetamines: (Moderate) Concurrent use of amphetamines and gastrointestinal acidifying agents, such as ascorbic acid, vitamin C, should beused with caution. Vitamin C lowers the absorption of amphetamines, resulting in reduced efficacy. In addition, ascorbic acid acts as a urinary acidifier, which reduces the renal tubular reabsorption of amphetamines, accelerating amphetamine clearance and reducing the duration of effect. If combined use is necessary, the amphetamine dose should be adjusted according to clinical response as needed.
    Anagrelide: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Antacids: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Anticoagulants: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Antithrombin III: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Apixaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Argatroban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Aspirin, ASA: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Carisoprodol: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Dipyridamole: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Omeprazole: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Oxycodone: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Aspirin, ASA; Pravastatin: (Moderate) Cautious use of injectable collagenase by patients taking more than150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
    Atenolol: (Minor) Calcium antacids (e.g., calcium carbonate) and supplements (e.g., other oral calcium salts) have been reported to reduce the mean peak concentrations by 51% and the AUC of atenolol by 32%. In another study, antacids reduced the AUC of atenolol by 33%. Separate doses of atenolol and calcium-containing antacids or supplements by at least 2 hours to minimize this potential interaction,. However, most clinicians consider the interaction of atenolol with antacids to be of minor clinical significance, since clinical efficacy (heart rate and blood pressure parameters) appear to be unchanged under usual intermittent clinical use.
    Atenolol; Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended. (Minor) Calcium antacids (e.g., calcium carbonate) and supplements (e.g., other oral calcium salts) have been reported to reduce the mean peak concentrations by 51% and the AUC of atenolol by 32%. In another study, antacids reduced the AUC of atenolol by 33%. Separate doses of atenolol and calcium-containing antacids or supplements by at least 2 hours to minimize this potential interaction,. However, most clinicians consider the interaction of atenolol with antacids to be of minor clinical significance, since clinical efficacy (heart rate and blood pressure parameters) appear to be unchanged under usual intermittent clinical use.
    Atracurium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Azilsartan; Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Bendroflumethiazide; Nadolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Beta-Carotene: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Betamethasone; Calcipotriene: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
    Betrixaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Bismuth Subsalicylate: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Bisphosphonates: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Bivalirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Bleomycin: (Moderate) Monitor for decreased efficacy of bleomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration of ascorbic acid and bleomycin may result in decreased efficacy of bleomycin.
    Calcipotriene: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
    Calcitonin: (Moderate) Calcitonin is given to hypercalcemic patients to reduce serum calcium concentrations. For the treatment of hypercalcemia, calcium supplements should be avoided. Calcium salts, including calcium carbonate, can elevate serum calcium concentrations and antagonize the effects of the calcitonin for this condition. For the treatment of osteoporosis adequate intake of calcium salts are necessary in conjunction with calcitonin. An increase in serum calcium concentrations helps to reduce bone resorption and loss of bone mass, and offsets the effect of calcitonin in lowering serum calcium levels.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Calcium Phosphate, Supersaturated: (Moderate) The concomitant use of oral sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous preparations in conjunction with antacids containing calcium (e.g., calcium carbonate, calcium salts) may bind the phosphate in the stomach and reduce its absorption. If the patient requires multiple mineral supplements or concurrent use of antacids, it is prudent to separate the administration of sodium phosphate salts from calcium containing products by at least one hour.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Cardiac glycosides: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Chlorothiazide: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Chlorthalidone; Clonidine: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Choline Salicylate; Magnesium Salicylate: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Cilostazol: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Ciprofloxacin: (Major) Administer oral ciprofloxacin at least 2 hours before or 6 hours after oral products that contain calcium. Ciprofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Cisatracurium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Clopidogrel: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cod Liver Oil: (Moderate) Concomitant cod liver oil and calcium supplementation should be undertaken with caution. The vitamin D contained within cod liver oil can increase serum calcium concentrations; the combination may result in hypercalcemia. Additionally, doses in excess of 1,500 to 2,000 mcg/day of vitamin A may lead to bone loss and can counteract the effects of supplementation with calcium salts. (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam.
    Conjugated Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Cyanocobalamin, Vitamin B12: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Dabigatran: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dalteparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Danaparoid: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Deferoxamine: (Major) Patients should be advised not to take ascorbic acid, vitamin C supplements along with deferoxamine chelation therapy unless such supplements are prescribed with the approval of their health care professional. Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. Vitamin C can be a beneficial adjunct in iron chelation therapy because it facilitates iron chelation and iron complex excretion. As an adjuvant to iron chelation therapy (e.g., deferoxamine), vitamin C (in doses up to 200 mg/day for adults, 50 mg/day in children < 10 years of age or 100 mg/day in older children) may be given in divided doses, starting after an initial month of regular treatment with deferoxamine. However, higher doses of ascorbic acid, vitamin C can facilitate iron deposition, particularly in the heart tissue, causing cardiac decompensation. In patients with severe chronic iron overload, the concomitant use of deferoxamine with > 500 mg/day PO of vitamin C in adults has lead to impairment of cardiac function; the dysfunction was reversible when vitamin C was discontinued. The manufacturer of deferoxamine recommends certain precautions for the coadministration of vitamin C with deferoxamine. First, vitamin C supplements should not be given concurrently with deferoxamine in patients with heart failure. Secondly, in other patients, such supplementation should not be started until 1 month of regular treatment with deferoxamine, and should be given only to patients receiving regular deferoxamine treatments. Do not exceed vitamin C doses of 200 mg/day for adults, 50 mg/day in children < 10 years of age, or 100 mg/day in older children, given in divided doses. Clinically monitor all patients, especially the elderly, for signs or symptoms of decreased cardiac function.
    Delafloxacin: (Major) Administer oral delafloxacin at least 2 hours before or 6 hours after oral products that contain calcium. Delafloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with fluoroquinolone bioavailability include antacids and multivitamins that contain calcium.
    Desirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Dienogest; Estradiol valerate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Diethylstilbestrol, DES: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Dipyridamole: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Disulfiram: (Moderate) As ascorbic acid, vitamin C has on occasion been used as a specific antidote for symptoms resulting from interaction between ethanol and disulfiram, it may be expected that the administration of large doses of vitamin C may interfere with the effectiveness of disulfiram given to patients to encourage abstinence from alcohol.
    Dolutegravir: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain either magnesium or aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
    Doxacurium: (Moderate) Calcium salts may antagonize the neuromuscular blocking effects of doxacurium.
    Doxycycline: (Moderate) Monitor for decreased efficacy of doxycycline during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of doxycycline.
    Drospirenone; Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Drospirenone; Ethinyl Estradiol: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Edetate Calcium Disodium, Calcium EDTA: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Edetate Disodium, Disodium EDTA: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Edoxaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Eltrombopag: (Major) Eltrombopag chelates polyvalent cations (e.g., calcium, aluminum, and magnesium) in food, mineral supplements, and antacids. In a clinical study, systemic exposure to eltrombopag was decreased by 70% when it was administered with a polyvalent cation-containing antacid. Administer eltrombopag at least 2 hours before or 4 hours after any oral products containing polyvalent cations, such as aluminum salts, (like aluminum hydroxide), calcium salts, (including calcium carbonate), and magnesium salts.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Enoxaparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Eptifibatide: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Erythromycin: (Moderate) Monitor for decreased efficacy of erythromycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of erythromycin.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for decreased efficacy of erythromycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of erythromycin.
    Esterified Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Levonorgestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Norethindrone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Norgestimate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estramustine: (Major) Administration of estramustine with calcium impairs the oral absorption of estramustine significantly, due to formation of a calcium-phosphate complex. Calcium-containing drugs must not be taken simultaneously with estramustine. Patients should be instructed to take estramustine with water at least 1 hour before or 2 hours after calcium supplements.
    Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estropipate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Desogestrel: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Etonogestrel: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norelgestromin: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norgestimate: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norgestrel: (Minor) Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethotoin: (Major) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours to help avoid this interaction. A similar interaction may occur with ethotoin.
    Fluphenazine: (Moderate) Monitor for decreased efficacy of fluphenazine during coadministration. Coadministration of ascorbic acid and fluphenazine may result in decreased plasma concentrations of fluphenazine due to acidification of the urine by ascorbic acid and increased excretion of fluphenazine.
    Fondaparinux: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Gallium: (Moderate) Concurrent administration products containing calcium salts may antagonize the effects of gallium nitrate.
    Gemifloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after gemifloxacin. Gemifloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Heparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended. (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH. (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Ibritumomab Tiuxetan: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Kanamycin: (Moderate) Monitor for decreased efficacy of kanamycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of kanamycin.
    Lepirudin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Levofloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after orally administered levofloxacin. Levofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Chelation of divalent cations with levofloxacin is less than with other quinolones. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Lincomycin: (Moderate) Monitor for decreased efficacy of lincomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of lincomycin.
    Magnesium Hydroxide: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Magnesium Salicylate: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Mestranol; Norethindrone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Methenamine: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH.
    Methenamine; Sodium Acid Phosphate: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) The therapeutic action of methenamine requires an acidic urine. Ascorbic acid, vitamin C can produce unpredictable changes in urine pH and should be avoided as a urinary acidifier. In addition, orange juice also should be avoided because citric acid ultimately may raise urine pH.
    Methyclothiazide: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Metolazone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Mexiletine: (Minor) Ascorbic acid, vitamin C in doses greater than 2 grams per day can lower urinary pH, potentially causing enhanced the plasma clearance of mexiletine.
    Mivacurium: (Moderate) Calcium salts may antagonize the neuromuscular blocking effects of mivacurium.
    Moxifloxacin: (Major) Administer oral moxifloxacin at least 4 hours before or 8 hours after oral products that contain calcium. Moxifloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Norfloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after norfloxacin. Norfloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Ofloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after ofloxacin. Ofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Omeprazole; Sodium Bicarbonate: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Pancuronium: (Moderate) Calcium salts usually reverse the effects of nondepolarizing neuromuscular blocking agents such as pancuronium.
    Pentosan: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Phosphorated Carbohydrate Solution: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Phosphorus Salts: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Phosphorus: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Platelet Inhibitors: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Potassium Phosphate; Sodium Phosphate: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Povidone-Iodine: (Severe) Collagenase can interact with other topically-applied medication products. Povidone-iodine inactivates collagenase and concurrent use should be avoided.
    Prasugrel: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Propranolol: (Minor) Ascorbic acid may reduce the oral bioavailability of propranolol. Advise patients against taking large doses of ascorbic acid with doses of propranolol.
    Rivaroxaban: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Rocuronium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers, such as rocuronium.
    Salsalate: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. If the urine is acidic prior to administration of an acidifying agent, the interaction should be minimal.
    Silver Nitrate: (Severe) Topical collagenase can interact with other topically-applied medication products. Care should be taken to avoid topical antimicrobials, such as silver nitrate. Silver ions and agents with a low pH (< 6) inhibit the enzymatic activity of collagenase.
    Silver Sulfadiazine: (Severe) Silver sulfadiazine should not be used with the proteolytic enzymes collagenase, papain, or sutilains because heavy metals such as silver inactivate these enzymes.
    Sodium Bicarbonate: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Sodium Fluoride: (Moderate) Absorption of sodium fluoride may be reduced by concomitant use of antacids that contain magnesium, aluminum, or calcium. An interval of at least 2 hours is advisable between administration of sodium fluoride and antacids.
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) The concomitant use of oral sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous preparations in conjunction with antacids containing calcium (e.g., calcium carbonate, calcium salts) may bind the phosphate in the stomach and reduce its absorption. If the patient requires multiple mineral supplements or concurrent use of antacids, it is prudent to separate the administration of sodium phosphate salts from calcium containing products by at least one hour.
    Streptomycin: (Moderate) Monitor for decreased efficacy of streptomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of streptomycin.
    Succinylcholine: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Tetracyclines: (Major) Divalent or trivalent cations readily chelate with tetracycline antibiotics, forming insoluble compounds. The oral absorption of these antibiotics will be significantly reduced by other orally administered compounds that contain calcium salts, particularly if the time of administration is within 60 minutes of each other. Calcium salts and tetracyclines should not be administered within 1 to 2 hours of each other, although doxycycline chelates less with calcium than other tetracyclines.
    Thiazide diuretics: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Thyroid hormones: (Major) Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements. To avoid the interaction, thyroid hormones should be administered at least 4 hours before or after ingestion of oral calcium supplements.
    Ticagrelor: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Ticlopidine: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Tinzaparin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Tirofiban: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Trientine: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of trientine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and trientine each inhibit oral absorption of the other, 2 hours should elapse between administration of trientine and iron doses.
    Tubocurarine: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Vecuronium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Vitamin A: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Vitamin D analogs: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Vorapaxar: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Warfarin: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site. (Minor) Monitor INR as per current standards of care when patients take vitamin C with warfarin. Limited case reports have suggested that high doses of ascorbic acid with warfarin may decrease the anticoagulation effects of warfarin. However, controlled studies have not confirmed an interaction. No effect was observed in patients on warfarin therapy treated with ascorbic acid doses up to 1,000 mg/day for 2 weeks.

    PREGNANCY AND LACTATION

    Pregnancy

    Collagenase injection is classified as FDA pregnancy risk category B. Human pharmacokinetic studies showed that collagenase levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord. No well-controlled studies are available in pregnant women for use of the injectable collagenase and the injections should be given to a pregnant woman only when clearly needed. Almost all patients develop anti-AUX-I and anti-AUX-II after injectable collagenase treatment; the clinical significance of anti-product antibody formation on a developing fetus is unknown. Human collagenase also plays a role in cervical ripening during labor, and the effects on labor or obstetric delivery are not completely understood. There is no information regarding the systemic absorption of topical collagenase ointment; theoretically systemic absorption would be influenced by application site size and other factors; use as directed rarely results in systemic adverse effects to the person to whom it is applied. Case reports describe topical collagenase ointment use for wound care during pregnancy within the medical literature, and use is generally considered compatible when clearly needed for proper wound care.

    Topical collagenase ointment has no specific precautions for use in breast-feeding women. According to the manufacturer, caution is advised in the use of injectable collagenase; however, human pharmacokinetic studies showed that collagenase concentrations were not quantifiable in the systemic circulation after injection into a Dupuytren’s cord. Consider the benefits of breast-feeding, the risk of 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Collagenase digests collagen in collagen deposits. Lysis of collagen deposits occurs, as collagenases hydrolyze collagen in its native triple helical conformation under physiological conditions.
     
    A Dupuytren’s cord is comprised mostly of collagen, and injection of collagenase into the cord may result in enzymatic disruption of the cord. In vitro data suggest that the AUX-I and AUX-II collagenases work synergistically to provide hydrolyzing activity towards collagen. The relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of collagenase in the treatment of Dupuytren’s contracture are unknown.
     
    The curvature deformity of Peyronie’s disease is caused by a collagen plaque. Intralesional injection of collagenase into the penile plaque may enzymatically disrupt the plaque and reduce signs and symptoms. In vitro data suggest collagenase targets Types I and III collagen found in explanted tissues containing Peyronie’s plaques. At higher doses and longer incubation times, non-fibrillar Type IV collagen is affected causing collagen lysis in small veins. However, in vitro and in vivo studies have not demonstrated structural damage to arteries, nerves, or large veins which contain Type IV collagen. In addition, collagen fragments derived from plaque disruption have been shown to generate increased vascular permeability, inflammatory responses, and regenerative changes; however, the effects of these changes have not been studied.
     
    Collagenase also digests collagen in necrotic tissue. Moist, necrotic tissue provides a medium for infection, initiates an inflammatory response, places a phagocytic demand on the wound, and retards wound healing. As collagen composes roughly 75% of dry tissue weight and provides the framework to hold necrotic cells to the tissue bed, collagen removal by collagenase facilitates granulation tissue formation. Granulation is necessary for proper epithelialization. Human collagenases are produced by macrophages, fibroblasts, and keratinocytes, which are all necessary for wound healing. Unlike mammalian collagenase, Clostridial collagenase is secreted as an active enzyme and splits collagen into small peptides. The small peptides appear to enhance chemotaxis of macrophages, monocytes, fibroblasts, neutrophils, and keratinocytes. In vitro data suggest that Clostridial collagenase and the small peptides promote epithelization by enhancing keratinocyte migration to the wound.

    PHARMACOKINETICS

    Collagenase is applied topically or is injected intralesionally into palpable cords in patients with Dupuytren's contractures.

    Topical Route

    Collagenase is applied topically directly to the wound bed. The optimal pH for enzymatic activity of collagenase is between 6 and 8. No information is available regarding the absorption, distribution, metabolism, or excretion of topically applied collagenase.

    Other Route(s)

    Intralesional Route
    No quantifiable concentrations of either microbial collagenase (AUX-I or AUX-II) were detected in plasma up to 30 days after injection of a single collagenase dose of 0.58 mg into a Dupuytren’s cord in 20 patients.
     
    Following each of 2 intralesional administrations (0.58 mg collagenase, separated by 24 hours) into the penile plaque of 19 subjects with Peyronie's disease, plasma levels of AUX-I and AUX-II in subjects with quantifiable levels (79% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal plasma concentrations of AUX-I and AUX-II were < 29 ng/mL and < 71 ng/mL, respectively, and were observed approximately within 10 minutes after injection. Within 30 minutes following dosing, all plasma levels were below the limits of quantification. No evidence of accumulation was evident following two sequential injections. No subject had quantifiable plasma levels 15 minutes after modeling of plaque on Day 3 (i.e., 24 hours after the second injection on Day 2).