PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    ADHD Adjunct Agents
    Centrally Acting Alpha Agonists
    Other Analgesics

    DEA CLASS

    Rx

    DESCRIPTION

    Centrally-acting alpha2-agonist 
    Oral and topical drug for HTN, ADHD, and autonomic hyperactivity (e.g., drug withdrawal syndromes)
    Epidural agent for refractory pain; also used for some psychiatric disorders

    COMMON BRAND NAMES

    Catapres, Catapres-TTS, Duraclon, Kapvay

    HOW SUPPLIED

    Catapres/Clonidine/Clonidine Hydrochloride Oral Tab: 0.1mg, 0.2mg, 0.3mg
    Catapres-TTS/Clonidine Percutaneous Film ER: 0.1mg, 0.2mg, 0.3mg, 24h
    Clonidine/Clonidine Hydrochloride/Duraclon Epidural Inj Sol: 1mL, 100mcg, 500mcg
    Clonidine/Clonidine Hydrochloride/Kapvay Oral Tab ER: 0.1mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage (immediate-release tablets)
    Adults

    Initially, 0.1 mg PO twice daily; increase by 0.1—0.2 mg/day PO until desired effect is achieved (usual dosage range 0.2—0.6 mg/day PO). Although the manufacturer recommends a maximum dose of 2.4 mg/day PO which is rarely used; further antihypertensive benefit may not be achieved at doses above 1.2 mg/day. Geriatric patients may require a lower initial dose due to increased risk of side effects.

    Adolescents†

    Initial dose of 0.1 mg PO twice daily titrated to a maximum of 2.4 mg/day has been recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.

    Children 12 years†

    Initial dose of 0.1 mg PO twice daily titrated to a maximum of 2.4 mg/day has been recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Alternatively, an initial weight-based dose of 5—10 mcg/kg/day PO in divided doses every 8—12 hours has been reported.

    Children < 12 years†

    Initial dose of 5—10 mcg/kg/day PO in divided doses every 8—12 hours has been reported. Increase gradually (every 5 to 7 days) to a maximum dosage of 0.9 mg/day. The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents does not recommend the use of clonidine for the management of hypertension in children < 12 years of age.

    Transdermal dosage
    Adults

    Initially, apply one Catapres TTS-1 (delivers 0.1 mg/24 hr) patch to an intact area of hairless skin on the upper arm or torso, once every 7 days. Adjust dosage every 1—2 weeks by changing or combining dosage systems. When applying a new patch, a different area of skin should be used. Because the effects of the transdermal system may not be evident for several days after the initial administration, it is recommended that previous antihypertensive medications be continued and gradually reduced.

    For the treatment of attention-deficit hyperactivity disorder (ADHD) in pediatric patients as monotherapy or as adjunctive therapy to a psychostimulant.
    NOTE: Clonidine is not considered a first-line agent for children with ADHD due to the potential cardiac effects and the availability of safer and more effective agents, such as some stimulants. Reports of sudden death and hypotension in children receiving oral clonidine in combination with other therapies for ADHD have been published, but causality has not been established. Children and infants may be more sensitive to the effects of clonidine. However, not all ADHD clinical trials evaluating clonidine have reported adverse cardiac effects. The American Heart Association has recommended that children and adolescents receiving clonidine be monitored for changes in blood pressure at treatment initiation, periodically during treatment, and when tapering the drug, even when clonidine is used for psychotropic indications.
    For the treatment of ADHD in children with tic disorders†.
    Oral dosage (clonidine immediate-release tablets)†
    Children† and Adolescents†

    In a 16-week, multicenter, randomized, controlled clinical trial (n = 136), children with ADHD and a chronic tic disorder received a final dose of 0.25—0.28 mg/day PO of clonidine, either alone or in combination with methylphenidate (roughly 26 mg/day PO). Children also received methylphenidate alone or placebo. The greatest ADHD benefit and improved tic severity compared to baseline was seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20—26% of each treatment group, including placebo. Sedation was common (28%) in the clonidine groups.[31596] NOTE: Due to the potential for adverse reactions, clonidine should be started at a dose of 0.05 mg/day PO and slowly titrated up as needed.

    Oral dosage (Kapvay extended-release tablets)

    NOTE: Extended-release clonidine tablets are not interchangeable with the immediate-release formulation.

    Children >= 6 years and Adolescents

    Initially 0.1 mg/day PO at bedtime. Increase the dose in 0.1 mg/day increments weekly up to 0.4 mg/day PO as needed to attain the desired response. Doses > 0.1 mg/day PO should be divided into 2 doses taken in the morning and at bedtime. If the morning and bedtime doses are not equal, the larger dose should be given at bedtime. When extended-release clonidine is added to a psychostimulant, the dosage of the psychostimulant may be adjusted according to patient response. Measure heart rate and blood pressure prior to beginning therapy, after dose increases, and periodically while on therapy. If a patient misses a dose, they should skip that dose and take the next dose as scheduled. When discontinuing, taper the dose in decrements of no more than 0.1 mg/day every 3—7 days to avoid rebound hypertension. Extended-release clonidine tablets are not interchangeable with the immediate-release formulation.

    Oral dosage (immediate-release tablets)†
    Adolescents and Children

    Initially, 0.05 mg PO per day. Increase by 0.05 mg/day every 3—7 days to a dose of 3—5 mcg/kg/day PO, given in 3—4 divided doses. Usual maximum dosage is 0.3 mg/day PO. Rarely, total daily doses of 0.4 mg/day PO have been prescribed, but are associated with an increased incidence of side effects.

    For the treatment of severe pain.
    In cancer patients when the pain is not adequately relieved by opiate analgesics alone including neuropathic pain†.
    NOTE: Clonidine has been designated an orphan drug by the FDA for this indication.
    NOTE: Epidural clonidine has been effective primarily in the subgroup of patients with neuropathic pain.
    Epidural dosage
    Adults

    Initially, 30 mcg/hr by continuous epidural infusion in combination with opioid analgesics, is recommended by the manufacturer. Dosage may be titrated up or down depending on pain relief and occurrence of adverse events, however, there is limited experience above the maximum rate of 40 mcg/hr. In clinical trials, bolus doses of epidural clonidine range from 100—900 mcg per dose. The dosage should be titrated to pain relief and incidence of side effects.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    Children

    Initially, 0.5 mcg/kg/hour by continuous epidural infusion and adjusted cautiously based upon pain relief and incidence of side effects.

    In postoperative patients in combination with opiate analgesics.
    NOTE: The manufacturer does not recommend the use of epidural clonidine in obstetrical, post-partum or peri-operative analgesia due to the risk of hemodynamic instability.
    Epidural dosage
    Adults

    Epidural clonidine 150 mcg in combination with fentanyl has been studied. This dose provided similar pain relief and increased the analgesia duration as compared to epidural fentanyl alone as a single dose. Epidural clonidine 450 mcg/day has been studied in combination with morphine. This dose resulted in improved pain relief and less rescue doses of morphine in comparison to epidural morphine alone in patients with postoperative pain.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of hypertensive urgency† or hypertensive emergency†.
    Oral dosage
    Adults

    0.1—0.2 mg PO every hour as required to a total of 0.6 mg.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of opiate agonist withdrawal†.
    Oral dosage
    Adults

    The usual initial dose is 0.1 mg to 0.2 mg PO, with titration to a maximum total dose of 1 mg/day PO, administered in two to four divided doses, according to response and tolerability (e.g., blood pressure). Maximal doses are generally administered for two to four days after cessation of the opiate during the time of maximal withdrawal. Clonidine doses are then tapered, and the drug is discontinued 7 to 10 days after cessation of the opiate. The American Psychiatric Association (APA) practice guidelines for substance abuse disorders state that an initial dose of clonidine 0.1 mg PO three times (total 0.3 mg per 24 hours) is usually sufficient to suppress signs of opiate withdrawal. Use of higher doses may be acceptable during inpatient detoxification since medical staff can monitor for hypotension and sedation. Adjust subsequent dosing until withdrawal symptoms are reduced. Hold the dose if blood pressure falls below 90/60 mmHg, and resume when BP returns to normal. The APA guidelines recommend limiting outpatient dispensing for unsupervised use to a 3-day supply of clonidine because treatment requires careful dose titration and clonidine overdoses can be life-threatening. Clonidine appears generally inferior to buprenorphine or methadone taper for opiate withdrawal treatment; however, clonidine is more effective than placebo and a useful alternative to buprenorphine for targeting noradrenergic-mediated withdrawal symptoms such as nausea, vomiting, diarrhea, cramps, and sweating.

    Geriatric

    See adult dosage. Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage and may require lower dosages.

    For the treatment of neonatal abstinence syndrome†.
    Oral dosage
    Neonates

    Dosages of 3—5 mcg/kg/day PO given in divided doses every 4—6 hours have been effective in treating opiate agonist withdrawal symptoms for a mean of 12 days in 6/7 infants addicted to opiates because of maternal methadone maintenance.

    For pheochromocytoma diagnosis†.
    Oral dosage
    Adults

    A single 0.3 mg PO dose administered after 30 minutes of inactivity successfully differentiated 10 patients with pheochromocytoma from 15 hypertensive patients without pheochromocytoma. Blood pressure, heart rate, and plasma catecholamines were assessed at 30, 60, 120, and 180 minutes post-dose. At 3 hours post-dose, norepinephrine concentrations were suppressed to normal or below normal in all patients without pheochromocytoma but in none of the 10 patients with the disease.

    For the symptomatic treatment of diabetic neuropathy†.
    Oral dosage
    Adults

    Initially, 0.1 mg PO at bedtime. Gradually increase to 0.5 mg PO each night.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of diabetic diarrhea†, diarrhea† related to opiate withdrawal, or refractory diarrhea† in cancer patients.
    NOTE: Clonidine has some antisecretory activity by modulating (decreasing) small intestinal transit; however, data are relatively limited and the agent is often used for refractory diarrheal cases.
    Oral dosage
    Adults

    Initially, 0.1 mg PO every 12 hours and increased over a period of 3 days to 0.5—0.6 mg PO every 12 hours. The effect of clonidine was studied in three insulin-dependent diabetic patients with chronic diarrhea in a challenge-dechallenge-challenge design. All three patients had a significant decline in stool volume during clonidine and diarrhea resumed when clonidine was withdrawn. Gastroparesis was not aggravated. Dosage was maintained for 19—21 days.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of alcohol withdrawal†.
    Oral dosage
    Adults

    Both oral and transdermal clonidine have been found successful in the management of acute ethanol withdrawal. Efficacy with clonidine is equivalent to chlordiazepoxide and clonidine may be preferable to avoid the development of benzodiazepine dependence. In one study, clonidine was dosed initially as 0.2 mg PO at 9PM on day 1; at 9AM, 1PM, and 6PM on day 2; at 9AM and 6PM on day 3; and a final dose at 9AM on day 4. Although blood pressure was lower in clonidine patients than in patients receiving chlordiazepoxide, no patient experienced significant hypotension or rebound hypertension.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For use as an adjunct to psychosocial interventions in the management of tobacco cessation† (smoking cessation†).
    Oral dosage
    Adults

    0.1 mg PO once or twice daily initially. Dose range in clinical trials: 0.1 mg/day to 0.75 mg/day, in divided doses. Begin clonidine shortly before (up to 3 days) or on the quit date. The dose may be increased by 0.1 mg/day per week if needed. Dividing the total daily dose is suggested to increase tolerability. Consider a dosage reduction in elderly patients due to greater sensitivity to clonidine at usual dosages. Treatment duration has varied across clinical trials, generally ranging from 3 to 10 weeks. Common side effects include dry mouth, sedation, dizziness, drowsiness, and constipation. There is no clear dose-response relationship; however, dose-related adverse effects limit the clinical usefulness of the drug. DISCONTINUATION: Reducing the dose gradually over 2 to 4 days may mitigate a rebound phenomenon of rapid increase in blood pressure, agitation, confusion, and/or tremor. According to the Agency for Healthcare Research and Quality (AHRQ) treatment guidelines, clonidine is appropriate as a second-line medication for treating tobacco use.

    Transdermal dosage
    Adults

    Initially, 0.1 mg/24 hours applied transdermally once weekly. May increase the dose by 0.1 mg/24 hours weekly if needed. Transdermal doses ranging from 0.1 mg/24 hours to 0.2 mg/24 hours strength patch applied once weekly have been used in clinical trials.  Consider low doses and slow titration in elderly patients because they may be more sensitive to common side effects of clonidine at usual dosages. Treatment duration has varied across clinical trials, generally ranging from 3 to 10 weeks. Common side effects include dry mouth, sedation, dizziness, drowsiness, and constipation. There is no clear dose-response relationship; however, dose-related adverse effects limit the clinical usefulness of the drug. According to the Agency for Healthcare Research and Quality (AHRQ) treatment guidelines, clonidine is appropriate as a second-line medication for treating tobacco use.

    For the treatment of hot flashes† due to menopause†.
    Oral dosage (immediate-release tablets)
    Adult females

    Initially, 0.05 mg PO twice daily or 0.1 mg PO once daily at bedtime. Higher doses of 0.1 mg PO twice daily or more may be necessary for some patients. Max studied: 0.2 mg PO twice daily. In a study of 194 postmenopausal women with breast cancer receiving tamoxifen, clonidine 0.1 mg PO once daily at bedtime reduced the number of hot flashes per day compared with placebo (p = 0.006); quality of life also improved. A meta-analysis estimates clonidine provides approximately a 1 hot flash/day reduction when compared to control groups; improvements in quality of life are also reported. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy consider clonidine effective for vasomotor symptoms of menopause; however, it is typically not used as a first-line agent in the treatment of hot flashes as it is less effective and associated with more adverse effects compared to other non-hormonal pharmacologic therapies (e.g., paroxetine, gabapentin, venlafaxine).

    Transdermal dosage
    Adult females

    A dose of one Catapres TTS-1 patch (delivers clonidine 0.1 mg/24 hours) once weekly has been suggested. A meta-analysis estimates clonidine (oral or transdermal) provides approximately a 1 hot flash/day reduction when compared to control groups; improvements in quality of life are also reported. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy consider clonidine effective for vasomotor symptoms of menopause; however, it is typically not used as a first-line agent in the treatment of hot flashes as it is less effective and associated with more adverse effects compared to other non-hormonal pharmacologic therapies (e.g., paroxetine, gabapentin, venlafaxine).

    For the treatment of hypertension and the subsequent decline in renal function associated with scleroderma renal crisis (SRC)†.
    Oral dosage
    Adults

    Initially, 0.1 mg PO twice daily, increased by 0.1—0.2 mg/day PO to attain blood pressure response.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For minimization of nephrotoxicity in patients receiving cyclosporine (i.e., cyclosporine nephrotoxicity prophylaxis†) and low-dose methotrexate for allogeneic bone marrow transplant.
    Transdermal dosage
    Adults

    A small study compared the effect of transdermal clonidine patches on cyclosporine-induced nephrotoxicity in allogeneic bone marrow transplant patients. Transdermal clonidine 0.1 mg/day (from 4 days prior to 31 days after transplantation), titrated to 0.2 mg/day (if DBP not < 90 mm Hg), has been studied in 8 transplant patients. Twenty-three allogeneic BMT patients did not receive clonidine. Data from 23 autologous BMT patients were also included in the evaluation. At the end of the study, mean serum creatinine in the allogeneic group receiving clonidine was significantly lower than the allogeneic group not receiving clonidine (1.1 mg/dL vs 1.6 mg/dL) and was not significantly different from the autologous BMT group (0.9 mg/dL). NOTE: The Catapres-TTS-1 transdermal patch delivers clonidine 0.1 mg/day over 7 days; whereas the Catapres-TTS-2 patch delivers clonidine 0.2 mg/day over 7 days.

    Geriatric

    See adult dosage. Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For use in peripheral nerve block† including brachial plexus†, intercostal† and peribulbar† blocks in combination with local anesthetics.
    Peripheral nerve block dosage
    Adults

    Epidural clonidine 30—150 mcg has been used to enhance the effects of lidocaine in peripheral nerve blocks. In cataract surgery, clonidine 2 mcg/kg in combination with 3—4 ml of 2% lidocaine resulted in decreased intraocular pressure and longer post-operative analgesia and akinesia than lidocaine alone.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of Tourette's syndrome†.
    Oral dosage
    Adults

    0.15—0.2 mg/day PO.

    Geriatric

    Consider dosage reduction (see adult dosage). Elderly patients may be more sensitive to the effects (sedation and hypotension) of the usual dosage.

    For the treatment of aggressive behavior and hyperactivity/inattentiveness in patients with autistic disorder†.
    Oral dosage
    Children and Adolescents 5 years and older

    Initially, 0.05 mg PO once daily in the evening. Increase to 0.05 mg PO twice daily after 3 days. Then continue to increase by 0.05 mg/day PO every 3 days as needed for symptom control. Usual dose range is 0.1 to 0.4 mg/day PO given in 3 to 4 divided doses (Max: 0.4 mg/day PO).

    Transdermal dosage
    Children and Adolescents 5 years and older

    Initial doses of 0.005 mg/kg/day rounded to the nearest available patch strength (patches are available in 3 strengths delivering doses of approximately 0.1, 0.2, or 0.3 mg/day over 7 days) were used in a small study including 7 pediatric patients (age range 5 to 12 years, weight range 19.1 to 52.7 kg). Patients weighing less than 25 kg were started on half a 0.1 mg/day patch for 3 days to minimize adverse reactions. The mean dose of clonidine used in the study was 0.16 +/- 0.09 mg/day. Although patches in this study were changed every 7 days, other authors have suggested that pediatric patients may require patches be changed earlier (i.e., every 5 days) due to variable absorption. Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction.

    For growth hormone deficiency diagnosis†.
    Oral dosage
    Children and Adolescents

    5 mcg/kg PO as a single dose (Max: 250 mcg PO). Maximal growth hormone secretion usually occurs 60 minutes after the dose. Blood should be drawn at 0, 30, 60, and 90 minutes after the dose of clonidine is given. Similarly, blood pressure should be measured at these same time intervals.

    For the treatment of hot flashes† due to prostate cancer† and associated induced androgen deficiency† ("andropause†") in men who have had surgical or medication induced castration.
    Transdermal dosage
    Adult males

    Apply one Catapres TTS-1 patch (delivers clonidine 0.1 mg/24 hours) once weekly. Limited data from a pilot study indicate that transdermal clonidine may have some benefit in reducing the frequency of hot flashes in men after bilateral orchiectomy; however a randomized clinical trial of transdermal clonidine showed no benefit compared to placebo.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.4 mg/day PO immediate-release tablets; two Catapres-TTS-3 transdermal patches/week (delivers 0.6 mg/day for 7 days) applied topically to skin; or 40 mcg/hr continuous epidural infusion.

    Geriatric

    2.4 mg/day PO immediate-release tablets; two Catapres-TTS-3 transdermal patches/week (delivers 0.6 mg/day for 7 days) applied topically to skin; or 40 mcg/hr continuous epidural infusion.

    Adolescents

    0.4 mg/day PO extended-release tablets; safety and efficacy of immediate-release tablets have not been established; however, doses up to 2.4 mg/day for hypertension have been recommended. Maximum doses of transdermal and epidural clonidine in pediatric patients have not been established.

    Children

    12 years: 0.4 mg/day PO extended-release tablets; safety and efficacy of immediate-release tablets have not been established; however, doses up to 2.4 mg/day for the treatment of hypertension have been recommended. Maximum doses of transdermal and epidural clonidine in pediatric patients have not been established.
    6—11 years: 0.4 mg/day PO extended-release tablets; safety and efficacy of immediate-release tablets have not been established; however, doses up to0.9 mg/day PO for the treatment of hypertension have also been recommended. Maximum doses of transdermal and epidural clonidine in pediatric patients have not been established.
    < 6 years: Safety and efficacy have not been established; however, doses up 0.9 mg/day PO for the treatment of hypertension have been recommended. Maximum doses of transdermal and epidural clonidine in pediatric patients have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Although no quantitative recommendations are available, it appears that dosage reductions may be considered in patients with severe hepatic impairment due to substantial metabolism of clonidine.

    Renal Impairment

    A lower initial dose may be beneficial; patients should be carefully monitored for bradycardia, sedation, and hypotension.
     
    Intermittent hemodialysis
    Clonidine is minimally removed by hemodialysis. In general, no supplemental dosage is needed following hemodialysis. Adjust dosage based on clinical response. 

    ADMINISTRATION

    Oral Administration

    Administer last dose of the day immediately prior to bedtime to ensure maximum overnight blood pressure control; the largest portion of the daily dose should also be taken just before bedtime.

    Oral Solid Formulations

    Immediate-release tablets (e.g., Catapres): May be taken with or without food. Upon discontinuation, slowly taper dose over 2—4 days to avoid withdrawal symptoms and rebound hypertension.
    Extended-release tablets (e.g., Kapvay): May be taken with or without food. Swallow whole; do not crush, cut, or chew. Upon discontinuation, slowly taper dose every 3—7 days to avoid withdrawal symptoms and rebound hypertension.

    Extemporaneous Compounding-Oral

    Extemporaneous oral suspension†: An oral suspension can be compounded as follows: Crush and grind 30 commercially available tablets of 0.2 mg clonidine hydrochloride (total: 6 mg clonidine) to a fine powder in a glass mortar. Add enough Purified Water, USP to form a paste (roughly 2 mL). Then add to the paste Simple Syrup, NF 15 mL, and triturate well. Transfer mortar contents to 60 mL amber glass bottle. Continue to add Simple Syrup, NF in increments to a total of 60 mL; shake after each increment until well suspended. The solution (0.1 mg/mL of clonidine) is stable for 28 days when stored in 60 mL amber glass bottles at 4 degrees C refrigeration; do not freeze. Protect from light. Shake well prior to use.

    Injectable Administration
    Other Injectable Administration

    Epidural Injection
    Epidural clonidine is preservative-free.
    Epidural clonidine is usually administered in combination with other opiate analgesics such as fentanyl or morphine.
    Health care professionals should be familiar with epidural infusion devices when administering epidural infusions.

    Topical Administration
    Transdermal Patch Formulations

    NOTE: The amount of active drug released after application of a clonidine transdermal system is directly proportional to the area covered by the system. 'Patches' are available as 3.5 cm2 (total clonidine content 2.5 mg, delivering 100 mcg/day); 7 cm2 (total clonidine content 5 mg, delivering 200 mcg/day); and 10.5 cm2 (total clonidine content 7.5 mg, delivering 300 mcg/day) over a period of 7 days. The total amount of drug in each system is greater than that delivered, to ensure constant release of the drug over 7 days.
    Do not cut or trim patch.
    Clonidine is absorbed better from the patch if applied on the upper arm or torso.
    Apply to any hairless site at the same time each week. Avoid applying to areas with cuts or calluses. Wash area with soap and water. Dry thoroughly. Apply patch using firm pressure over patch to ensure contact with skin, especially around edges. If patch becomes loose during the 7-day wearing period, apply the adhesive overlay over the patch. If patch is overly loose or falls off, apply another patch. Rotate sites each week.
    Instruct patient on proper application of patch. Patches should not be affected by showering, bathing, or swimming.
    Patches must be removed prior to cardioversion or defibrillation to prevent burns to the patient. Also, removal of the Catapres-TTS patch before undergoing magnetic resonance imaging (MRI) is recommended because the patch contains aluminum.

    STORAGE

    Catapres:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Catapres-TTS:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Duraclon:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Kapvay:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    NEXICLON XR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Clonidine is contraindicated in patients with a hypersensitivity to clonidine. Generalized rash, urticaria, and angioedema have occurred with clonidine use.
     
    Administration of epidural clonidine above the C4 dermatome is contraindicated because there are no adequate safety data to support such use.

    Abrupt discontinuation, vomiting

    Abrupt discontinuation of clonidine, regardless of route of administration, can precipitate a withdrawal syndrome consisting of rebound increases in both serum and urine catecholamines. Symptoms of nervousness, agitation, headache, tremor, and rebound hypertension have been associated with clonidine withdrawal. Rarely, hypertensive encephalopathy, cerebrovascular accidents, and death have been reported. Patients at higher risk of experiencing adverse consequences of withdrawal include those with a history of hypertension or other cardiovascular disorders, receiving higher doses of clonidine, or receiving concomitant beta-blocker therapy. Pediatric patients receiving oral clonidine who experience gastrointestinal illness associated with vomiting may also be at risk for withdrawal due to abrupt inability to take medication. Careful monitoring of infusion pump function and catheter tubing for obstruction or dislodgement is recommended in patients receiving epidural clonidine to prevent inadvertent abrupt discontinuation.If it is necessary to discontinue clonidine, doses should be slowly tapered over 2—4 days to avoid withdrawal symptoms. Patients who have received clonidine therapy for greater than 4 weeks may require slower dosage tapers (i.e., dosage reduction every 3 days). If it is necessary to discontinue extended-release clonidine (Kapvay), reduce the dose by increments of <= 0.1 mg every 3—7 days. Monitoring of blood pressure and heart rate during weaning is recommended, even when clonidine is used for psychotropic indications.

    AV block, bradycardia, cerebrovascular disease, dehydration, heart failure, hypotension, myocardial infarction, orthostatic hypotension, syncope

    The hypotensive effects of clonidine may decrease perfusion and worsen ischemia in patients with cerebrovascular disease, recent myocardial infarction, or severe heart failure. The sympatholytic action of clonidine may worsen sinus node dysfunction and AV block, especially in patients taking other sympatholytic agents. Because clonidine decreases blood pressure and heart rate, the manufacturer of clonidine extended-release tablets (Kapvay) recommends cautious use of clonidine in patients with a history of hypotension, AV block, bradycardia, or cardiovascular disease. Patients with a history of syncope or conditions that may increase the risk of syncope such as hypotension, orthostatic hypotension, bradycardia, or dehydration should also be treated with caution.

    Labor, obstetric delivery, pregnancy

    Adequate and well-controlled studies of clonidine have not been performed during pregnancy in humans. Risk-benefit should be considered before use in pregnant patients; use only if clearly needed. One study found that clonidine crosses the placenta easily, and its concentrations were equal in maternal serum and umbilical cord serum and amniotic fluid concentrations were up to 4 times that found in serum. There is one case report suggesting that fetuses who are exposed to long-term clonidine (more than 300 mcg/day) during pregnancy may be more likely to develop sleep disorders later in life. The manufacturer does not recommend the use of epidural clonidine as an analgesic during labor and obstetric delivery, or for post-partum or peri-operative analgesia due to the risks of hemodynamic instability, especially hypotension and bradycardia. However, potential benefits of clonidine may outweigh the possible risks in a rare obstetrical, post-partum, or perioperative patient. Several trials examining the efficacy, safety, or dosing of epidural clonidine in obstetrics have been reported. In a study comparing epidural clonidine combined with bupivacaine and bupivacaine alone for analgesia during labor, there was no difference in maternal blood pressure decreases and Apgar scores at 1 and 5 minutes between the two groups. The duration of labor was prolonged in patients receiving clonidine.

    Females

    Females and lower weight patients may be more susceptible to the hypotensive effects of epidural clonidine.

    Breast-feeding

    According to the manufacturer, because clonidine is excreted in breast milk, it should be administered cautiously to breast-feeding women. Clonidine is excreted in breast milk at concentrations that exceed maternal plasma. In addition, clonidine may affect prolactin and oxytocin concentrations, which may theoretically impact establishment of lactation in select individuals. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safe and effective use of immediate-release oral clonidine and transdermal clonidine have not been established in neonates, infants, children or adolescents. Safety and efficacy of Kapvay extended release tablets have not been established in children < 6 years. Because clonidine decreases blood pressure and heart rate, the manufacturer recommends cautious use of clonidine extended-release tablets in pediatric patients with a history of hypotension, AV block, bradycardia, or cardiovascular disease. Pediatric patients with a history of syncope or conditions that may increase the risk of syncope such as hypotension, orthostatic hypotension, bradycardia or dehydration should also be treated with caution. The American Heart Association (AHA) has recommended that children and adolescents receiving clonidine be monitored for changes in blood pressure at treatment initiation, periodically during treatment, and when tapering the drug, even when clonidine is used for psychotropic indications. In addition, the AHA recommends obtaining a detailed patient and family history and physical examination prior to the therapy initiation; obtaining a baseline electrocardiogram (ECG) is also a reasonable addition to the initial evaluation. The use of epidural clonidine should be restricted to those children with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques.

    Depression

    Use clonidine cautiously in patients with a history of major depression because the drug can induce depressive episodes.

    Driving or operating machinery

    Warn patients of the potential sedative and hypotensive effects of clonidine and advised against driving or operating machinery, or performing other hazardous tasks, until they are aware of how the medication affects them.

    Sick sinus syndrome

    Use clonidine cautiously in patients with sinus node function impairment such as sick sinus syndrome, although its effects on cardiac conduction appear to be slight.

    Raynaud's phenomenon, thromboangiitis obliterans (Buerger's disease)

    Use clonidine cautiously in patients with Raynaud's phenomenon or thromboangiitis obliterans (Buerger's disease). Clonidine may exacerbate these conditions.

    Diabetes mellitus

    Clonidine should be used cautiously in patients with diabetes mellitus because transient elevations in blood glucose have been noted. It has, however, been used safely in many diabetic patients.

    Renal disease, renal failure, renal impairment

    Clonidine has been used safely in patients with renal disease. Clonidine is 45% renally excreted and drug concentrations may accumulate in renal failure. Therefore, the manufacturer recommends careful monitoring and that patients with renal impairment may benefit from a lower initial dose. In clinical practice, dosage adjustments are usually not clinically needed in patients with renal failure or renal disease, and the dosage of clonidine is titrated to achieve clinical goals.

    Anticoagulant therapy, coagulopathy, infection

    Clonidine epidural injection is contraindicated in patients receiving anticoagulant therapy or in patients with a coagulopathy. Epidural clonidine is also contraindicated in patients with an infection at the site of injection.

    Cardiac disease

    Epidural clonidine should be used cautiously in patients with severe cardiac disease or who are hemodynamically unstable due to the potential for severe hypotension. When clonidine is administered into the upper thoracic spinal segments more profound decreases in blood pressure may be seen.

    Intrathecal administration

    The manufacturer does not recommend intrathecal administration of clonidine. Due to clonidine's lipophilicity, increased effects may be noticed following intrathecal administration, although, inadvertent intrathecal administration has not been associated with a significant increase in side effects. The use of intrathecal clonidine in intra- and postoperative analgesia and in obstetrics (labor and Cesarean section) have been reported.

    Defibrillation (cardioversion), magnetic resonance imaging (MRI)

    Clonidine transdermal systems should be removed prior to defibrillation (cardioversion) because the drug can alter electrical conductivity, increasing the likelihood that electrical arcing will occur. In addition, because some clonidine transdermal systems (e.g., Catapres-TTS, others) contain aluminum or other metal components, patients should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.

    Polyarteritis nodosa, scleroderma, systemic lupus erythematosus (SLE)

    Absorption of transdermal clonidine can be decreased in patients with polyarteritis nodosa, scleroderma, or systemic lupus erythematosus (SLE), and the patches should not be placed on affected areas.

    Skin abrasion

    Absorption of transdermal clonidine can be increased in areas of skin irritation or skin abrasion, so placement of the patches in these areas should be avoided.

    Surgery

    Careful consideration should be given to the scheduling of clonidine doses near the time of surgery; specific recommendations are available that are dependent on the dosage form. Oral administration of immediate-release clonidine should be continued to within 4 hours of surgery and resumed as soon as possible thereafter. Although the manufacturers of clonidine injection and Kapvay brand extended-release clonidine for ADHD do not provide specific recommendations regarding dosing near surgery, these formulations should not be abruptly discontinued due to the risk of withdrawal symptoms. Transdermal clonidine therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery; additional measures to control blood pressure should be readily available if necessary. If transdermal clonidine therapy is initiated during the perioperative period, clinicians must be aware that therapeutic plasma clonidine concentrations are not achieved until 2—3 days after initial application of the transdermal therapeutic system.

    Pheochromocytoma

    Clonidine is not expected to have a therapeutic effect on hypertension caused by pheochromocytoma.

    Geriatric

    Geriatric patients should be treated with caution because they are more likely to have decreased renal function and are more susceptible to the hypotensive and sedative effects of clonidine; dosage reduction of the normal initial adult dosage may be considered when used for hypertension. Data for the use of Duraclon (clonidine epidural injection) for pain management are limited in the elderly.There are no data to support efficacy and safety for the use of clonidine (Kapvay) in the treatment of adults with attention-deficit disorder (ADHD). According to the Beers Criteria, clonidine is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided as a first-line antihypertensive in this population due to the high risk of adverse CNS effects and the possibility of bradycardia or orthostatic hypotension. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. There are many drug interactions that can potentiate the effects of antihypertensives. Some agents, such as clonidine, require a gradual taper to avoid adverse consequences caused by abrupt discontinuation.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 0-4.0
    stroke / Early / 0-1.0
    angioedema / Rapid / 0-1.0
    ileus / Delayed / 0-1.0
    GI obstruction / Delayed / 0-1.0
    AV block / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 32.0-47.0
    hypotension / Rapid / 44.0-47.0
    confusion / Early / 13.0-38.0
    erythema / Early / 0.5-26.0
    constipation / Delayed / 1.0-10.0
    dyspnea / Early / 6.0-6.0
    chest pain (unspecified) / Early / 5.3-5.3
    hallucinations / Early / 5.0-5.0
    contact dermatitis / Delayed / 5.0-5.0
    urinary incontinence / Early / 0-4.0
    sinus tachycardia / Rapid / 0-3.0
    edema / Delayed / 0.5-3.0
    impotence (erectile dysfunction) / Delayed / 2.0-3.0
    hypoventilation / Rapid / 2.6-2.6
    depression / Delayed / 1.0-1.0
    hepatitis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 1.0-1.0
    parotitis / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    palpitations / Early / 0.5-0.5
    skin ulcer / Delayed / 0.5-0.5
    urinary retention / Early / 0.1-0.1
    fluid retention / Delayed / 0.1-0.1
    hyperesthesia / Delayed / Incidence not known
    delirium / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    blurred vision / Early / Incidence not known
    meningitis / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    xerostomia / Early / 0-40.0
    anxiety / Delayed / 38.0-38.0
    drowsiness / Early / 12.0-33.0
    pruritus / Rapid / 0.7-26.0
    headache / Early / 1.0-20.0
    infection / Delayed / 5.0-20.0
    dizziness / Early / 2.0-16.0
    fatigue / Early / 4.0-16.0
    abdominal pain / Early / 0-15.0
    nausea / Early / 1.0-13.0
    vomiting / Early / 5.0-10.5
    nightmares / Early / 4.0-9.0
    irritability / Delayed / 6.0-9.0
    vesicular rash / Delayed / 7.0-7.0
    insomnia / Early / 0.5-6.0
    anorexia / Delayed / 1.0-6.0
    diaphoresis / Early / 5.0-5.0
    skin hyperpigmentation / Delayed / 5.0-5.0
    tremor / Early / 1.0-4.0
    nasal congestion / Early / 2.0-4.0
    agitation / Early / 3.0-3.0
    lethargy / Early / 3.0-3.0
    libido decrease / Delayed / 3.0-3.0
    throat irritation / Early / 3.0-3.0
    emotional lability / Early / 2.0-2.0
    rash (unspecified) / Early / 1.0-2.0
    maculopapular rash / Early / 0-1.0
    nocturia / Early / 1.0-1.0
    gynecomastia / Delayed / 1.0-1.0
    dysgeusia / Early / 1.0-1.0
    nasal dryness / Early / 0-1.0
    urticaria / Rapid / 0.5-0.5
    alopecia / Delayed / 0.2-0.2
    weight gain / Delayed / 0.1-0.1
    paresthesias / Delayed / Incidence not known
    fever / Early / Incidence not known
    malaise / Early / Incidence not known
    restlessness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    syncope / Early / Incidence not known
    pallor / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    xerophthalmia / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Acetaminophen; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Acetazolamide: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Acrivastine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Albiglutide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Aldesleukin, IL-2: (Moderate) Antihypertensive agents may potentiate the hypotension seen with aldesleukin, IL-2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alogliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alogliptin; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alogliptin; Pioglitazone: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alpha-glucosidase Inhibitors: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alprazolam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and central-acting antihypertensive agents may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving central-acting adrenergic agents should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.
    Amiodarone: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate including amiodarone. Monitor for potential bradycardia or atrioventricular block during coadministration.
    Amitriptyline: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Amitriptyline; Chlordiazepoxide: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown. (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Amoxapine: (Major) Concurrent use of clonidine with amoxapine should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by cyclic antidepressants; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of amoxapine with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a cyclic antidepressant and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of a cyclic antidepressant (amitriptyline) with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Amphetamine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amphetamine; Dextroamphetamine Salts: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amphetamine; Dextroamphetamine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aripiprazole: (Minor) Due to aripiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Articaine; Epinephrine: (Major) Sympathomimetics, such as epinephrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with clonidine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with clonidine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Benzodiazepines: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Benzonatate: (Moderate) Epidural clonidine may prolong the duration of action of local anesthetics, including both sensory and motor blockade.
    Benzphetamine: (Major) Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of clonidine. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed.
    Beta-blockers: (Major) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., beta-blockers). Severe bradycardia resulting in hospitalization and pacemaker insertion has been reported during combination therapy with clonidine and other sympatholytic agents. Concomitant use of clonidine with beta-blockers can also cause additive hypotension. Beta-blockers should not be substituted for clonidine when modifications are made in a patient's antihypertensive regimen because beta-blocker administration during clonidine withdrawal can augment clonidine withdrawal, which may lead to a hypertensive crisis. If a beta-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with central-acting adrenergic agents (e.g., clonidine).
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Bromocriptine: (Minor) Bromocriptine has only minimal affinity for adrenergic receptors; however, hypotension can occur during bromocriptine administration. Orthostatic hypotension occurs in 6% of acromegaly patients receiving the drug. Hypotension occurred frequently (approximately 30%) in postpartum studies, which in rare cases approached a decline in supine pressure of almost 60 mmHg. It is unknown if bromocriptine is the exact cause of this effect. However, the drug should be used cautiously with other medications known to lower blood pressure such as antihypertensive agents. Monitoring of blood pressure should be considered, especially during the initial weeks of concomitant therapy. Bromocriptine suppresses prolactin secretion from the anterior pituitary gland; therefore, the reduction in prolactin levels resulting from bromocriptine administration may be antagonized by prolactin-enhancing antihypertensive medications such as methyldopa and reserpine.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Brompheniramine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Canagliflozin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbetapentane; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Carbinoxamine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Carbinoxamine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Carbonic anhydrase inhibitors: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Cardiac glycosides: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate such as cardiac glycosides.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ceritinib: (Major) Avoid coadministration of ceritinib with clonidine due to the risk of additive bradycardia. If unavoidable, monitor heart rate and blood pressure regularly. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary.
    Cetirizine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlordiazepoxide: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlorpheniramine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Chlorpromazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Clomipramine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Clonazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clorazepate: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in blood pressure in untreated hypertensive patients. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Codeine; Phenylephrine; Promethazine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Cyclobenzaprine: (Moderate) Cyclobenzaprine is structurally related to the tricyclic antidepressants and Clonidine's antihypertensive effect can be reduced by TCAs. Caution is warranted when combining cyclobenzaprine with clonidine.
    Cyclosporine: (Minor) Clonidine can inhibit cyclosporine-induced glomerular vasoconstriction and has been shown to offset cyclosporine-induced nephrotoxicity. Clonidine may adversely affect cyclosporine pharmacokinetics; limited data suggest that cyclosporine concentrations increase - dramatically, in some cases - when clonidine is added. Until more data are available, clinicians should use clonidine cautiously in patients stabilized on cyclosporine.
    Dapagliflozin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Dapagliflozin; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Dapagliflozin; Saxagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Under the influence of sympatholytic medicinal products such as clonidine, the signs and symptoms of hypoglycemia may be reduced or absent in patients taking antidiabetic agents. In addition, clonidine has been reported to either increase or reduce the blood glucose-lowering effect of antidiabetic agents. Monitor blood glucose.
    Desipramine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Desloratadine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as clonidine, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Dexmethylphenidate: (Moderate) Dexmethylphenidate can reduce the hypotensive effect of antihypertensive agents, including clonidine. Periodic evaluation of blood pressure is advisable during concurrent use of dexmethylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of dexmethylphenidate.
    Dextroamphetamine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents. Diazoxide can enhance the hyperglycemic, hyperuricemic and antihypertensive effects of thiazide diuretics.
    Diclofenac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diclofenac; Misoprostol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diethylpropion: (Major) Sympathomimetics, such as diethylpropion, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Diflunisal: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Digitoxin: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate such as cardiac glycosides.
    Digoxin: (Moderate) Clonidine can produce bradycardia and should be used cautiously in patients who are receiving other drugs that lower the heart rate such as cardiac glycosides.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Diltiazem: (Moderate) Monitor heart rate in patients receiving concomitant clonidine and agents known to affect sinus node function or AV nodal conduction (e.g., diltiazem). Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Diphenhydramine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diphenhydramine; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Diphenhydramine; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Dobutamine: (Major) Sympathomimetics, such as dobutamine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Dopamine: (Major) Sympathomimetics, such as dopamine, can antagonize the antihypertensive effects of clonidine when administered concomitantly.Patients should be monitored for loss of blood pressure control.
    Doxepin: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Dulaglutide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Empagliflozin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Empagliflozin; Linagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Empagliflozin; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Ephedrine: (Major) Sympathomimetics, such as ephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly.Patients should be monitored for loss of blood pressure control.
    Epinephrine: (Major) Sympathomimetics, such as epinephrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Epoprostenol: (Moderate) The concomitant administration of epoprostenol with other antihypertensive agents can result in additive hypotensive effects. This can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Esomeprazole; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Estazolam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethanol: (Major) Advise patients to avoid or limit alcohol use while taking clonidine. Clonidine may potentiate the CNS-depressive effects of alcohol. Watch for an enhancement of hypotensive effects as well as orthostatic hypotension, dizziness, or fatigue may be induced or exacerbated.
    Etodolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Exenatide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Famotidine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fenoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fexofenadine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Fluphenazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Flurazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Flurbiprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Glipizide; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Glyburide; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Guaifenesin; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Guaifenesin; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Haloperidol: (Moderate) Disturbances of orthostatic regulation (e.g., orthostatic hypotension, dizziness, fatigue) and additive sedation may occur in patients receiving concomitant clonidine and antipsychotics. Also, based on observations in patients in a state of alcoholic delirium, high intravenous doses of clonidine may increase the arrhythmogenic potential (QT prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. A causal relationship and relevance for clonidine oral tablets have not been established.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrocodone; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Hydrocodone; Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Hydrocodone; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Oxycodone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Imipramine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Incretin Mimetics: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Indomethacin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Insulin Degludec; Liraglutide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Insulin Glargine; Lixisenatide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Insulins: (Moderate) Monitor patients receiving insulin closely for changes in glycemic control when clonidine is instituted. Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Isoproterenol: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Ketoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Ketorolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Lansoprazole; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of clonidine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of clonidine, a centrally-acting antihypertensive that decreases noradrenergic activity. Use of another antidepressant would be preferable in patients taking clonidine.
    Linagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Linagliptin; Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents, and may also mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Liraglutide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Lisdexamfetamine: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Lixisenatide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving this combination should be monitored for changes in glycemic control.
    Loratadine; Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Lorazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Maprotiline: (Major) Concurrent use of clonidine with maprotiline should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by cyclic antidepressants, such as maprotiline. If coadministration of maprotiline with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed.
    Meclofenamate Sodium: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mefenamic Acid: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Meglitinides: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Mesoridazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Metformin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Metformin; Pioglitazone: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Metformin; Repaglinide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Metformin; Rosiglitazone: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Metformin; Saxagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Under the influence of sympatholytic medicinal products such as clonidine, the signs and symptoms of hypoglycemia may be reduced or absent in patients taking antidiabetic agents. In addition, clonidine has been reported to either increase or reduce the blood glucose-lowering effect of antidiabetic agents. Monitor blood glucose.
    Metformin; Sitagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Methamphetamine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Methazolamide: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Methylphenidate: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including clonidine. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and clonidine, particularly during initial coadministration and after dosage increases of methylphenidate.
    Midazolam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Midodrine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Miglitol: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Milnacipran: (Major) Milnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of milnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because milnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of centrally-acting alpha-2 agonists such as clonidine. Use of another antidepressant would be preferable in patients taking clonidine.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mirtazapine: (Major) Clonidine stimulates central alpha-2 adrenergic receptors. Mirtazapine is known to have inhibitory effects on these same receptors. Mirtazapine may antagonize the antihypertensive and other pharmacologic effects of clonidine. Use of another antidepressant would be preferable in patients taking clonidine.
    Monoamine oxidase inhibitors: (Severe) Monoamine oxidase inhibitors (MAOIs) may interact with antihypertensive medications. If a patient receiving an MAOI is started on clonidine, severe hypertension may occur, and this reaction may be followed by hypotension, which may be severe. Additionally, if a patient is withdrawn from clonidine, an excess of circulating catecholamines may occur. The clinician should use these agents together with caution; blood pressure should be monitored frequently.
    Nabumetone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Naproxen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Naproxen; Sumatriptan: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Nateglinide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Norepinephrine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Nortriptyline: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Opiate Agonists: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Oxaprozin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Oxazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by clonidine. If these drugs are used together, closely monitor for changes in blood pressure.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perphenazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Perphenazine; Amitriptyline: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown. (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Phendimetrazine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Phenothiazines: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Phentermine: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Phentermine; Topiramate: (Major) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Phenylephrine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Phenylephrine; Promethazine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Pimozide: (Moderate) Disturbances of orthostatic regulation (e.g., orthostatic hypotension, dizziness, fatigue) and additive sedation may be induced or exacerbated in patients receiving concomitant clonidine and antipsychotics. Caution patients to avoid hazardous tasks, such as driving or operating machinery, until the effects of concurrent use are known. Also, based on observations in patients in a state of alcoholic delirium, it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. A causal relationship and relevance for clonidine oral tablets have not been established.
    Piroxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Pramlintide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. While clonidine has not been shown to significantly impair glucose tolerance in most human studies, patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Prilocaine; Epinephrine: (Major) Sympathomimetics, such as epinephrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Prochlorperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Protriptyline: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Pseudoephedrine: (Moderate) Sympathomimetics, such as pseudoephedrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Quazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Quetiapine: (Moderate) Disturbances of orthostatic regulation (e.g., orthostatic hypotension, dizziness, fatigue) and additive sedation may be induced or exacerbated in patients receiving concomitant clonidine and antipsychotics. Caution patients to avoid hazardous tasks, such as driving or operating machinery, until the effects of concurrent use are known. Also, based on observations in patients in a state of alcoholic delirium, it has been suggested that high intravenous doses of clonidine may increase the arrhythmogenic potential (QT prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. A causal relationship and relevance for clonidine oral tablets have not been established.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Rasagiline: (Moderate) Orthostatic hypotension has been reported during administration of rasagiline; caution is advised during concurrent use with antihypertensive agents. Patients receiving rasagiline in combination with an antihypertensive should be instructed to rise slowly from a sitting position, and to report syncope, and changes in heart rate or blood pressure to their health care provider. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious hypertensive reactions with agents affecting catecholamine release (e.g., guanabenz, reserpine, guanethidine) are unlikely.
    Repaglinide: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritodrine: (Major) Sympathomimetics, such as ritodrine, can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Rofecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Saxagliptin: (Moderate) Under the influence of sympatholytic medicinal products such as clonidine, the signs and symptoms of hypoglycemia may be reduced or absent in patients taking antidiabetic agents. In addition, clonidine has been reported to either increase or reduce the blood glucose-lowering effect of antidiabetic agents. Monitor blood glucose.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Simvastatin; Sitagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Sitagliptin: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Sulfonylureas: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Sulindac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Temazepam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiazolidinediones: (Moderate) Clonidine may potentiate or weaken the hypoglycemic effects of antidiabetic agents and may mask the signs and symptoms of hypoglycemia. Patients receiving clonidine concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Thiethylperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Thioridazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolmetin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Trandolapril; Verapamil: (Moderate) Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil. Monitor heart rate in patients receiving concomitant clonidine and verapamil which is known to affect sinus node function or AV nodal conduction.
    Trazodone: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    Triazolam: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Tricyclic antidepressants: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Trifluoperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Trimipramine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Valdecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
    Verapamil: (Moderate) Complete AV block resulting in a nodal rhythm and sinus bradycardia resulting in hospitalization and pacemaker insertion have been reported during combination therapy of clonidine with diltiazem or verapamil. Monitor heart rate in patients receiving concomitant clonidine and verapamil which is known to affect sinus node function or AV nodal conduction.
    Yohimbine: (Major) Yohimbine is a selective alpha 2-adrenoceptor antagonist. This pharmacologic action is the direct opposite of clonidine. Therefore, yohimbine should not be administered to patients stabilized on clonidine.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Adequate and well-controlled studies of clonidine have not been performed during pregnancy in humans. Risk-benefit should be considered before use in pregnant patients; use only if clearly needed. One study found that clonidine crosses the placenta easily, and its concentrations were equal in maternal serum and umbilical cord serum and amniotic fluid concentrations were up to 4 times that found in serum. There is one case report suggesting that fetuses who are exposed to long-term clonidine (more than 300 mcg/day) during pregnancy may be more likely to develop sleep disorders later in life. The manufacturer does not recommend the use of epidural clonidine as an analgesic during labor and obstetric delivery, or for post-partum or peri-operative analgesia due to the risks of hemodynamic instability, especially hypotension and bradycardia. However, potential benefits of clonidine may outweigh the possible risks in a rare obstetrical, post-partum, or perioperative patient. Several trials examining the efficacy, safety, or dosing of epidural clonidine in obstetrics have been reported. In a study comparing epidural clonidine combined with bupivacaine and bupivacaine alone for analgesia during labor, there was no difference in maternal blood pressure decreases and Apgar scores at 1 and 5 minutes between the two groups. The duration of labor was prolonged in patients receiving clonidine.

    MECHANISM OF ACTION

    Clonidine is an agonist at presynaptic alpha2-receptors in the medulla, specifically, the nucleus tractus solitarius (i.e., the depressor area of the vasomotor center of the medulla oblongata). Stimulation of these receptors results in the inhibition of sympathetic outflow and tone. Suppression of efferent sympathetic pathways decreases vascular tone in the heart, kidneys, and peripheral vasculature; lowers peripheral resistance; and reduces blood pressure. Reflex tachycardia usually does not occur. Instead, stimulation of the central alpha-receptors by clonidine results in a reciprocal increase in vagal tone, causing an increase in baroreceptor activity and bradycardia. Clonidine is also a partial agonist at presynaptic alpha2-adrenergic receptors of peripheral nerves in vascular smooth muscle, however, this site of action contributes little, if anything, to its antihypertensive effects. Doses higher than those required to lower blood pressure are necessary to demonstrate agonism at this peripheral site. Further, it has been shown that alpha2-agonists that cannot penetrate the blood-brain barrier do not effectively lower blood pressure. Agonism at peripheral presynaptic alpha2-receptors may interfere with the peripheral regulation of norepinephrine.
     
    Intravenous administration or large oral doses of clonidine also can stimulate alpha1-receptors in peripheral vascular smooth muscle, resulting in acute vasoconstriction and a transient increase in blood pressure. An accurate correlation between clonidine's plasma concentrations and its antihypertensive effects is evident only at lower plasma concentrations. Higher plasma concentrations of clonidine will result in reduced antihypertensive activity because of the increased contribution of the pressor effect.
     
    Inhibition of sympathetic outflow by clonidine results in a variety of pharmacodynamic effects. In the supine position, decreased sympathetic tone reduces heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV), with essentially no change in the total peripheral resistance (TPR), renal blood flow (RBF), renal plasma flow (RPF), glomerular filtration rate (GFR), urinary potassium excretion, or renal vascular resistance (RVR). Urinary sodium and chloride excretion are increased, however. Thus, the principal antihypertensive effect in the supine position is related to the reduction in cardiac output secondary to the reduced stroke volume and heart rate.
     
    In the erect position (45-degree tilt), clonidine reduces MAP, CO, HR, and TPR, with no significant change in stroke volume. Cardiac output due to clonidine decreases less in hypertensive patients than in normal patients, and the antihypertensive effects of the drug appear to be related to a reduction in both cardiac output and TPR, with the effects of the reduced TPR predominating in the erect position. Renin and aldosterone output are reduced. Clonidine appears to decrease catecholamine excretion during prolonged therapy, but it does not deplete catecholamine stores. As an antihypertensive, clonidine reduces LVH and does not cause detrimental effects on glucose tolerance, although sexual dysfunction is a significant problem.
     
    Clonidine is used to treat hypertension and the subsequent decline of renal function in patients with scleroderma renal crisis (SRC). SRC is associated with elevated peripheral renin concentrations. Clonidine reduces plasma renin activity by reducing sympathetic activity while increasing parasympathetic activity.
     
    Because of clonidine's ability to inhibit sympathetic outflow, it has been used successfully to manage withdrawal from opiate agonists, ethanol, or nicotine; and 'hot flashes' associated with menopause. By inhibiting intrarenal vasoconstriction, clonidine has been used to offset cyclosporine-induced nephrotoxicity. Since pheochromocytomas are not under neurologic control, clonidine has been used successfully to differentiate the presence of these tumors from other hypertension-associated disease states.
     
    Clonidine administered epidurally produces a dose-dependent analgesia that is not antagonized by opiate antagonists. By preventing pain signal transmission to the brain, clonidine produces analgesia at presynaptic and postjunctional alpha2-adrenoceptors in the spinal cord. Yohimbine, an alpha2-adrenoreceptor antagonist, will partially reverse the analgesic and sedation effects of epidural clonidine with no effect on clonidine-induced changes in blood pressure or heart rate. Clonidine-induced analgesia occurs only in body regions innervated by spinal segments where analgesic concentrations of clonidine are present. Clonidine enhances epidural or peripheral nerve blocks by blocking the conduction of C and A delta fibers and increasing potassium conductance in neurons and causing local vasoconstriction decreasing the elimination of the local anesthetic.

    PHARMACOKINETICS

    Clonidine is administered epidurally, orally, and via transdermal patch. Fifty percent (50%) of a circulating dose is metabolized in the liver to inactive compounds. Unchanged drug (40—60%) and its metabolites are excreted in the urine and feces.
     
    Affected cytochrome P450 isoenzymes: none

    Oral Route

    Immediate- and extended-release clonidine have different pharmacokinetics characteristics; dose substitution on a mg-for-mg basis will result in differences in exposure. Food does not influence the pharmacokinetics of oral clonidine. The pharmacokinetics of clonidine are dose-proportional in the range of 100—600 mcg. Elimination half-life of clonidine is approximately 12—16 hours.
     
    Immediate-release (IR) formulations
    After oral administration of IR formulation, peak plasma concentrations are reached in approximately 1—5 hours. The absolute oral bioavailability is 70—80%. Blood pressure begins to decrease within 30—60 minutes, with maximal hypotensive effects occurring in 2—4 hours. Mean single-dose pharmacokinetic parameters in healthy adult patients (fasted-state; n = 15) during clinical trials were as follows: Cmax = 443 pg/mL; AUC = 7313 hour x pg/mL; Tmax = 2.07 hours; half-life = 12.57 hours.
     
    Extended-release (ER) formulations
    After oral administration of ER formulation, peak clonidine concentrations were approximately 50% of those achieved with the IR formulation and occurred approximately 5 hours later. Similar half-lives were observed and total systemic bioavailability after the ER formulation was approximately 89% of that following the IR formulation. Mean single-dose pharmacokinetic parameters in healthy adult patients (fasted-state; n = 14) during clinical were as follows: Cmax = 258 pg/mL; AUC = 6729 hour x pg/mL; Tmax = 6.5 hours; half-life = 12.65 hours.

    Other Route(s)

    Transdermal Route
    The clonidine transdermal system consists of a patch, or 0.2 mm thick film, that contains four layers of a microporous polypropylene membrane. This patch holds a reservoir of clonidine that is released and absorbed across the skin at a constant rate over a 7-day period. The absolute bioavailability of clonidine from the transdermal patch is approximately 60%. Steady-state clonidine plasma concentrations are reached within 3 days after transdermal application to the upper outer arm and increase linearly with increasing size of the transdermal patch. Mean steady-state plasma concentrations with the 3.5 cm2 (0.1 mg clonidine/day), 7 cm2 (0.2 mg clonidine/day) and 10.5 cm2 (0.3 mg clonidine/day) systems are approximately 0.4 ng/mL, 0.8 ng/mL, and 1.1 ng/mL, respectively. Similar clonidine steady-state concentrations are reached after application to the chest. Steady-state clonidine plasma levels remain constant after removal of one system and application of a new system of the same size. After removal of the transdermal system, clonidine plasma concentrations decline slowly with a half-life of approximately 20 hours.
     
    Epidural Route
    Following epidural administration, peak clonidine plasma and cerebrospinal fluid concentrations were achieved in 19 and 26 minutes, respectively. Epidurally administered clonidine distributes into plasma via the epidural veins. Clonidine is highly lipid soluble and distributes widely throughout the body tissues, including the central nervous system. The CSF elimination half-life of clonidine is 1.3 hours. After an epidural dose of clonidine, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak concentration of clonidine in the plasma and CSF compared to men. The pharmacokinetics of epidural clonidine in children 1—9 years of age is similar to adults.