Clonidine Hydrochloride

INDICATIONS AND USAGE Clonidine hydrochloride tablets, USP are indicated in the treatment of hypertension. Clonidine hydrochloride tablets, USP may be employed alone or concomitantly with other antihypertensive agents.

DOSAGE AND ADMINISTRATION Adults The dose of clonidine hydrochloride tablets, USP must be adjusted according to the patient’s individual blood pressure response. The following is a general guide to its administration. Initial Dose 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. Maintenance Dose Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. Renal Impairment Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

Adults The dose of clonidine hydrochloride tablets, USP must be adjusted according to the patient’s individual blood pressure response. The following is a general guide to its administration.

Initial Dose 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.

Maintenance Dose Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.

Renal Impairment Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

CONTRAINDICATIONS Clonidine hydrochloride tablets, USP should not be used in patients with known hypersensitivity to clonidine (see PRECAUTIONS ).

ADVERSE REACTIONS Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine hydrochloride tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established. Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol. Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares. Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria. Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting. Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention. Hematologic: Thrombocytopenia. Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. Musculoskeletal: Leg cramps and muscle or joint pain. Oro-otolaryngeal: Dryness of the nasal mucosa. Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Drug Interactions: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated. Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology ). 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. Causal relationship and relevance for clonidine oral tablets have not been established. Toxicology: In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

DESCRIPTION Clonidine hydrochloride, USP is a centrally acting alpha-agonist hypotensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base. The inactive ingredients are dibasic calcium phosphate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate. The clonidine hydrochloride tablets 0.2 mg and 0.3 mg also contains FD&C Yellow #6 aluminum lake. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. This is an image of the structural formula for clonidine hydrochloride.

Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula: Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol. This is an image of the structural formula for clonidine hydrochloride.

OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD 50 of clonidine is 206 and 465 mg/kg, respectively.

HOW SUPPLIED Clonidine Hydrochloride Tablets, USP are supplied as: 0.1 mg White round shaped, biconvex, scored tablets, debossed with "U" and "135" on either side of breakline on one side and plain on other side. Bottles of 30: NDC 87063-181-30 (repackaged from NDC 29300-468-XX) Bottles of 60: NDC 87063-181-60 (repackaged from NDC 29300-468-XX) Bottles of 90: NDC 87063-181-90 (repackaged from NDC 29300-468-XX) Bottles of 100: NDC 87063-181-01 (relabeled from NDC 29300-468-01) Bottles of 120: NDC 87063-181-12 (repackaged from NDC 29300-468-XX) 0.2 mg White rounded off oval shaped, biconvex tablets, with score line having "U" and "136" debossed across the score line on one side and plain on other side. Bottles of 30: NDC 87063-182-30 (repackaged from NDC 29300-136-XX) Bottles of 60: NDC 87063-182-60 (repackaged from NDC 29300-136-XX) Bottles of 90: NDC 87063-182-90 (repackaged from NDC 29300-136-XX) Bottles of 100: NDC 87063-182-01 (relabeled from NDC 29300-136-01) Bottles of 120: NDC 87063-182-12 (repackaged from NDC 29300-136-XX) 0.3 mg White rounded off oval shaped, biconvex tablets with score line having "U" and "137" debossed across the score line on one side and plain on other side. Bottles of 30: NDC 87063-183-30 (repackaged from NDC 29300-137-XX) Bottles of 60: NDC 87063-183-60 (repackaged from NDC 29300-137-XX) Bottles of 90: NDC 87063-183-90 (repackaged from NDC 29300-137-XX) Bottles of 100: NDC 87063-183-01 (relabeled from NDC 29300-137-01) Bottles of 120: NDC 87063-183-12 (repackaged from NDC 29300-137-XX) Store at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. Please address medical inquiries to Unichem's toll free # 1-866-562-4616. Relabeled and Repackaged by: Enovachem PHARMACEUTICALS Torrance, CA 90501