Clonidine Hydrochloride

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

• Withdrawal:
• Patients should be instructed not to discontinue therapy without consulting their physician.
• Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.
• The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations.
• Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal.
• When discontinuing therapy with clonidine hydrochloride tablets, the physician should reduce the dose gradually over 2 to 4 days to
• avoid withdrawal symptomatology.
• An excessive rise in blood pressure following discontinuation of clonidine hydrochloride tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine.
• If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine hydrochloride tablets.
• Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.
• General:
• In patients who have developed localized contact sensitization to transdermal clonidine, continuation of transdermal clonidine or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.
• In patients who develop an allergic reaction to transdermal clonidine, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).
• The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.
• There are postmarketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol and temporary cardiac pacing while taking clonidine.
• In hypertension caused by pheochromocytoma, no therapeutic effect of clonidine hydrochloride tablets can be expected.
• Perioperative Use:
• Administration of clonidine hydrochloride tablets should be continued to within 4 hours of surgery and resumed as soon as possible thereafter.
• Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required.
• Information for Patients:
• Patients should be cautioned against interruption of clonidine hydrochloride tablets therapy without their physician’s advice.
• Since patients may experience a possible sedative effect, dizziness, or accommodation disorder with use of clonidine, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.
• Also, inform patients that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.
• Patients who wear contact lenses should be cautioned that treatment with clonidine hydrochloride tablets may cause dryness of eyes.
• 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.
• Carcinogenesis, Mutagenesis, Impairment of Fertility:
• Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m 2 basis).
• There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.
• Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times MRDHD).
• In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 mcg/kg to 2,000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m 2 basis).
• Pregnancy Teratogenic Effects Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride tablets produced no evidence of a teratogenic or embryotoxic potential in rabbits.
• In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m 2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating.
• Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15.
• Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m 2 basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 mcg/kg).
• No adequate, well-controlled studies have been conducted in pregnant women.
• Clonidine crosses the placental barrier (see CLINICAL PHARMACOLOGY, Pharmacokinetics ).
• Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
• Nursing Mothers:
• As clonidine hydrochloride is excreted in human milk, caution should be exercised when clonidine hydrochloride tablets are administered to a nursing woman.
• Pediatric Use:
• Safety and effectiveness in pediatric patients have not been established in adequate and well-controlled trials (see WARNINGS, Withdrawal ).

• 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.