on in vitro studies, high concentration of alcohol may increase the rate of release of clonidine extended-release tablets. sedating drugs: clonidine may potentiate the cns-depressive effects of alcohol, barbiturates or other sedating drugs. ( 7 ) tricyclic antidepressants: may reduce the hypotensive effect of clonidine, necessitating an increase in clonidine dose. ( 7 ) drugs known to affect sinus node function or av nodal conduction (e.g., digitalis, calcium channel blockers, beta-blockers): additive effects such as bradycardia and av block. ( 7 )

esulted 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 extended-release tablets, reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. an excessive rise in blood pressure following discontinuation of clonidine extended-release tablets 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is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine extended-release tablets.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. 5.2 general precautions in patients who have developed localized contact sensitization to a clonidine transdermal system, substitution of oral clonidine therapy may be associated with the development of a generalized skin rash. in patients who develop an allergic reaction to a clonidine transdermal system, substitution of oral clonidine may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). monitor carefully and up-titrate slowly in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure. patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. the sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs. 5.3 perioperative use clonidine extended-release tablets may be administered up to 28 hours prior to surgery and resumed the following day. blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required.

aily may be made at weekly intervals if necessary until the desired response is achieved. the therapeutic doses most commonly employed have ranged from 0.17 mg to 0.52 mg once daily. clonidine extended-release tablets were studied at doses of 0.17 to 0.52 mg once daily. doses higher than 0.52 mg per day were not evaluated and are not recommended. 2.3 patients currently using clonidine hydrochloride immediate-release tablets the recommended dose of clonidine extended-release tablets for patients who are currently taking clonidine hydrochloride immediate-release tablets is provided in the table below. clonidine extended-release tablets equivalent dose of clonidine hcl immediate-release tablets initial dose 0.17 mg once daily 0.1 mg twice daily maintenance dose titration increments 0.09 mg once daily 0.05 mg twice daily common doses used for blood pressure effect 0.17 mg once daily 0.1 mg twice daily 0.34 mg once daily 0.2 mg twice daily 0.52 mg once daily 0.3 mg twice daily 2.4 renal impairment adjust dosage according to the degree of impairment. in patients with end stage kidney disease on maintenance dialysis, start at 0.09 mg per day and up-titrate slowly to minimize dose related adverse events. monitor patients carefully, especially for bradycardia, sedation and hypotension. only a minimal amount of clonidine is removed during routine hemodialysis. in patients with moderate to severe kidney impairment not undergoing dialysis, initiate clonidine at the same dose as for patients without renal impairment. up-titrate slowly and monitor for dose-related adverse events.

lease clonidine most adverse reactions are mild and tend to diminish with continued therapy. the most frequent (which also appear to be dose-related) are dry mouth (approximately 40%); drowsiness (approximately 33%); dizziness (approximately 16%); constipation and sedation (approximately 10% each). the following less frequent adverse reactions have also been reported in patients receiving immediate-release clonidine, 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 (cns): 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.

on in vitro studies, high concentration of alcohol may increase the rate of release of clonidine extended-release tablets. sedating drugs: clonidine may potentiate the cns-depressive effects of alcohol, barbiturates or other sedating drugs. ( 7 ) tricyclic antidepressants: may reduce the hypotensive effect of clonidine, necessitating an increase in clonidine dose. ( 7 ) drugs known to affect sinus node function or av nodal conduction (e.g., digitalis, calcium channel blockers, beta-blockers): additive effects such as bradycardia and av block. ( 7 )

n 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. because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.2 nursing mothers clonidine is secreted in human milk. 8.3 pediatric use safety and effectiveness in pediatric patients have not been established. 8.4 geriatric use elderly patients may benefit from a lower initial dose [ see dosage and administration (2) ]. 8.5 patients with renal impairment the initial dosage should be based on the degree of impairment. monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. only a minimal amount of clonidine is removed during routine hemodialysis.

e was no washout period between phases or treatments. studies with immediate-release clonidine hydrochloride have demonstrated a moderate reduction (15% to 20%) in cardiac output in the supine position with no change in the peripheral resistance. at a 45° tilt, there is a smaller reduction in cardiac output and a decrease of peripheral resistance. during long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise. tolerance to the antihypertensive effect may develop in some patients, necessitating a re-evaluation of therapy. other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. the exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated. clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use. 12.3 pharmacokinetics following single doses of clonidine extended-release tablets 0.17 mg, clonidine mean (s.d.) peak plasma concentrations of 0.49 (±0.09) ng/ml occurred at 7.8 (±1.7) hours. the plasma half-life of clonidine was 13.7 (±3.0) hours. there was no effect of food on the pharmacokinetic parameters. a = clonidine extended-release tablets (0.17 mg qd) fasted b = clonidine ir tablet (0.1 mg clonidine hydrochloride q12h) fasted c = clonidine extended-release tablets (0.17 mg qd) fed in the multi-dose study, mild to moderate hypertensive patients were randomized to er and bid ir clonidine formulations. the following plot shows the sitting blood pressure values for each treatment group at day 22. the half-life may increase up to 41 hours in patients with severe impairment of renal function. following oral administration of clonidine about 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. about 50% of the absorbed dose is metabolized in the liver. figure1 figure2

onths 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.