Clonidine

5 WARNINGS AND PRECAUTIONS Patients should not discontinue therapy without consulting a physician. Dose reduction should be performed gradually over a 2- to 4-day period to avoid withdrawal symptomatology. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. ( 5.1 ) Monitor closely and up-titrate slowly in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure. ( 5.2 ) Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. ( 5.2 ) In perioperative use, clonidine extended-release tablets may be administered up to 28 hours prior to surgery and resumed the following day. ( 5.3 ) 5.1 Withdrawal Instruct patients not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has 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 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is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine extended-release tablets.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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in detail elsewhere in the labeling: Withdrawal [ see Warnings and Precautions (5.1) ] Allergic reactions [ see Warnings and Precautions (5.2) ] There is very little experience with clonidine extended-release tablets in controlled trials. Based on this limited experience, the adverse event profile appears similar with the immediate-release clonidine formulation. The most commonly expected adverse reactions are dry mouth, drowsiness, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 1-877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clonidine Extended-Release Tablets Clinical Trial Experience There is very limited experience with clonidine extended-release tablets in controlled trials. Based on this limited experience, the adverse event profile appears similar with to the immediate-release clonidine formulation. 6.2 Experience with Immediate-Release 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy Category C ( 8.1 ) Clonidine is secreted in human milk. ( 8.2 ) Safety and effectiveness in children have not been established. ( 8.3 ) Renal impairment: Dose may need adjustment. ( 2.4 ) 8.1 Pregnancy Pregnancy Category C. Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride 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. 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.

10 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.