Nexiclon XR

1 INDICATIONS AND USAGE NEXICLON XR is indicated in the treatment of hypertension. NEXICLON XR may be employed alone or concomitantly with other antihypertensive agents. NEXICLON XR is a central alpha-adrenergic agonist indicated for: Treatment of hypertension ( 1 )

2 DOSAGE AND ADMINISTRATION The dose of NEXICLON XR must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration in adults. Initial dose: 0.17 mg once daily. Elderly patients may benefit from a lower initial dose. Initial dose is recommended to be administered at bedtime. ( 2.1 ) Maintenance dose: Further increments of 0.09 mg once daily 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. ( 2.2 ) Patients with renal impairment: Up-titrate slowly (2.4) 2.1 Initial Dose Dosing with NEXICLON XR should be initiated at 0.17 mg once daily. Elderly patients may benefit from a lower initial dose [ see Use in Specific Populations (8.4) ]. Initial dose is recommended to be administered at bedtime. 2.2 Maintenance Dose Further increments of 0.09 mg once daily 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. NEXICLON XR was 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 NEXICLON XR for patients who are currently taking clonidine hydrochloride immediate-release tablets is provided in the table below. NEXICLON XR (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.

4 CONTRAINDICATIONS NEXICLON XR should not be used in patients with known hypersensitivity to clonidine [ see Warnings and Precautions (5.2) ]. Known hypersensitivity to clonidine (rash, angioedema) (4)

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, NEXICLON XR 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 NEXICLON XR, reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms. An excessive rise in blood pressure following discontinuation of NEXICLON XR 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 NEXICLON XR. 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 NEXICLON XR 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.

7 DRUG INTERACTIONS No drug interaction studies have been conducted with NEXICLON XR. The following have been reported with other oral formulations of clonidine. 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. 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 Nonclinical Toxicology (13.2) ]. Alcohol: Based on in vitro studies, high concentration of alcohol may increase the rate of release of NEXICLON XR. 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 )

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 NEXICLON XR 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 Athena Bioscience LLC at 1-833-874-2664 and www.athenabioscience.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 NEXICLON XR Clinical Trial Experience There is very limited experience with NEXICLON XR 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.