QLONILIK

5 WARNINGS AND PRECAUTIONS QLONILIK can cause bradycardia, cardiac conduction abnormalities, and symptomatic hypotension. ( 5.1 ) Abrupt discontinuation of QLONILIK can cause rebound hypertension with elevated plasma catecholamines, especially with higher doses or concomitant beta-blocker use. Symptoms of abrupt discontinuation include tachycardia, rapid blood pressure elevation, headache, nervousness, and agitation. ( 5.2 ) QLONILIK may cause sedation. Advise patients who engage in potentially hazardous activities, such as operating machinery or driving, of possible sedative effects. Avoid use with other central nervous system (CNS) depressants ( 5.3 ) 5.1 Bradycardia, Cardiac Conduction Abnormalities, and Symptomatic Hypotension Treatment with QLONILIK can cause bradycardia, cardiac conduction abnormalities, and symptomatic hypotension [see Adverse Reactions (6.1) ]. The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There have been post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring intravenous (IV) atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate QLONILIK slowly in patients with a history of syncope, cardiac conduction abnormalities, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. Monitor blood pressure and heart rate and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Avoid the use of drugs that can affect the sinus node function or AV node conduction [see Drug Interactions (7) ]. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as symptomatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. 5.2 Rebound Hypertension Abrupt discontinuation of QLONILIK can cause rebound hypertension with elevated plasma catecholamines, especially with higher doses or concomitant beta-blocker use. Symptoms of abrupt discontinuation include tachycardia, rapid blood pressure elevation, headache, nervousness, and agitation. Serious cases of hypertensive encephalopathy, stroke, and death have been reported after abrupt clonidine discontinuation. To reduce the risk of rebound hypertension, taper clonidine gradually over 2-4 days. If rebound hypertension occurs, reverse hypertensive crisis with oral clonidine or IV phentolamine. When discontinuing concurrent beta-blocker therapy, withdraw the beta-blocker several days before beginning clonidine taper. Administration of QLONILIK should be continued up to 4 hours before 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. 5.3 Sedation and Somnolence QLONILIK may cause sedation. Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of possible sedative effects of clonidine. Avoid use with other central nervous system (CNS) depressants, as this combination may cause excessive drowsiness or sedation [see Drug Interactions (7) ].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth (40%), drowsiness (33%); dizziness (16%); constipation and sedation (10%, respectively). 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, headache, pallor, malaise, weakness, and withdrawal syndrome. Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, syncope, and tachycardia. Central Nervous System: Agitation, anxiety, delirium, hallucinations (including visual and auditory), insomnia, mental depression, behavioral changes, paresthesia, sleep disorder, and vivid dreams or nightmares. Gastrointestinal: Anorexia, constipation, nausea, and vomiting. Hematologic: Thrombocytopenia. Hepatobiliary: Hepatitis and transaminitis. Hypersensitivity: Angioedema, hives, pruritus, rash, and urticaria. Metabolic: Transient elevation of blood glucose or serum creatine phosphokinase, and weight gain. Musculoskeletal: Leg cramps and muscle or joint pain. Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes. Renal and Urinary: Difficulty in micturition, nocturia, and urinary retention. Reproductive System and Breast Disorders: Gynecomastia. erectile dysfunction, and loss of libido. Vascular: Raynaud’s phenomenon. Most common adverse reactions are dry mouth, drowsiness, dizziness, constipation and sedation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma, Inc. at 1-844-321-1443 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.