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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypotension/bradycardia/syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated. Advise patients to avoid becoming dehydrated or overheated. ( 5.1 ) Somnolence/Sedation: Has been observed with clonidine HCl extended-release. Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to clonidine HCl extended-release. ( 5.2 ) Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently. ( 5.5 ) 5.1 Hypotension/Bradycardia Treatment with clonidine HCl extended-release can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1) ] . Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate clonidine HCl extended-release slowly in patients with a history of hypotension, 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. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. 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. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine HCl extended-release+stimulant versus 7% treated with placebo+stimulant reported somnolence. Before using clonidine HCl extended-release with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with clonidine HCl extended-release. Advise patients to avoid use with alcohol. 5.3 Rebound Hypertension Abrupt discontinuation of clonidine HCl extended-release can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine 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. No studies evaluating abrupt discontinuation of clonidine HCl extended-release in children with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of clonidine HCl extended-release in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue clonidine HCl extended-release therapy without consulting their physician due to the potential risk of withdrawal effects. 5.4 Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine HCl extended-release therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine HCl extended-release may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). 5.5 Cardiac Conduction Abnormalities 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 IV atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate clonidine HCl extended-release slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.
6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia [see Warnings and Precautions (5.1) ] Sedation and somnolence [see Warnings and Precautions (5.2) ] Rebound hypertension [see Warnings and Precautions (5.3) ] Allergic reactions [see Warnings and Precautions (5.4) ] Cardiac Conduction Abnormalities [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth. ( 6.1 ) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience 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. Two clonidine HCl extended-release ADHD clinical studies (Study 1, CLON-301 and Study 2, CLON-302) evaluated 256 patients in two 8-week placebo-controlled studies. A third clonidine HCl extended-release ADHD clinical study (Study 3, SHN-KAP-401) evaluated 135 children and adolescents in a 40- week placebo-controlled randomized-withdrawal study. Study 1: Fixed-dose Clonidine HCl Extended-Release Monotherapy Study 1 (CLON-301) was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine HCl extended-release in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Events Leading to Discontinuation of C lonidine HCl Extended-Release – Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation. The most common adverse reactions that led to discontinuation were somnolence and fatigue. Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2. Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Treatment Period (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine HCl Extended-Release 0.2 mg/day N=76 Clonidine HCl Extended-Release 0.4 mg/day N=78 Placebo (N=76) PSYCHIATRIC DISORDERS Somnolence * Nightmare Emotional Disorder Aggression Tearfulness Enuresis Sleep Terror Poor Quality Sleep 38% 4% 4% 3% 1% 0% 3% 0% 31% 9% 4% 1% 3% 4% 0% 3% 4% 0% 1% 0% 0% 0% 0% 1% NERVOUS SYSTEM DISORDERS Headache Insomnia Tremor Abnormal Sleep-Related Event 20% 5% 1% 3% 13% 6% 4% 1% 16% 1% 0% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain Nausea Constipation Dry Mouth 15% 4% 1% 0% 10% 5% 6% 5% 12% 3% 0% 1% GENERAL DISORDERS Fatigue † Irritability 16% 9% 13% 5% 1% 4% CARDIAC DISORDERS Dizziness Bradycardia 7% 0% 3% 4% 5% 0% INVESTIGATIONS Increased Heart Rate 0% 3% 0% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3% 4% 4% * Somnolence includes the terms "somnolence" and "sedation". † Fatigue includes the terms "fatigue" and "lethargy". Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Taper Period* (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine HCl Extended-Release 0.2 mg/day N=76 Clonidine HCl Extended-Release 0.4 mg/day N=78 Placebo (N=76) Abdominal Pain Upper 0% 6% 3% Headache 5% 2% 3% Gastrointestinal Viral 0% 5% 0% Somnolence 2% 3% 0% Heart Rate Increased 0% 3% 0% Otitis Media Acute 3% 0% 0% * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6 to 8; Placebo dose, weeks 6 to 8 Study 2: Flexible-dose Clonidine HCl Extended-Release as Adjunctive Therapy to Psychostimulants Study 2 (CLON-302) was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine HCl extended-release as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes during which clonidine HCl extended-release was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine HCl extended-release treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, decreased appetite, dizziness. Adverse Events Leading to Discontinuation – There was one patient in the CLON+STM group (1%) who discontinued because of an adverse event (severe bradyphrenia, with severe fatigue). Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4. Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Treatment Period (Study 2) Preferred Term Percentage of Patients Reporting Event Clonidine HCl Extended-Release+STM (N=102) PBO+STM (N=96) PSYCHIATRIC DISORDERS Somnolence * Aggression Affect Lability Emotional Disorder 19% 2% 2% 2% 7% 1% 1% 0% GENERAL DISORDERS Fatigue † Irritability 14% 2% 4% 7% NERVOUS SYSTEM DISORDERS Headache Insomnia 7% 4% 12% 3% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 7% 4% RESPIRATORY DISORDERS Nasal Congestion 2% 2% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6% 3% CARDIAC DISORDERS Dizziness 5% 1% * Somnolence includes the terms: "somnolence" and "sedation". † Fatigue includes the terms "fatigue" and "lethargy". Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5. Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Taper Period* (Study 2) Preferred Term Percentage of Patients Reporting Event Clonidine HCl Extended-Release+STM (N=102) PBO+STM (N=96) Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0% Rash 2% 0% * Taper Period: weeks 6 to 8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine HCl extended-release discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine HCl extended-release monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on clonidine HCl extended-release 0.2 mg/day and -8.8 mmHg on clonidine HCl extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine HCl extended-release 0.2 mg/day and -7.3 mmHg on clonidine HCl extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine HCl extended-release 0.2 mg/day and -7.7 beats per minute on clonidine HCl extended-release 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on clonidine HCl extended-release 0.2 mg/day and -5.6 mmHg on clonidine HCl extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine HCl extended-release 0.2 mg/day and -5.4 mmHg on clonidine HCl extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine HCl extended-release 0.2 mg/day and -3.0 beats per minute on clonidine HCl extended-release 0.4 mg/day. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clonidine HCl extended-release. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events exclude those already mentioned in 6.1: Psychiatric: hallucinations Cardiovascular: Q-T prolongation