Clonidineside effects

The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia Sedation and somnolence Rebound hypertension Allergic reactions Cardiac Conduction Abnormalities 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. 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. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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 hydrochloride extended-release tablet 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 hydrochloride extended-release tablet 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 Hydrochloride Extended-Release Tablets 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 hydrochloride extended-release tablets 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 greater than or equal to 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Events Leading to Discontinuation of Clonidine Hydrochloride Extended-Release Tablets – 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 greater than or equal to 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2. Commonly observed adverse reactions (incidence of greater than or equal to 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Treatment Period (Study 1) Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day 0.4 mg/day Placebo Preferred Term N=76 N=78 (N=76) PSYCHIATRIC DISORDERS Somnolence* 38% 31% 4% Nightmare 4% 9% 0% Emotional Disorder 4% 4% 1% Aggression 3% 1% 0% Tearfulness 1% 3% 0% Enuresis 0% 4% 0% Sleep Terror 3% 0% 0% Poor Quality Sleep 0% 3% 1% NERVOUS SYSTEM DISORDERS Headache 20% 13% 16% Insomnia 5% 6% 1% Tremor 1% 4% 0% Abnormal Sleep-Related Event 3% 1% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 15% 10% 12% Nausea 4% 5% 3% Constipation 1% 6% 0% Dry Mouth 0% 5% 1% GENERAL DISORDERS Fatigue† 16% 13% 1% Irritability 9% 5% 4% CARDIAC DISORDERS Dizziness 7% 3% 5% Bradycardia 0% 4% 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". Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Taper Period* (Study 1) Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day 0.4 mg/day Placebo Preferred Term N=76 N=78 (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 Hydrochloride Extended-Release Tablets 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets were initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine hydrochloride extended-release tablet treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of greater than or equal to 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 greater than or equal to 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) Percentage of Patients Reporting Event Clonidine Hydrochloride Extended-Release Tablets +STM PBO+STM Preferred Term (N=102) (N=96) PSYCHIATRIC DISORDERS Somnolence* 19% 7% Aggression 2% 1% Affect Lability 2% 1% Emotional Disorder 2% 0% GENERAL DISORDERS Fatigue † 14% 4% Irritability 2% 7% NERVOUS SYSTEM DISORDERS Headache 7% 12% Insomnia 4% 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 greater than or equal to 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) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets +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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release tablets. 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