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 Tris Pharma, Inc. at 940-0358 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. The safety of ONYDA XR for the treatment of ADHD in pediatric patients 6 years and older is based upon adequate and well-controlled studies of clonidine hydrochloride extended-release tablets (referred to as “clonidine hydrochloride extended-release” in this section). The safety results of these adequate and well-controlled studies of clonidine hydrochloride extended-release tablets are presented below. Two clonidine hydrochloride extended-release ADHD clinical studies (Study 1 and Study 2) evaluated 256 patients in two 8-week placebo-controlled studies. A third clonidine hydrochloride extended-release ADHD clinical study (Study 3) evaluated 135 pediatric patients 6 to 17 years of age in a 40-week placebo-controlled randomized‑withdrawal study.

Study 1: Fixed-dose clonidine hydrochloride extended-release Monotherapy Study 1 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 in pediatric patients 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 Reactions Leading to Discontinuation of clonidine hydrochloride 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 1.

Table 1: Common Adverse Reactions Occurring in ≥2%of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Treatment Period (Study 1) Preferred Term Clonidine hydrochloride extended-release tablets 0.2 mg/day N=76 (%) Clonidine hydrochloride extended-release tablets 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 GASTRO-INTESTINAL 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 2.

Table 2: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Taper Period* (Study 1) Preferred Term Clonidine hydrochloride extended-release tablets 0.2 mg/day N=76 (%) Clonidine hydrochloride extended-release tablets 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 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose clonidine hydrochloride extended-release as Adjunctive Therapy to Psychostimulants Study 2 was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride extended-release as adjunctive therapy to a psychostimulant in pediatric patients 6 to 17 years of age who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes, during which clonidine hydrochloride extended‑release was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine hydrochloride 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 Reactions Leading to Discontinuation: There was one patient in the clonidine hydrochloride extended-release + stimulant (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 3.

Table 3: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial -Treatment Period (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) PBO+Stimulant 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 GASTRO-INTESTINAL 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 4.

Table 4: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial -Taper Period + (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) Placebo+Stimulant 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 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release discontinued from the pediatric monotherapy study due to adverse reactions, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine hydrochloride extended-release monotherapy treated patients were 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 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was ‑4.0 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride 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 hydrochloride extended‑release 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release 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 (and excludes those already mentioned in Section 6.1 ). 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.

Psychiatric: hallucinations Cardiovascular: Q-T prolongation