Clonidine Hydrochloride (Page 2 of 7)
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)]
6.1 Clinical Trials 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 tablets 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 tablets 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.
| * Somnolence includes the terms “somnolence” and “sedation”. † Fatigue includes the terms “fatigue” and “lethargy”. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Percentage of Patients Reporting Event | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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* | 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 DISORDERSFatigue† Irritability | 16% 9% | 13%5% | 1% 4% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CARDIAC DISORDERSDizziness Bradycardia | 7% 0% | 3% 4% | 5% 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| INVESTIGATIONSIncreased Heart Rate | 0% | 3% | 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| METABOLISM AND NUTRITION DISORDERSDecreased Appetite | 3% | 4% | 4% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
| * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6 to 8; Placebo dose, weeks 6 to 8 | ||||||||||||||||||||||||||||||
| Preferred Term | Percentage of Patients Reporting Event | |||||||||||||||||||||||||||||
| Clonidine Hydrochloride Extended-Release Tablet 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% | |||||||||||||||||||||||||||
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 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 tablets 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.
| * Somnolence includes the terms: “somnolence” and “sedation”.† Fatigue includes the terms “fatigue” and “lethargy”. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Preferred Term | Percentage of Patients Reporting Event | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clonidine Hydrochloride Extended-Release Tablets +STM (N=102) | PBO+STM(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% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
| * Taper Period: weeks 6 to 8 | ||||||||||||||||||||||
| Preferred Term | Percentage of Patients Reporting Event | |||||||||||||||||||||
| 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% | ||||||||||||||||||||
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.
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