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 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 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 ≥ 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 ≥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)
*
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 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%

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)
*
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 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%

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 tablets 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)
*
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 ≥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)

* 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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