Clonidine Hydrochloride Extended-Release (Page 2 of 7)

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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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 hydrochloride extended-release tablets 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)]

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.

Additional pediatric use information for patients ages 6 to 17 years is approved for Concordia Pharmaceuticals, Inc.’s KAPVAY® (clonidine hydrochloride) extended-release tablets. However, due to Concordia Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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)

Percentage of Patients Reporting Event

Clonidine Hydrochloride Extended-Release Tablets

Clonidine Hydrochloride Extended-Release Tablets

Placebo

Preferred Term

0.2 mg/day

0.4 mg/day

(N=76)

N=76

N=78

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”.

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

Clonidine Hydrochloride Extended-Release Tablets

Clonidine Hydrochloride Extended-Release Tablets

Preferred Term

0.2 mg/day

0.4 mg/day

Placebo

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 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 ≥ 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)

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 ≥ 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

Clonidine Hydrochloride Extended-Release Tablets + STM

PBO + STM

Preferred Term

(N=102)

(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.

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