Clonidine Hydrochloride: Package Insert and Label Information

CLONIDINE HYDROCHLORIDE- clonidine hydrochloride tablet, extended release
Solco Healthcare LLC

1 INDICATIONS AND USAGE

Clonidine hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

Clonidine hydrochloride extended-release tablets are an extended-release tablet to be taken orally with or without food. Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of clonidine release.Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of clonidine hydrochloride extended-release tablets for other clonidine products on a mg-per-mg basis is not recommended [see Clinical Pharmacology (12.3)].

2.2 Dose Selection

The dose of clonidine hydrochloride extended-release tablets, administered either as monotherapy or as adjunctive therapy to a psychostimulant, should be individualized according to the therapeutic needs and response of the patient. Dosing should be initiated with one 0.1 mg tablet at bedtime, and the daily dosage should be adjusted in increments of 0.1 mg/day at weekly intervals until the desired response is achieved. Doses should be taken twice a day, with either an equal or higher split dosage being given at bedtime (see Table 1).

Table 1 Clonidine Hydrochloride Extended-Release Tablets Dosing Guidance

Total Daily Dose

Morning Dose

Bedtime Dose

0.1 mg/day

0.1 mg

0.2 mg/day

0.1 mg

0.1 mg

0.3 mg/day

0.1 mg

0.2 mg

0.4 mg/day

0.2 mg

0.2 mg

Doses of clonidine hydrochloride extended-release tablets higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.

When clonidine hydrochloride extended-release tablets are being added-on to a psychostimulant, the dose of the psychostimulant can be adjusted depending on the patient’s response to clonidine hydrochloride extended-release tablets.

2.3 Discontinuation

When discontinuing clonidine hydrochloride extended-release tablets, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension [see Warnings and Precautions (5.3)].

2.4 Missed Doses

If patients miss a dose of clonidine hydrochloride extended-release tablets, they should skip that dose and take the next dose as scheduled. Do not take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period.

3 DOSAGE FORMS AND STRENGTHS

Clonidine hydrochloride extended-release tablets are available in one strength, 0.1 mg as an extended-release formulation. The 0.1 mg tablets are white, non-scored, standard convex with debossing on one side. The 0.1 mg tablets are round. Clonidine hydrochloride extended-release tablets must be swallowed whole and never crushed, cut or chewed.

4 CONTRAINDICATIONS

Clonidine hydrochloride extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension/Bradycardia

Treatment with clonidine hydrochloride extended-release tablets can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1)]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate clonidine hydrochloride extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.

5.2 Sedation and Somnolence

Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine hydrochloride extended-release tablets+stimulant versus 7% treated with placebo+stimulant reported somnolence. Before using clonidine hydrochloride extended-release tablets with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with clonidine hydrochloride extended-release tablets. Advise patients to avoid use with alcohol.

5.3 Rebound Hypertension

Abrupt discontinuation of clonidine hydrochloride extended-release tablets can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in children with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of clonidine hydrochloride extended-release tablets in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue clonidine hydrochloride extended-release tablets therapy without consulting their physician due to the potential risk of withdrawal effects.

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.

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”.

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)

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 6-8; Placebo dose, weeks 6-8

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 tablet 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

PBO+STM

(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%

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 6-8

Preferred Term

Percentage of Patients Reporting Event

Clonidine Hydrochloride Extended-Release Tablets+STM

PBO+STM

(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%

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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