Clonazepam (Page 4 of 7)

ADVERSE REACTIONS

The adverse experiences for clonazepam orally disintegrating tablets are provided separately for patients with seizure disorders and with panic disorder.

Seizure Disorders: The most frequently occurring side effects of clonazepam orally disintegrating tablets are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%. In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, including those identified during postapproval use of clonazepam orally disintegrating tablets are:

Cardiovascular: Palpitations

Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema

Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums

Genitourinary: Dysuria, enuresis, nocturia, urinary retention

Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia

Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase

Musculoskeletal: Muscle weakness, pains

Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain

Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, “glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo

Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis, (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances). The following paradoxical reactions have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams

Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages

Panic Disorder: Adverse events during exposure to clonazepam orally disintegrating tablets were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials:
Adverse Events Associated With Discontinuation of Treatment:
Overall, the incidence of discontinuation due to adverse events was 17% in clonazepam orally disintegrating tablets compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (≥1 %) associated with discontinuation and a dropout rate twice or greater for clonazepam orally disintegrating tablets than that of placebo included the following:

Table 2 Most Common Adverse Events (≥1%) Associated with Discontinuation of Treatment

Adverse Event

Clonazepam orally disintegrating tablets (N=574)

Placebo (N=294)

Somnolence

7%

1%

Depression

4%

1%

Dizziness

1%

<1%

Nervousness

1%

0%

Ataxia

1%

0%

Intellectual Ability Reduced

1%

0%

Adverse Events Occurring at an Incidence of 1% or More Among Clonazepam orally disintegrating tablets -Treated Patients:

Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials. Events reported in 1% or more of patients treated with clonazepam orally disintegrating tablets (doses ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.

The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials.

Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.

Table 3. Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-Controlled Clinical Trials*
* Events reported by at least 1% of patients treated with clonazepam orally disintegrating tablets and for which the incidence was greater than that for placebo.
† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for adverse event incidence was ≤0.1.
‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102 (placebo) for male, and 334 (clonazepam), 192 (placebo) for female.

Clonazepam Maximum Daily Dose

Adverse Event by Body System

<1mg

1 to <2mg

2 to <3mg

3mg

All Clonazepam orally disintegrating tablets Groups

Placebo

n=96

n=129

n=113

n=235

N=574

N=294

%

%

%

%

%

%

Central & Peripheral Nervous System

Somnolence

26

35

50

36

37

10

Dizziness

5

5

12

8

8

4

Coordination Abnormal

1

2

7

9

6

0

Ataxia

2

1

8

8

5

0

Dysarthria

0

0

4

3

2

0

Psychiatric

Depression

7

6

8

8

7

1

Memory Disturbance

2

5

2

5

4

2

Nervousness

1

4

3

4

3

2

Intellectual Ability Reduced

0

2

4

3

2

0

Emotional Lability

0

1

2

2

1

1

Libido Decreased

0

1

3

1

1

0

Confusion

0

2

2

1

1

0

Respiratory System

Upper Respiratory Tract Infection

10

10

7

6

8

4

Sinusitis

4

2

8

4

4

3

Rhinitis

3

2

4

2

2

1

Coughing

2

2

4

0

2

0

Pharyngitis

1

1

3

2

2

1

Bronchitis

1

0

2

2

1

1

Gastrointestinal System

Constipation

0

1

5

3

2

2

Appetite Decreased

1

1

0

3

1

1

Abdominal Pain

2

2

2

0

1

1

Body as a Whole

Fatigue

9

6

7

7

7

4

Allergic Reaction

3

1

4

2

2

1

Musculoskeletal

Myalgia

2

1

4

0

1

1

Resistance Mechanism Disorders

Influenza

3

2

5

5

4

3

Urinary System

Micturition Frequency

1

2

2

1

1

0

Urinary Tract Infection

0

0

2

2

1

0

Vision Disorders

Blurred Vision

1

2

3

0

1

1

Reproductive Disorders

Female

Dysmenorrhea

0

6

5

2

3

2

Colpitis

4

0

2

1

1

1

Male

Ejaculation Delayed

0

0

2

2

1

0

Impotence

3

0

2

1

1

0

Commonly Observed Adverse Events:

Table 4. Incidence of Most Commonly Observed Adverse Events* in Acute Therapy in Pool of 6- to 9-Week Trials
*Treatment-emergent events for which the incidence in the clonazepam patients was ≥5% and at least twice that in the placebo patients.

Adverse Event

Clonazepam (N=574)

Placebo (N=294)

Somnolence

37%

10%

Depression

7%

1%

Coordination Abnormal

6%

0%

Ataxia

5%

0%

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