Clonazepam (Page 5 of 7)

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%

Treatment-Emergent Depressive Symptoms

In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of clonazepam-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of clonazepam-treated patients compared to 1% of placebo-treated patients. While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression.

Other Adverse Events Observed During the Premarketing Evaluation of Clonazepam in Panic Disorder

Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with clonazepam at multiple doses during clinical trials. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the events occurred during treatment with clonazepam, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency. These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients.

Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized

Cardiovascular Disorders: chest pain, hypotension postural

Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching

Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids

Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness

Heart Rate and Rhythm Disorders: palpitation

Metabolic and Nutritional Disorders: thirst, gout

Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee

Platelet, Bleeding and Clotting Disorders: bleeding dermal

Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal, illusion, nightmares, sleep disorder, suicide ideation, yawning

Reproductive Disorders, Female: breast pain, menstrual irregularity

Reproductive Disorders, Male: ejaculation decreased

Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis

Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy

Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder

Special Senses Other, Disorders: taste loss

Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration

Vascular (Extracardiac) Disorders: thrombophlebitis leg

Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Clonazepam is a Schedule IV controlled substance.

Physical and Psychological Dependence

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving clonazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see CLINICAL PHARMACOLOGY , Clinical Trials), patients were gradually withdrawn during a 7 week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.

OVERDOSAGE

Human Experience

Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes.

Overdose Management

Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Dialysis is of no known value.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS , WARNINGS and PRECAUTIONS , should be consulted prior to use.

Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

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