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KLONOPINŽ

KLONOPIN®

(clonazepam/Roche)


DESCRIPTION
ACTIONS
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DRUG ABUSE AND DEPENDENCE
DRUG INTERACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

DESCRIPTION: Klonopin is available as scored tablets containing 0.5 mg, 1 mg or 2 mg clonazepam/Roche. Each tablet also contains lactose, magnesium stearate, microcrystalline cellulose and corn starch, with the following dye systems: 0.5 mg-FD&C Yellow No. 6; 1 mg-FD&C Blue No. 1 and FD&C Blue No. 2.

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of 315.7 and the following structural formula:

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ACTIONS: In laboratory animals, Klonopin exhibits several pharmacologic properties which are characteristic of the benzodiazepine class of drugs. Convulsions produced in rodents by pentylenetetrazol or electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are likewise produced by Klonopin. In humans it is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.

Single oral dose administration of Klonopin to humans gave maximum blood levels of drug, in most cases, within one to two hours. The half-life of the parent compound varied from approximately 18 to 50 hours, and the major route of excretion was in the urine. In humans, five metabolites have been identified. In general, the biotransformation of clonazepam followed two pathways: oxidative hydroxylation at the C-3 position and reduction of the 7-nitro function to form 7-amino and/or 7-acetyl-amino derivatives.

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INDICATIONS: Klonopin is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, Klonopin may be useful.

In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within three months of administration. In some cases, dosage adjustment may reestablish efficacy.

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CONTRAINDICATIONS: Klonopin should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.

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WARNINGS: Since Klonopin produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle. They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during Klonopin therapy (see Drug Interactions).

Usage in Pregnancy: The effects of Klonopin in human pregnancy and nursing infants are unknown.

Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even mild seizures do not pose some hazards to the developing embryo or fetus.

These considerations should be weighed in treating or counseling epileptic women of childbearing potential.

Use of Klonopin in women of childbearing potential should be considered only when the clinical situation warrants the risk. Mothers receiving Klonopin should not breast feed their infants. In a two-generation reproduction study with Klonopin given orally to rats at 10 or 100 mg/kg/day, there was a decrease in the number of pregnancies and a decrease in the number of offspring surviving. until weaning. When Klonopin was administered orally to pregnant rabbits at 0.2, 1.0, 5.0 or 10.0 mg/kg/day, a nondose-related incidence of cleft palates, open eyelids, fused sternebrae and limb defects was observed at the 0.2 and 5.0 mg/kg/day levels. Nearly all of the malformations were seen from one dam in each of the affected dosages.

Usage in Children: Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of Klonopin is important in pediatric patients.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.)

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PRECAUTIONS: When used in patients in whom several different types of seizure disorders coexist, Klonopin may increase the incidence or precipitate the onset of generalized tonic-clonic seizures (grand mal). This may require the addition of appropriate anticonvulsants or an increase in their dosages. The concomitant use of valproic acid and clonazepam may produce absence status.

Periodic blood counts and liver function tests are advisable during long term therapy with Klonopin.

The abrupt withdrawal of Klonopin, particularly in those patients on long-term, high-close therapy, may precipitate status epilepticus. Therefore. when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being gradually withdrawn. the simultaneous substitution of another anticonvulsant may be indicated. Metabolites of Klonopin are excreted by the kidneys to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.

Klonopin may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions. Because of this and the possibility of respiratory depression, Klonopin should be used with caution in patients with chronic respiratory diseases.

Information for Patients: To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.

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ADVERSE REACTIONS: The most frequently occurring side effects of Klonopin are referable to CNS depression. Experience to date 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, are:

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, suicidal attempt (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances).

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

Cardiovascular: Palpitations.

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

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

Genitourinary: Dysuria, enuresis, nocturia, urinary retention. Musculoskeletal: Muscle weakness, pains. Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain.

Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia.

Hepatic: Transient elevations of serum transaminases and alkaline phosphatase.

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DRUG ABUSE AND 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. 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.

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DRUG INTERACTIONS: The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

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

Methylphenidate or caffeine and sodium benzoate may be given to combat CNS depression. Dialysis is of no known value.

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DOSAGE AND ADMINISTRATION: Infants and Children: Klonopin is administered orally. In order to minimize drowsiness, the initial dose for infants and children (Up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.

Adults: The initial dose for adults should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every three days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

The use of multiple anticonvulsants may recruit in an increase of depressant adverse effects. This should be considered before adding Klonopin to an existing anticonvulsant regimen.

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HOW SUPPLIED: Scored tablets-0.5 mg, orange; 1 mg, blue; 2 mg, white-bottles of 100; Tel-E-DoseŽ, packages of 100, available in boxes of four reverse-numbered cards of 25.

Distributed by Hoffmann-La Roche Inc.
Nutley, New Jersey 07110-1199.

Manufactured by Roche Pharma, Inc.
Manati, Puerto Rico 00674.

13-20-71802-0392                                         Revised July 1991
13-06 71800- 0392                                          Printed in USA






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