Clonex

/ Teva

Typical or atypical petit mal, Lennox-Gastaut syndrome (petit mal variant),generalized primary or secondary tonic-clonic seizures including grand mal and focal seizures.
The use of multiple anticonvulsant therapy may result in an increase of depressant adverse effects. This should be considered before including Clonex in an existing anti-convulsant regimen.
Infants and Children In order to minimize drowsiness, the initial dosage for infants and children (up to 10 years of age or 30 kg body weight) should be 0.01-0.03 mg/kg/ body weight/day given in 2-3 divided doses. Dosage should be increased by no more than 0.25- 0.5 mg every 3 days, until a daily maintenance dosage of 0.1-0.2 mg/kg body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dosage should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before retiring.
Adults The initial adult dosage should not exceed 1.5 mg/day, divided into 3 doses. Dosage may be increased by increments of 0.5-1 mg every 3 days, until seizures are adequately controlled or until side effects preclude any further increase. The maintenance dosage must be individualized for each patient, depending on response. The maximum recommended daily dosage is 20 mg.
Panic Disorder
Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. It is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make
further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.
Treatment should be discontinued gradually, with a decrease of 0.25 mg daily every 3 days, until the drug is completely withdrawn.
Pediatric Patients There is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age.
Use in Geriatrics There is no clinical trial experience with clonazepam in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. The effectiveness of clonazepam in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. Therefore, the physician who elects to use Clonex for
extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Typical or atypical petit mal, Lenox Gastaut syndrome (petit mal variant), generalized primary or secondary tonic-clonic seizures, including grand mal and focal seizures, panic disorders with or without agorophobia.

Known hypersensitivity to benzodiazepines, or to any other ingredient of the preparation. Clinical or biochemical evidence of significant liver disease. Acute pulmonary insufficiency. Sleep apnea syndrome. Breastfeeding. Acute narrow-angle glaucoma (benzodiazepines may be used in patients with open-angle glaucoma who are receiving appropriate therapy.
Suicidal Behavior and Ideation: Antiepileptics drugs (AEDs), including clonazepam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior…. Anyone considering prescribing clonazepam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Since clonazepam produces CNS depression, patients should be warned that their ability to perform potentially-hazardous tasks requiring mental alertness or physical coordination, such as driving a vehicle or operating machinery, may be impaired. The same warning applies to childhood activities such as riding a bicycle or playing near traffic. Patients should also be warned about the concomitant use of alcohol or other CNS- depressant drugs during clonazepam therapy. Prolonged use may cause dependence. Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepine drugs. These symptoms include convulsions, tremor, abdominal and muscle cramps, vomiting and sweating. When discontinuing therapy in patients who have used these agents for prolonged periods, the dosage should be decreased gradually to avoid the possibility of withdrawal symptoms. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. Clonex generally has a beneficial effect on behavior disturbances in epileptic patients. In certain cases, paradoxical effects such as aggressiveness, irritability, agitation, psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue Clonex therapy. Clonazepam may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver). Clonazepam is considered to be probably nonporphyrinogenic at low doses, although there is some conflicting evidence of porphyrinogenicity at higher doses. Therefore, in patients with porphyria, clonazepam must be used with care.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with clonazepam. The data currently available are not sufficient to determine the genotoxic potential of clonazepam. In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day (low dose approximately 5 times and 24 times the maximum recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic disorder, respectively, on a mg/m2 basis), there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning.
Use in Pregnancy: The effects of clonazepam in human pregnancy 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 two agents are also the most commonly prescribed anti-convulsants; 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. 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.
See prescribing information for full details.

When used in patients in whom several different types of seizure disorders coexist, clonazepam 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 clonazepam. The abrupt withdrawal of clonazepam, particularly in those patients on long-term high-dose therapy, may precipitate status epilepticus. Therefore, when discontinuing clonazepam, gradual withdrawal is essential. While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.
Metabolites of clonazepam 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. Because of a possible muscular relaxant effect, caution should be exercised when administering this drug to patients with myasthenia gravis. Clonazepam 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, clonazepam should be used with caution in patients with chronic respiratory disease gravis.
See prescribing information for full details.

Adverse reactions with different benzodiazepines vary in type and frequency. Some are dose-related, while others involve individual patient sensitivity. Although not all of the following adverse reactions have been attributed specifically to each benzodiazepine drug, the potential for their occurrence exists. This should be borne in mind when drugs of this class are administered.
The most commonly reported side effects have been drowsiness, fatigue and ataxia, especially in elderly or debilitated patients. Drowsiness and fatigue, if they occur, are usually observed at the beginning of therapy, and generally diminish during continued medication or upon decreasing the dosage. Infrequently reported side effects are listed below.
Neurological: 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). The following paradoxical reactions have been observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams Occasionally, prolonged use with this medicine may cause behavioral changes and paranoid symptoms.
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages.
Cardiovascular: Palpitations.
Dermatological: 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.
Musculoskeletal: Muscle weakness, pains.
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia.
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase.
Other: Dehydration, general deterioration, fever lymphadenopathy, weight loss or gain.
Panic Disorder: Adverse events during exposure to clonazepam 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. 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. See prescribing information for full details.

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Ranitidine and propantheline, agents that decrease stomach acidity, do not greatly alter clonazepam pharmacokinetics. Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels. Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving clonazepam.
Benzodiazepines may have a potentiating effect on centrally-acting drugs such as neuroleptics, tranquilizers, antidepressants, alcohol, narcotics, barbiturates, hypnotics, phenothiazines, thioxanthene and butyrophenone class of antipsychotic agents, monoamine oxidase inhibitors, tricyclic antidepressants, other anticonvulsant drugs, analgesics and anesthetics. When these drugs are administered concomitantly with benzodiazepines, their dosage should be reduced.
Concomitant administration of some benzodiazepines with cimetidine may result in decreased benzodiazepine plasma clearance and increased plasma half-lives and concentrations of benzodiazepines. Therefore, dosage reductions of the benzodiazepines may be necessary in patients receiving concomitant therapy with cimetidine.
Estrogen-containing oral contraceptives, when concomitantly administered with benzodiazepines, may inhibit the hepatic metabolism of the benzodiazepines that are metabolized primarily by nitro-reduction (specifically nitro benzodiazepines such as nitrazepam, flunitrazepam), possibly resulting in delayed elimination, and, during long-term use, increase in serum concentrations of benzodiazepine.
Concomitant administration of benzodiazepines with antacids may decrease the rate but not the extent of gastrointestinal absorption. This may lead to a decrease or delay in the sedative effects of single doses.
Erythromycin may cause inhibition of the hepatic metabolism of benzodiazepines that are metabolized by oxidation, resulting in delayed elimination and increased plasma concentration of the benzodiazepines. Caution should therefore by exercised and patient monitoring may be necessary.
Benzodiazepines may also intensify the response to alcohol. Patients should avoid drinking alcohol while under treatment with this drug.
Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.

Pregnancy: The effects of clonazepam in human pregnancy 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 two agents are also the most commonly prescribed anti-convulsants; 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. 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.
General Concerns About Benzodiazepines: An increased risk of congenital malformations associated with the use of benzodiazepine drugs has been suggested in several studies. There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Advice Regarding the Use of Clonazepam in Women of Childbearing Potential: In general, the use of clonazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The specific considerations addressed above regarding the use of anticonvulsants for epilepsy in women of childbearing potential should be weighed in treating or counseling these women. Because of experience with other members of the benzodiazepine class, clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency in the treatment of panic disorder, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant, they should communicate with their physician about the desirability of discontinuing the drug.
Use in Breastfeeding: Benzodiazepines are excreted in breast milk. Since neonates metabolize this drug more slowly than adults, and accumulation of the drug and its metabolites to toxic levels is possible, it should not be administered to nursing women
Use in Labor and Delivery: The effect of clonazepam on labor and delivery in humans has not been specifically studied; however, perinatal complications have been reported in children born to mothers who have been receiving benzodiazepines late in pregnancy, including findings suggestive of either excess benzodiazepine exposure or of withdrawal phenomena
Use in Pediatrics: Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a risk-benefit consideration of the long-term use of Clonex is important in the treatment of children with this drug. There is no clinical experience with clonazepam in panic disorder patients under 18 years of age.
See prescribing information for full details.

Manifestations: Symptoms of clonazepam overdose, like those produced by other CNS depressants, include somnolence, confusion, coma and diminished reflexes.
Treatment: 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 prescribing information 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.