Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
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.
Loss of Effect: In some studies, up to 30% of patients who initially responded have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.
Laboratory Testing During Long-Term Therapy
Periodic blood counts and liver function tests are advisable during long-term therapy with clonazepam.
Psychiatric and Paradoxical Reactions: Paradoxical reactions, such as agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations, and psychoses are known to occur when using benzodiazepines (see ADVERSE REACTIONS: Psychiatric). Should this occur, the use of the drug should be discontinued gradually (see PRECAUTIONS: Risks of Abrupt Withdrawaland DRUG ABUSE AND DEPENDENCE: Physical and Psychological Dependence). Paradoxical reactions are more likely to occur in children and in the elderly.
Risks of Abrupt Withdrawal
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 While clonazepam is being gradually withdrawn, the simultaneous substitution of another anticonvulsant may be indicated.
Caution in Renally Impaired Patients
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.
Hypersalivation
Clonazepam may produce an increase in salivation. This should be considered before giving the drug to patients who have difficulty handling secretions.
Respiratory Depression
Clonazepam may cause respiratory depression and should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, sleep apnea).
Porphyria
Clonazepam may have a porphyrogenic effect and should be used with care in patients with porphyria.
Information for Patients
A clonazepam tablets Medication Guide must be given to the patient each time clonazepam tablets are dispensed, as required by law. Patients should be instructed to take clonazepam only as prescribed. Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam:
Risks from Concomitant Use with Opioids
Inform patients and caregivers that potentially fatal additive effects may occur if clonazepam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS, Risks from Concomitant Use With Opioidsand PRECAUTIONS, Drug Interactions).
Dose Changes
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.
Interference with Cognitive and Motor Performance
Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.
Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including clonazepam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with clonazepam (see PRECAUTIONS: Pregnancy). Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy).
Nursing
Patients should be advised to notify their physician if they are breastfeeding or intend to breastfeed during therapy.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol while taking clonazepam.
Drug Interactions
Effect of Concomitant Use of Benzodiazepines and Opioids
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.
Effect of Clonazepam on the Pharmacokinetics of Other Drugs
Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or phenobarbital. Clonazepam has the potential to influence concentrations of phenytoin. Monitoring of phenytoin concentration is recommended when clonazepam is coadministrated with phenytoin. The effect of clonazepam on the metabolism of other drugs has not been investigated.
Effect of Other Drugs on the Pharmacokinetics of Clonazepam
Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.
In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.
The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19 inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers, such as phenytoin, carbamazepine, lamotrigine, and phenobarbital induce clonazepam metabolism, causing an approximately 38% 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 (e.g., fluconazole), should be used cautiously in patients receiving clonazepam because they may impair the metabolism of clonazepam leading to exaggerated concentrations and effects.
Pharmacodynamic 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been conducted with clonazepam.
Mutagenesis
The data currently available are not sufficient to determine the genotoxic potential of clonazepam.
Impairment of Fertility
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and 100 mg/kg/day, there was a decrease in the number of pregnancies and in the number of offspring surviving until weaning. The lowest dose tested is approximately 5 and 24 times the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and 4 mg/day for panic disorder, respectively, on a body surface area (mg/m2) basis.
Pregnancy
There are no adequate and well-controlled studies of clonazepam in pregnant women. Available human data on the risk of teratogenicity are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
In three studies in which clonazepam was administered orally to pregnant rabbits at doses of 0.2, 1, 5, or 10 mg/kg/day during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed at all doses, in a low, non-dose-related incidence. The lowest dose tested is less than the maximum recommended human dose (MRHD) of 20 mg/day for seizure disorders and similar to the MRHD of 4 mg/day for panic disorder, on a mg/m2 basis. Reductions in maternal weight gain occurred at doses of 5 mg/kg/day or greater and reduction in embryofetal growth occurred in one study at a dose of 10 mg/kg/day.
No adverse maternal or embryofetal effects were observed in mice or rats following oral administration of clonazepam during organogenesis of doses up to 15 or 40 mg/kg/day, respectively (4 and 20 times the MRHD of 20 mg/day for seizure disorders and 20 and 100 times the MRHD of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
Data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines.
To provide information regarding the effects of in utero exposure to clonazepam, physicians are advised to recommend that pregnant patients taking clonazepam enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on this registry can also be found at the website http://www.aedpregnancyregistry.org/.
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 (see PRECAUTIONS: Pregnancy).
Nursing Mothers
The effects of clonazepam on the breastfed infant and on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clonazepam and any potential adverse effects on the breastfed infant from clonazepam or from the underlying maternal condition.
Pediatric Use
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 clonazepam is important in pediatric patients being treated for seizure disorder (see INDICATIONS AND USAGEand DOSAGE AND ADMINISTRATION).
Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.
Geriatric Use
Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. 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 elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam and observed closely.