WARNINGS
Interference With Cognitive and Motor Performance
Since Klonopin produces CNS depression, patientsreceiving this drug should be cautioned against engaging in hazardousoccupations requiring mental alertness, such as operating machineryor driving a motor vehicle. They should also be warned about the concomitantuse of alcohol or other CNS-depressant drugs during Klonopin therapy(see PRECAUTIONS: Drug Interactions and Information for Patients).
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Klonopin, increasethe risk of suicidal thoughts or behavior in patients taking thesedrugs for any indication. Patients treated with any AED for any indicationshould be monitored for the emergence or worsening of depression,suicidal thoughts or behavior, and/or any unusual changes in moodor behavior.
Pooled analyses of 199 placebo-controlledclinical trials (mono- and adjunctive therapy) of 11 different AEDsshowed that patients randomized to one of the AEDs had approximatelytwice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidalthinking or behavior compared to patients randomized to placebo. Inthese trials, which had a median treatment duration of 12 weeks, theestimated incidence rate of suicidal behavior or ideation among 27,863AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treatedpatients, representing an increase of approximately one case of suicidalthinking or behavior for every 530 patients treated. There were foursuicides in drug-treated patients in the trials and none in placebo-treatedpatients, but the number is too small to allow any conclusion aboutdrug effect on suicide.
The increased risk ofsuicidal thoughts or behavior with AEDs was observed as early as oneweek after starting drug treatment with AEDs and persisted for theduration of treatment assessed. Because most trials included in theanalysis did not extend beyond 24 weeks, the risk of suicidal thoughtsor behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistentamong drugs in the data analyzed. The finding of increased risk withAEDs of varying mechanisms of action and across a range of indicationssuggests that the risk applies to all AEDs used for any indication.The risk did not vary substantially by age (5-100 years) in the clinicaltrials analyzed.
Table 1 shows absolute andrelative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugsin the Pooled Analysis | Indication | Placebo Patientswith Events Per 1000 Patients | Drug Patientswith Events Per 1000 Patients | Relative Risk:Incidence of Events in Drug Patients/Incidence in Placebo Patients | Risk Difference:Additional Drug Patients with Events per 1000 Patients |
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
The relative risk for suicidal thoughts or behaviorwas higher in clinical trials for epilepsy than in clinical trialsfor psychiatric or other conditions, but the absolute risk differenceswere similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Klonopin or any other AEDmust balance the risk of suicidal thoughts or behavior with the riskof untreated illness. Epilepsy and many other illnesses for whichAEDs are prescribed are themselves associated with morbidity and mortalityand an increased risk of suicidal thoughts and behavior. Should suicidalthoughts and behavior emerge during treatment, the prescriber needsto consider whether the emergence of these symptoms in any given patientmay be related to the illness being treated.
Patients, their caregivers, and families should be informed thatAEDs increase the risk of suicidal thoughts and behavior and shouldbe advised of the need to be alert for the emergence or worseningof the signs and symptoms of depression, any unusual changes in moodor behavior, or the emergence of suicidal thoughts, behavior, or thoughtsabout self-harm. Behaviors of concern should be reported immediatelyto healthcare providers.
Pregnancy Risks
Data from several sources raise concerns about theuse of Klonopin during pregnancy.
Animal Findings
In three studies in which Klonopin was administeredorally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (lowdose approximately 0.2 times the maximum recommended human dose of20 mg/day for seizure disorders and equivalent to the maximum doseof 4 mg/day for panic disorder, on a mg/m2 basis) duringthe period of organogenesis, a similar pattern of malformations (cleftpalate, open eyelid, fused sternebrae and limb defects) was observedin a low, non-dose-related incidence in exposed litters from all dosagegroups. Reductions in maternal weight gain occurred at dosages of5 mg/kg/day or greater and reduction in embryo-fetal growth occurredin one study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetaleffects were observed in mice and rats following administration duringorganogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively(4 and 20 times the maximum recommended human dose of 20 mg/day forseizure disorders and 20 and 100 times the maximum dose of 4 mg/dayfor panic disorder, respectively, on a mg/m2 basis).
General Concerns and ConsiderationsAbout Anticonvulsants
Recent reports suggest an association between theuse of anticonvulsant drugs by women with epilepsy and an elevatedincidence of birth defects in children born to these women. Data aremore extensive with respect to diphenylhydantoin and phenobarbital,but these are also the most commonly prescribed anticonvulsants; lesssystematic or anecdotal reports suggest a possible similar associationwith the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggestingan elevated incidence of birth defects cannot be regarded as adequateto prove a definite cause and effect relationship. There are intrinsicmethodologic problems in obtaining adequate data on drug teratogenicityin humans; the possibility also exists that other factors (eg, geneticfactors or the epileptic condition itself) may be more important thandrug therapy in leading to birth defects. The great majority of motherson anticonvulsant medication deliver normal infants. It is importantto note that anticonvulsant drugs should not be discontinued in patientsin whom the drug is administered to prevent seizures because of thestrong possibility of precipitating status epilepticus with attendanthypoxia and threat to life. In individual cases where the severityand frequency of the seizure disorder are such that the removal ofmedication does not pose a serious threat to the patient, discontinuationof the drug may be considered prior to and during pregnancy; however,it cannot be said with any confidence that even mild seizures do notpose some hazards to the developing embryo or fetus.
General Concerns About Benzodiazepines
An increased risk of congenital malformations associatedwith the use of benzodiazepine drugs has been suggested in severalstudies.
There may also be non-teratogenic risksassociated with the use of benzodiazepines during pregnancy. Therehave been reports of neonatal flaccidity, respiratory and feedingdifficulties, and hypothermia in children born to mothers who havebeen receiving benzodiazepines late in pregnancy. In addition, childrenborn to mothers receiving benzodiazepines late in pregnancy may beat some risk of experiencing withdrawal symptoms during the postnatalperiod.
Advice Regarding the Use of Klonopinin Women of Childbearing Potential
In general, the use of Klonopin in women of childbearingpotential, and more specifically during known pregnancy, should beconsidered only when the clinical situation warrants the risk to thefetus.
The specific considerations addressedabove regarding the use of anticonvulsants for epilepsy in women ofchildbearing potential should be weighed in treating or counselingthese women.
Because of experience with othermembers of the benzodiazepine class, Klonopin is assumed to be capableof causing an increased risk of congenital abnormalities when administeredto a pregnant woman during the first trimester. Because use of thesedrugs 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 pregnantat the time of institution of therapy should be considered. If thisdrug is used during pregnancy, or if the patient becomes pregnantwhile taking this drug, the patient should be apprised of the potentialhazard to the fetus. Patients should also be advised that if theybecome pregnant during therapy or intend to become pregnant, theyshould communicate with their physician about the desirability ofdiscontinuing the drug.
Withdrawal Symptoms
Withdrawal symptoms of the barbiturate type haveoccurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
PRECAUTIONS
General
Worsening of Seizures
When used in patients in whom several different typesof seizure disorders coexist, Klonopin may increase the incidenceor precipitate the onset of generalized tonic-clonic seizures (grandmal). This may require the addition of appropriate anticonvulsantsor an increase in their dosages. The concomitant use of valproic acidand Klonopin may produce absence status.
Laboratory Testing During Long-TermTherapy
Periodic blood counts and liver function tests areadvisable during long-term therapy with Klonopin.
Risks of Abrupt Withdrawal
The abrupt withdrawal of Klonopin, particularly inthose patients on long-term, high-dose therapy, may precipitate statusepilepticus. Therefore, when discontinuing Klonopin, gradual withdrawalis essential. While Klonopin is being gradually withdrawn, the simultaneoussubstitution of another anticonvulsant may be indicated.
Caution in Renally Impaired Patients
Metabolites of Klonopin are excreted by the kidneys;to avoid their excess accumulation, caution should be exercised inthe administration of the drug to patients with impaired renal function.
Hypersalivation
Klonopin may produce an increase in salivation. Thisshould be considered before giving the drug to patients who have difficultyhandling secretions. Because of this and the possibility of respiratorydepression, Klonopin should be used with caution in patients withchronic respiratory diseases.
Information for Patients
Patients should be instructed to take Klonopin onlyas prescribed. Physicians are advised to discuss the following issueswith patients for whom they prescribe Klonopin:
Dose Changes
To assure the safe and effective use of benzodiazepines,patients should be informed that, since benzodiazepines may producepsychological and physical dependence, it is advisable that they consultwith their physician before either increasing the dose or abruptlydiscontinuing this drug.
Interference With Cognitive and MotorPerformance
Because benzodiazepines have the potential to impairjudgment, thinking or motor skills, patients should be cautioned aboutoperating hazardous machinery, including automobiles, until they arereasonably certain that Klonopin therapy does not affect them adversely.
Suicidal Thinking and Behavior
Patients, their caregivers, and families should becounseled that AEDs, including Klonopin, may increase the risk ofsuicidal thoughts and behavior and should be advised of the need tobe alert for the emergence or worsening of symptoms of depression,any unusual changes in mood or behavior, or the emergence of suicidalthoughts, behavior, or thoughts about self-harm. Behaviors of concernshould be reported immediately to healthcare providers.
Pregnancy
Patients should be advised to notify their physicianif they become pregnant or intend to become pregnant during therapywith Klonopin (see WARNINGS: PregnancyRisks). Patients should be encouraged to enroll in theNorth American Antiepileptic Drug (NAAED) Pregnancy Registry if theybecome pregnant. This registry is collecting information about thesafety of antiepileptic drugs during pregnancy. To enroll, patientscan call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy).
Nursing
Patients should be advised not to breastfeed an infantif they are taking Klonopin.
Concomitant Medication
Patients should be advised to inform their physiciansif they are taking, or plan to take, any prescription or over-the-counterdrugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol whiletaking Klonopin.
Drug Interactions
Effect of Clonazepam on the Pharmacokineticsof Other Drugs
Clonazepam does not appear to alter the pharmacokineticsof phenytoin, carbamazepine or phenobarbital. The effect of clonazepamon the metabolism of other drugs has not been investigated.
Effect of Other Drugs on the Pharmacokineticsof Clonazepam
Literature reports suggest that ranitidine, an agentthat decreases stomach acidity, does not greatly alter clonazepampharmacokinetics.
In a study in which the 2mg clonazepam orally disintegrating tablet was administered with andwithout propantheline (an anticholinergic agent with multiple effectson the GI tract) to healthy volunteers, the AUC of clonazepam was10% lower and the Cmax of clonazepam was 20% lower whenthe orally disintegrating tablet was given with propantheline comparedto when it was given alone.
Fluoxetine doesnot affect the pharmacokinetics of clonazepam. Cytochrome P-450 inducers,such as phenytoin, carbamazepine and phenobarbital, induce clonazepammetabolism, causing an approximately 30% decrease in plasma clonazepamlevels. Although clinical studies have not been performed, based onthe 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.
Pharmacodynamic Interactions
The CNS-depressant action of the benzodiazepine classof drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbituratehypnotics, antianxiety agents, the phenothiazines, thioxanthene andbutyrophenone classes of antipsychotic agents, monoamine oxidase inhibitorsand the tricyclic antidepressants, and by other anticonvulsant drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted withclonazepam.
The data currently available arenot sufficient to determine the genotoxic potential of clonazepam.
In a two-generation fertility study in which clonazepamwas given orally to rats at 10 and 100 mg/kg/day (low dose approximately5 times and 24 times the maximum recommended human dose of 20 mg/dayfor seizure disorder and 4 mg/day for panic disorder, respectively,on a mg/m2 basis), there was a decrease in the number ofpregnancies and in the number of offspring surviving until weaning.
Pregnancy
Teratogenic Effects
Pregnancy Category D (see WARNINGS: Pregnancy Risks).
To provide information regarding the effects of in uteroexposure to Klonopin, physicians are advised to recommend that pregnantpatients taking Klonopin enroll in the NAAED Pregnancy Registry. Thiscan be done by calling the toll free number 1-888-233-2334, and mustbe done by patients themselves. Information on this registry can alsobe found at the website http://www.aedpregnancyregistry.org/.
Labor and Delivery
The effect of Klonopin on labor and delivery in humanshas not been specifically studied; however, perinatal complicationshave been reported in children born to mothers who have been receivingbenzodiazepines late in pregnancy, including findings suggestive ofeither excess benzodiazepine exposure or of withdrawal phenomena (see WARNINGS: Pregnancy Risks).
Nursing Mothers
Mothers receiving Klonopin should not breastfeedtheir infants.
Pediatric Use
Because of the possibility that adverse effects onphysical or mental development could become apparent only after manyyears, a benefit-risk consideration of the long-term use of Klonopinis important in pediatric patients being treated for seizure disorder(see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).
Safety and effectiveness in pediatric patientswith panic disorder below the age of 18 have not been established.
Geriatric Use
Clinical studies of Klonopin did not include sufficientnumbers of subjects aged 65 and over to determine whether they responddifferently from younger subjects. Other reported clinical experiencehas not identified differences in responses between the elderly andyounger patients. In general, dose selection for an elderly patientshould be cautious, usually starting at the low end of the dosingrange, 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 ispossible that liver disease will impair clonazepam elimination. Metabolitesof Klonopin are excreted by the kidneys; to avoid their excess accumulation,caution should be exercised in the administration of the drug to patientswith impaired renal function. Because elderly patients are more likelyto have decreased hepatic and/or renal function, care should be takenin dose selection, and it may be useful to assess hepatic and/or renalfunction at the time of dose selection.
Sedatingdrugs may cause confusion and over-sedation in the elderly; elderlypatients generally should be started on low doses of Klonopin andobserved closely.
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