KLONOPIN® TABLETSCIV
(clonazepam)
KLONOPIN® WAFERS CIV
(clonazepamorally disintegrating tablets)
Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation containing 1 mg or 2 mg of clonazepam.
Klonopin is indicated for the following:
Seizure Disorders: 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 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.
Panic Disorder: Klonopin is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
The efficacy of Klonopin was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use Klonopin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
KLONOPIN® TABLETSCIV
(clonazepam)
KLONOPIN® WAFERS CIV
(clonazepamorally disintegrating tablets)
DESCRIPTION
Klonopin, a benzodiazepine, is available as scoredtablets with a K-shaped perforation containing 0.5 mg of clonazepamand unscored tablets with a K-shaped perforation containing 1 mg or2 mg of clonazepam. Each tablet also contains lactose, magnesium stearate,microcrystalline cellulose and corn starch, with the following colorants:0.5 mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C BlueNo. 1 Lake and FD&C Blue No. 2 Lake.
Klonopinis also available as an orally disintegrating tablet containing 0.125mg, 0.25 mg, 0.5 mg, 1 mg or 2 mg clonazepam. Each orally disintegratingtablet also contains gelatin, mannitol, methylparaben sodium, propylparabensodium and xanthan gum.
Chemically, clonazepamis 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H -1,4-benzodiazepin-2-one. It is a light yellow crystallinepowder. It has a molecular weight of 315.72 and the following structuralformula:
CLINICAL PHARMACOLOGY
Pharmacodynamics
The precise mechanism by which clonazepam exertsits antiseizure and antipanic effects is unknown, although it is believedto be related to its ability to enhance the activity of gamma aminobutyricacid (GABA), the major inhibitory neurotransmitter in the centralnervous system. Convulsions produced in rodents by pentylenetetrazolor, to a lesser extent, electrical stimulation are antagonized, asare convulsions produced by photic stimulation in susceptible baboons.A taming effect in aggressive primates, muscle weakness and hypnosisare also produced. In humans, clonazepam is capable of suppressingthe spike and wave discharge in absence seizures (petit mal) and decreasingthe frequency, amplitude, duration and spread of discharge in minormotor seizures.
Pharmacokinetics
Clonazepam is rapidly and completely absorbed afteroral administration. The absolute bioavailability of clonazepam isabout 90%. Maximum plasma concentrations of clonazepam are reachedwithin 1 to 4 hours after oral administration. Clonazepam is approximately85% bound to plasma proteins. Clonazepam is highly metabolized, withless than 2% unchanged clonazepam being excreted in the urine. Biotransformationoccurs mainly by reduction of the 7-nitro group to the 4-amino derivative.This derivative can be acetylated, hydroxylated and glucuronidated.Cytochrome P-450 including CYP3A, may play an important role in clonazepamreduction and oxidation. The elimination half-life of clonazepam istypically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independentthroughout the dosing range. There is no evidence that clonazepaminduces its own metabolism or that of other drugs in humans.
Pharmacokinetics in Demographic Subpopulationsand in Disease States
Controlled studies examining the influence of genderand age on clonazepam pharmacokinetics have not been conducted, norhave the effects of renal or liver disease on clonazepam pharmacokineticsbeen studied. Because clonazepam undergoes hepatic metabolism, itis possible that liver disease will impair clonazepam elimination.Thus, caution should be exercised when administering clonazepam tothese patients.
Clinical Trials
Panic Disorder
The effectiveness of Klonopin in the treatment ofpanic disorder was demonstrated in two double-blind, placebo-controlledstudies of adult outpatients who had a primary diagnosis of panicdisorder (DSM-IIIR) with or without agoraphobia. In these studies,Klonopin was shown to be significantly more effective than placeboin treating panic disorder on change from baseline in panic attackfrequency, the Clinician's Global Impression Severity of Illness Scoreand the Clinician's Global Impression Improvement Score.
Study 1 was a 9-week, fixed-dose study involving Klonopindoses of 0.5, 1, 2, 3 or 4 mg/day or placebo. This study was conductedin four phases: a 1-week placebo lead-in, a 3-week upward titration,a 6-week fixed dose and a 7-week discontinuance phase. A significantdifference from placebo was observed consistently only for the 1 mg/daygroup. The difference between the 1 mg dose group and placebo in reductionfrom baseline in the number of full panic attacks was approximately1 panic attack per week. At endpoint, 74% of patients receiving clonazepam1 mg/day were free of full panic attacks, compared to 56% of placebo-treatedpatients.
Study 2 was a 6-week, flexible-dosestudy involving Klonopin in a dose range of 0.5 to 4 mg/day or placebo.This study was conducted in three phases: a 1-week placebo lead-in,a 6-week optimal-dose and a 6-week discontinuance phase. The meanclonazepam dose during the optimal dosing period was 2.3 mg/day. Thedifference between Klonopin and placebo in reduction from baselinein the number of full panic attacks was approximately 1 panic attackper week. At endpoint, 62% of patients receiving clonazepam were freeof full panic attacks, compared to 37% of placebo-treated patients.
Subgroup analyses did not indicate that there were anydifferences in treatment outcomes as a function of race or gender.
INDICATIONS AND USAGE
Seizure Disorders
Klonopin is useful alone or as an adjunct in thetreatment of the Lennox-Gastaut syndrome (petit mal variant), akineticand 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 lossof anticonvulsant activity, often within 3 months of administration.In some cases, dosage adjustment may reestablish efficacy.
Panic Disorder
Klonopin is indicated for the treatment of panicdisorder, with or without agoraphobia, as defined in DSM-IV. Panicdisorder is characterized by the occurrence of unexpected panic attacksand associated concern about having additional attacks, worry aboutthe implications or consequences of the attacks, and/or a significantchange in behavior related to the attacks.
Theefficacy of Klonopin was established in two 6- to 9-week trials inpanic disorder patients whose diagnoses corresponded to the DSM-IIIRcategory of panic disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpectedpanic attacks, ie, a discrete period of intense fear or discomfortin which four (or more) of the following symptoms develop abruptlyand reach a peak within 10 minutes: (1) palpitations, pounding heartor accelerated heart rate; (2) sweating; (3) trembling or shaking;(4) sensations of shortness of breath or smothering; (5) feeling ofchoking; (6) chest pain or discomfort; (7) nausea or abdominal distress;(8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization(feelings of unreality) or depersonalization (being detached fromoneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias(numbness or tingling sensations); (13) chills or hot flushes.
The effectiveness of Klonopin in long-term use, that is,for more than 9 weeks, has not been systematically studied in controlledclinical trials. The physician who elects to use Klonopin for extendedperiods should periodically reevaluate the long-term usefulness ofthe drug for the individual patient (see DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
Clonazepam is available as a tablet or an orallydisintegrating tablet (wafer). The tablets should be administeredwith water by swallowing the tablet whole. The orally disintegratingtablet should be administered as follows: After opening the pouch,peel back the foil on the blister. Do not push tablet through foil.Immediately upon opening the blister, using dry hands, remove thetablet and place it in the mouth. Tablet disintegration occurs rapidlyin saliva so it can be easily swallowed with or without water.
Seizure Disorders
Adults
The initial dose for adults with seizure disordersshould not exceed 1.5 mg/day divided into three doses. Dosage maybe increased in increments of 0.5 to 1 mg every 3 days until seizuresare adequately controlled or until side effects preclude any furtherincrease. Maintenance dosage must be individualized for each patientdepending upon response. Maximum recommended daily dose is 20 mg.
The use of multiple anticonvulsants may result in an increaseof depressant adverse effects. This should be considered before addingKlonopin to an existing anticonvulsant regimen.
Pediatric Patients
Klonopin is administered orally. In order to minimizedrowsiness, the initial dose for infants and children (up to 10 yearsof age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/daybut 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 thirdday until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weighthas been reached, unless seizures are controlled or side effects precludefurther increase. Whenever possible, the daily dose should be dividedinto three equal doses. If doses are not equally divided, the largestdose should be given before retiring.
Geriatric Patients
There is no clinical trial experience with Klonopinin seizure disorder patients 65 years of age and older. In general,elderly patients should be started on low doses of Klonopin and observedclosely (see PRECAUTIONS: GeriatricUse).
Panic Disorder
Adults
The initial dose for adults with panic disorder is0.25 mg bid. An increase to the target dose for most patients of 1mg/day may be made after 3 days. The recommended dose of 1 mg/dayis based on the results from a fixed dose study in which the optimaleffect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day inthat study were less effective than the 1 mg/day dose and were associatedwith more adverse effects. Nevertheless, it is possible that someindividual patients may benefit from doses of up to a maximum doseof 4 mg/day, and in those instances, the dose may be increased inincrements of 0.125 to 0.25 mg bid every 3 days until panic disorderis controlled or until side effects make further increases undesired.To reduce the inconvenience of somnolence, administration of one doseat bedtime may be desirable.
Treatment shouldbe discontinued gradually, with a decrease of 0.125 mg bid every 3days, until the drug is completely withdrawn.
There is no body of evidence available to answer the question ofhow long the patient treated with clonazepam should remain on it.Therefore, the physician who elects to use Klonopin for extended periodsshould periodically reevaluate the long-term usefulness of the drugfor the individual patient.
Pediatric Patients
There is no clinical trial experience with Klonopinin panic disorder patients under 18 years of age.
Geriatric Patients
There is no clinical trial experience with Klonopinin panic disorder patients 65 years of age and older. In general,elderly patients should be started on low doses of Klonopin and observedclosely (see PRECAUTIONS: GeriatricUse).
HOW SUPPLIED
Klonopin tablets are available as scored tabletswith a K-shaped perforation—0.5 mg, orange (NDC 0004-0068-01);and unscored tablets with a K-shaped perforation—1 mg, blue(NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottlesof 100.
Imprint on tablets:
0.5 mg — 1/2 KLONOPIN (front)
ROCHE(scored side)
1mg — 1 KLONOPIN (front)
ROCHE(reverse side)
ROCHE(reverse side)
KlonopinWafers (clonazepam orally disintegrating tablets) are white, roundand debossed with the tablet strength expressed as a fraction or wholenumber (1/8, 1/4, 1/2, 1, or 2). The tablets are available in blisterpackages of 60 (10 pouches/carton) as follows:
0.125 mg debossed 1/8, (NDC 0004-0279-22)
0.25 mgdebossed 1/4, (NDC0004-0280-22)
0.5mg debossed 1/2, (NDC 0004-0281-22)
1mg debossed 1, (NDC 0004-0282-22)
2mgdebossed 2, (NDC 0004-0283-22)
Store at25°C (77°F); excursions permitted to 15° to 30°C(59° to 86°F).
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.
ADVERSE REACTIONS
The adverse experiences for Klonopin are providedseparately for patients with seizure disorders and with panic disorder.
Seizure Disorders
The most frequently occurring side effects of Klonopinare referable to CNS depression. Experience in treatment of seizureshas shown that drowsiness has occurred in approximately 50% of patientsand ataxia in approximately 30%. In some cases, these may diminishwith 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 (the behavior effects are more likely to occur in patientswith a history of psychiatric disturbances). The following paradoxicalreactions have been observed: excitability, irritability, aggressivebehavior, agitation, nervousness, hostility, anxiety, sleep disturbances,nightmares and vivid dreams
Respiratory: Chest congestion, rhinorrhea,shortness of breath, hypersecretion in upper respiratory passages
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle andfacial 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
Miscellaneous: Dehydration,general deterioration, fever, lymphadenopathy, weight loss or gain
Hematopoietic: Anemia,leukopenia, thrombocytopenia, eosinophilia
Hepatic: Hepatomegaly, transient elevationsof serum transaminases and alkaline phosphatase
Panic Disorder
Adverse events during exposure to Klonopin were obtainedby spontaneous report and recorded by clinical investigators usingterminology of their own choosing. Consequently, it is not possibleto provide a meaningful estimate of the proportion of individualsexperiencing adverse events without first grouping similar types ofevents into a smaller number of standardized event categories. Inthe tables and tabulations that follow, CIGY dictionary terminologyhas been used to classify reported adverse events, except in certaincases in which redundant terms were collapsed into more meaningfulterms, as noted below.
The stated frequenciesof 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 thefirst time or worsened while receiving therapy following baselineevaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials
Adverse Events Associated With Discontinuationof Treatment
Overall, the incidence of discontinuation due toadverse events was 17% in Klonopin compared to 9% for placebo in thecombined data of two 6- to 9-week trials. The most common events (=1%)associated with discontinuation and a dropout rate twice or greaterfor Klonopin than that of placebo included the following:
Table 2Most Common Adverse Events(=1%) Associated with Discontinuation of Treatment Adverse Event Klonopin (N=574) Placebo (N=294)
Somnolence 7% 1%
Depression 4% 1%
Dizziness 1% <1%
Nervousness 1% 0%
Ataxia 1% 0%
Intellectual Ability Reduced 1% 0%
Adverse Events Occurring at an Incidenceof 1% or More Among Klonopin-Treated Patients
Table 3 enumeratesthe incidence, rounded to the nearest percent, of treatment-emergentadverse events that occurred during acute therapy of panic disorderfrom a pool of two 6- to 9-week trials. Events reported in 1% or moreof patients treated with Klonopin (doses ranging from 0.5 to 4 mg/day)and for which the incidence was greater than that in placebo-treatedpatients are included.
The prescriber shouldbe aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the courseof usual medical practice where patient characteristics and otherfactors differ from those that prevailed in the clinical trials. Similarly,the cited frequencies cannot be compared with figures obtained fromother clinical investigations involving different treatments, usesand investigators. The cited figures, however, do provide the prescribingphysician with some basis for estimating the relative contributionof drug and nondrug factors to the side effect incidence in the populationstudied.
Table3 Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-ControlledClinical TrialsEvents reported by at least 1% of patientstreated with Klonopin and for which the incidence was greater thanthat for placebo. ClonazepamMaximum Daily Dose
Adverse Event by Body System <1mg
n=96
% 1-<2mg
n=129
% 2-<3mg
n=113
% =3mg
n=235
% All Klonopin Groups
N=574
% Placebo
N=294
%
Central & Peripheral Nervous System
Somnolence 1 26 35 50 36 37 10
Dizziness 5 5 12 8 8 4
Coordination Abnormal 1 2 7 9 6 0
Ataxia 2 1 8 8 5 0
Dysarthria 0 0 4 3 2 0
Psychiatric
Depression 7 6 8 8 7 1
Memory Disturbance 2 5 2 5 4 2
Nervousness 1 4 3 4 3 2
Intellectual Ability Reduced 0 2 4 3 2 0
Emotional Lability 0 1 2 2 1 1
Libido Decreased 0 1 3 1 1 0
Confusion 0 2 2 1 1 0
Respiratory System
Upper Respiratory Tract Infection 10 10 7 6 8 4
Sinusitis 4 2 8 4 4 3
Rhinitis 3 2 4 2 2 1
Coughing 2 2 4 0 2 0
Pharyngitis 1 1 3 2 2 1
Bronchitis 1 0 2 2 1 1
Gastrointestinal System
Constipation 0 1 5 3 2 2
Appetite Decreased 1 1 0 3 1 1
Abdominal Pain 2 2 2 0 1 1
Body as a Whole
Fatigue 9 6 7 7 7 4
Allergic Reaction 3 1 4 2 2 1
Musculoskeletal
Myalgia 2 1 4 0 1 1
Resistance Mechanism Disorders
Influenza 3 2 5 5 4 3
Urinary System
Micturition Frequency 1 2 2 1 1 0
Urinary Tract Infection 0 0 2 2 1 0
Vision Disorders
Blurred Vision 1 2 3 0 1 1
Reproductive DisordersDenominatorsfor events in gender-specific systems are: n=240 (clonazepam), 102(placebo) for male, and 334 (clonazepam), 192 (placebo) for female.
Female
Dysmenorrhea 0 6 5 2 3 2
Colpitis 4 0 2 1 1 1
Male
Ejaculation Delayed 0 0 2 2 1 0
Impotence 3 0 2 1 1 0
1 Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel)for adverse event incidence was =0.10.
Commonly Observed Adverse Events
Table 4 Incidenceof Most Commonly Observed Adverse EventsTreatment-emergentevents for which the incidence in the clonazepam patients was =5%and at least twice that in the placebo patients. in AcuteTherapy in Pool of 6- to 9-Week Trials Adverse Event
(Roche PreferredTerm) 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-controlledtrials, adverse events classified under the preferred term "depression"were reported in 7% of Klonopin-treated patients compared to 1% ofplacebo-treated patients, without any clear pattern of dose relatedness.In these same trials, adverse events classified under the preferredterm "depression" were reported as leading to discontinuation in 4%of Klonopin-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 inHAM-D scores in the clonazepam group than the placebo group suggestingthat clonazepam-treated patients were not experiencing a worseningor emergence of clinical depression.
Other Adverse Events Observed Duringthe Premarketing Evaluation of Klonopin in Panic Disorder
Following is a list of modified CIGY terms that reflecttreatment-emergent adverse events reported by patients treated withKlonopin at multiple doses during clinical trials. All reported eventsare included except those already listed in Table 3 or elsewhere in labeling, those events for whicha drug cause was remote, those event terms which were so general asto be uninformative, and events reported only once and which did nothave a substantial probability of being acutely life-threatening.It is important to emphasize that, although the events occurred duringtreatment with Klonopin, they were not necessarily caused by it.
Events are further categorized by body system and listedin order of decreasing frequency. These adverse events were reportedinfrequently, 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: abdominaldiscomfort, gastrointestinal inflammation, stomach upset, toothache,flatulence, pyrosis, saliva increased, tooth disorder, bowel movementsfrequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolicand Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, painnape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swellingknee
Platelet,Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreamingexcessive, libido loss, appetite increased, libido increased, reactionsdecreased, aggressive reaction, apathy, attention lack, excitement,feeling mad, hunger abnormal, illusion, nightmares, sleep disorder,suicide ideation, yawning
Reproductive Disorders, Female: breastpain, menstrual irregularity
Reproductive Disorders, Male: ejaculationdecreased
ResistanceMechanism Disorders: infection mycotic, infection viral,infection streptococcal, herpes simplex infection, infectious mononucleosis,moniliasis
RespiratorySystem Disorders: sneezing excessive, asthmatic attack,dyspnea, nosebleed, pneumonia, pleurisy
Skin and Appendages Disorders: acneflare, alopecia, xeroderma, dermatitis contact, flushing, pruritus,pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
UrinarySystem Disorders: dysuria, cystitis, polyuria, urinary incontinence,bladder dysfunction, urinary retention, urinary tract bleeding, urinediscoloration
Vascular(Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes,visual field defect, xerophthalmia
REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO KLONOPIN
Below is a sample of reports where side effects / adverse reactions may be related to Klonopin. The information is not vetted and should not be cosidered as verified clinical evidence.
Possible Klonopin side effects / adverse reactions in 40 year old female
Reported by a consumer/non-health professional from United States on 2009-04-02
Patient: 40 year old female
Reactions: Road Traffic Accident, Loss of Consciousness
Adverse event resulted in: hospitalization
Suspect drug(s):
Ambien CR
Dosage: unk
Administration route: Oral
Indication: Insomnia
Klonopin
Dosage: unk
Administration route: Oral
Indication: Drug USE FOR Unknown Indication
Seroquel
Dosage: unk
Indication: Drug USE FOR Unknown Indication
Possible Klonopin side effects / adverse reactions in 82 year old female
Reported by a individual with unspecified qualification from United States on 2009-04-06
Patient: 82 year old female weighing 68.0 kg (149.7 pounds)
Reactions: Overdose, Unresponsive TO Stimuli, Pulse Absent
Adverse event resulted in: life threatening event, hospitalization, disablity
Suspect drug(s):
Klonopin
Possible Klonopin side effects / adverse reactions in 59 year old male
Reported by a consumer/non-health professional from United States on 2009-04-08
Patient: 59 year old male
Reactions: Completed Suicide
Adverse event resulted in: death
Suspect drug(s):
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.
OVERDOSAGE
Human Experience
Symptoms of clonazepam overdosage, like those producedby other CNS depressants, include somnolence, confusion, coma anddiminished reflexes.
Overdose Management
Treatment includes monitoring of respiration, pulseand blood pressure, general supportive measures and immediate gastriclavage. Intravenous fluids should be administered and an adequateairway maintained. Hypotension may be combated by the use of levarterenolor metaraminol. Dialysis is of no known value.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicatedfor the complete or partial reversal of the sedative effects of benzodiazepinesand may be used in situations when an overdose with a benzodiazepineis known or suspected. Prior to the administration of flumazenil,necessary measures should be instituted to secure airway, ventilationand intravenous access. Flumazenil is intended as an adjunct to, notas a substitute for, proper management of benzodiazepine overdose.Patients treated with flumazenil should be monitored for resedation,respiratory depression and other residual benzodiazepine effects foran appropriate period after treatment. Theprescriber should be aware of a risk of seizure in association withflumazenil treatment, particularly in long-term benzodiazepine usersand in cyclic antidepressant overdose. The complete flumazenilpackage insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted priorto use.
Flumazenilis not indicated in patients with epilepsy who have been treated withbenzodiazepines. Antagonism of the benzodiazepine effect in such patientsmay provoke seizures.
Serious sequelaeare rare unless other drugs or alcohol have been taken concomitantly.
CONTRAINDICATIONS
Klonopin should not be used in patients with a historyof sensitivity to benzodiazepines, nor in patients with clinical orbiochemical evidence of significant liver disease. It may be usedin patients with open angle glaucoma who are receiving appropriatetherapy but is contraindicated in acute narrow angle glaucoma.
