April 28, 2016
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Included as part of the PRECAUTIONS section.


Somnolence Or Sedation

ONFI causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.

In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of ONFI is known.

Potentiation Of Sedation From Concomitant Use With Central Nervous System Depressants

Since ONFI has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.

Withdrawal Symptoms

Abrupt discontinuation of ONFI should be avoided. ONFI should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation [see DOSAGE AND ADMINISTRATION].

Withdrawal symptoms occurred following abrupt discontinuation of ONFI; the risk of withdrawal symptoms is greater with higher doses.

As with all antiepileptic drugs, ONFI should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.

Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation. Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.

Physical And Psychological Dependence

Patients with a history of substance abuse should be under careful surveillance when receiving ONFI or other psychotropic agents because of the predisposition of such patients to habituation and dependence [see Drug Abuse and Dependence].

Suicidal Behavior And Ideation

Antiepileptic drugs (AEDs), including ONFI, 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.

Serious Dermatological Reactions

Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with ONFI in both children and adults during the post-marketing period. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. ONFI should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug 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 behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing ONFI 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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

Inform patients or caregivers of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with ONFI and with each prescription refill. Review the ONFI Medication Guide with every patient or caregiver prior to initiation of treatment. Instruct patients or caregivers that ONFI should be taken only as prescribed.

Somnolence Or Sedation

Advise patients or caregivers to check with their healthcare provider before ONFI is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol [see WARNINGS AND PRECAUTIONS].

If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that ONFI does not affect them adversely (e.g., impair judgment, thinking or motor skills).

Increasing Or Decreasing The ONFI Dose

Inform patients or caregivers to consult their healthcare provider before increasing the ONFI dose or abruptly discontinuing ONFI. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Interactions With Hormonal Contraceptives

Counsel women to also use non-hormonal methods of contraception when ONFI is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing ONFI to ensure contraceptive reliability [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

Serious Dermatological Reactions

Advise patients or caregivers that serious skin reactions have been reported in patients taking ONFI. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking ONFI, patients or caregivers should consult with healthcare providers immediately [see WARNINGS AND PRECAUTIONS].

Suicidal Thinking And Behavior

Counsel patients, their caregivers, and their families that AEDs, including ONFI, may increase the risk of suicidal thoughts and behavior and advise them 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 of self-harm. Patients should report behaviors of concern immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].

Use In Pregnancy

Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

Encourage patients to enroll in the 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 1-888233-2334. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org [see Use in Specific Populations].

Use In Nursing

Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility


The carcinogenic potential of clobazam has not been adequately assessed.

In a limited study in rats, oral administration of clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.


Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays. Impairment of Fertility

There are no adequate studies of the effects of clobazam on fertility.

Use In Specific Populations


Pregnancy Registry

To provide information regarding the effects of in utero exposure to ONFI, physicians are advised to recommend that pregnant patients taking ONFI enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Pregnancy Category C

There are no adequate and well-controlled studies of ONFI in pregnant women and no adequate developmental toxicity studies of clobazam in animals.

Although limited, the available animal data suggest developmental toxicity, including an increased incidence of fetal abnormalities following oral administration of clobazam to pregnant animals at doses similar to those used clinically.

Data for other benzodiazepines suggest the possibility of adverse effects in animals and humans. Long-term effects on neurobehavioral and immunological function have been reported in rodents following prenatal exposure to benzodiazepines. Neonatal flaccidity, respiratory and feeding difficulties, hypothermia, and withdrawal symptoms have been reported in infants born to mothers who received benzodiazepines, including clobazam, late in pregnancy.

Therefore, ONFI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

ONFI is excreted in human milk. The effects of this exposure on infants are unknown.

Pediatric Use

The safety and effectiveness in patients less than 2 years of age have not been established.

In a study in which clobazam (4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.

Geriatric Use

Clinical studies of ONFI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day. Patients should be titrated initially to 10-20 mg/day. Patients may be titrated further to a maximum daily dose of 40 mg if tolerated [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

CYP2C19 Poor Metabolizers

Concentrations of clobazam's active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in extensive metabolizers. For this reason, dosage modification is recommended [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Renal Impairment

The pharmacokinetics of ONFI were evaluated in patients with mild and moderate renal impairment. There were no significant differences in systemic exposure (AUC and Cmax) between patients with mild or moderate renal impairment and healthy subjects. No dose adjustment is required for patients with mild and moderate renal impairment. There is essentially no experience with ONFI in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hepatic Impairment

ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 12/4/2013


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