Included as part of the "PRECAUTIONS" Section
Risks From Concomitant Use With Opioids
Concomitant use of benzodiazepines, including SYMPAZAN™, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe SYMPAZAN™ concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when SYMPAZAN™ is used with opioids [see DRUG INTERACTIONS].
Potentiation Of Sedation From Concomitant Use With Central Nervous System Depressants
Since SYMPAZAN™ 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 [see DRUG INTERACTIONS].
Somnolence Or Sedation
SYMPAZAN™ causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related [see ADVERSE REACTIONS].
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 SYMPAZAN™ is known.
Abrupt discontinuation of SYMPAZAN™ should be avoided. SYMPAZAN™ should be tapered by decreasing the dosage every week by 5-10 mg/day until discontinuation [see DOSAGE AND ADMINISTRATION].
Withdrawal symptoms occurred following abrupt discontinuation of SYMPAZAN™; the risk of withdrawal symptoms is greater with higher doses.
As with most antiepileptic drugs, SYMPAZAN™ should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.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.
Serious Dermatological Reactions
Serious skin reactions, including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam 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. SYMPAZAN™ 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 [see CONTRAINDICATIONS].
Physical And Psychological Dependence
Patients with a history of substance abuse should be under careful surveillance when receiving SYMPAZAN™ 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 SYMPAZAN™, 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.
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
||Placebo Patients with Events per 1000 Patients
||Drug Patients with Events per 1000 Patients
Incidence of Drug Events in Drug Patients/ Incidence in Placebo Patients
Additional Drug Patients with Events per 1000 Patients
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 SYMPAZAN™ 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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Risks From Concomitant Use With Opioids
Inform patients and caregivers that potentially fatal additive effects may occur if SYMPAZAN™ is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS , DRUG INTERACTIONS].
Somnolence Or Sedation
Advise patients or caregivers to check with their healthcare provider before SYMPAZAN™ 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 SYMPAZAN™ does not affect them adversely (e.g., impair judgment, thinking or motor skills).
Increasing Or Decreasing The Sympazantm Dose
Inform patients or caregivers to consult their healthcare provider before increasing the SYMPAZAN™ dose or abruptly discontinuing SYMPAZAN™. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure [see DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS].
Inform patients or caregivers that SYMPAZAN™ is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients [see WARNINGS AND PRECAUTIONS].
Interactions With Hormonal Contraceptives
Counsel women to also use non-hormonal methods of contraception when SYMPAZAN™ is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing SYMPAZAN™ 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 clobazam. 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 SYMPAZAN™, 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 SYMPAZAN™, 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
Advise pregnant women and women of childbearing potential that the use of ONFI during pregnancy can cause fetal harm which may occur early in pregnancy before many women know they are pregnant. Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.
Advise patients that there is a pregnancy registry that collects information about the safety of antiepileptic drugs during pregnancy [see Use In Specific Populations].
Use In Lactation
Counsel patients that SYMPAZAN™ is excreted in breast milk. Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy and counsel nursing mothers to observe their infants for poor sucking and somnolence [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for 2 years did not result in an increase in tumors. The highest dose tested was approximately 3 times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2).
In rats, oral administration of clobazam for 2 years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD.
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
In a fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84, and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN™, during pregnancy. Physicians are advised to recommend that pregnant patients taking SYMPAZAN™ 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. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
There are no adequate and well-controlled studies of SYMPAZAN™ in pregnant women. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. Although some early epidemiological studies suggested a relationship between benzodiazepine drug use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations. More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies. There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment. There are clinical considerations regarding exposure to benzodiazepines during the second and third trimester of pregnancy or immediately prior to or during childbirth. These risks include decreased fetal movement and/or fetal heart rate variability, “floppy infant syndrome,” dependence, and withdrawal [see Clinical Considerations and Human Data]. Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data].
Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
SYMPAZAN™ should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Advise pregnant women and women of childbearing age of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and to 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Fetal/Neonatal Adverse Reactions
Infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Observe newborns who are exposed to SYMPAZAN™ in utero during the later stages of pregnancy for symptoms of withdrawal and manage accordingly.
Labor and Delivery
Administration of benzodiazepines immediately prior to or during childbirth can result in a floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe exposed newborns for these symptoms and manage accordingly.
Although there are no adequate and well controlled studies of SYMPAZAN™ in pregnant women, there is information about benzodiazepines as a class. Dolovich et al. published a metaanalysis of 23 studies that examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. The authors considered case-control and cohort studies separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61— 1.35) or for oral cleft (OR 1.19; 95% CI 0.34—4.15). The data from the case control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32—6.84) and oral cleft (OR 1.79; 95% CI 1.13— 2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only three studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and one study that considered cardiac malformations. The authors found no new studies with an outcome of oral clefts. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91—1.25).
Neonatal Withdrawal and Floppy Infant Syndrome
Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of clobazam during the later stages of pregnancy and peripartum period have been reported in the postmarketing experience. Findings in published scientific literature suggest that the major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. Data from observational studies suggest that fetal exposure to benzodiazepines is associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome.
In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and Ndesmethylclobazam lower than those in humans at the MRHD.
Oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low-effect dose for adverse effects on pre-and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
SYMPAZAN™ is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as SYMPAZAN™, may have effects of lethargy, somnolence and poor sucking. The effect of SYMPAZAN™ on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMPAZAN™ and any potential adverse effects on the breastfed infant from SYMPAZAN™ or from the underlying maternal condition. If exposing a breastfed infant to SYMPAZAN™, observe for any potential adverse effects.
Monitoring for Adverse Reactions
Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Monitor breastfed infants for possible sedation and poor sucking. Data Scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.
Females And Males Of Reproductive Potential
Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology].
Safety and effectiveness for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients 2 years of age and older have been established in two adequate and well-controlled studies [see Clinical Studies].
Safety and effectiveness in patients less than 2 years of age have not been established.
Juvenile Animal Data
In a study in which clobazam (0, 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.
Clinical studies of clobazam 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, dosage modification is recommended [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].
The pharmacokinetics of clobazam 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 SYMPAZAN™ in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, Ndesmethylclobazam, is dialyzable [see CLINICAL PHARMACOLOGY].
SYMPAZAN™ is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9) [see DOSAGE AND ADMINISTRATION]. There is inadequate information about metabolism of SYMPAZAN™ in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].