Sympazan
clobazam · Film · Oral
Uses
1 INDICATIONS AND USAGE SYMPAZAN ® is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older. SYMPAZAN ® is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older ( 1 ).
Dosage and administration
For doses above 5 mg/day, administer in two divided doses ( 2.1 ) Patients weighing 30 kg or less: Initiate at 5 mg daily, and titrate as tolerated up to 20 mg daily ( 2.1 ) Patients weighing greater than 30 kg: Initiate at 10 mg daily, and titrate as tolerated up to 40 mg daily ( 2.1 ) Dosage adjustment is needed in following groups: ○ Geriatric patients ( 2.4 , 8.5 ) ○ Known CYP2C19 poor metabolizers ( 2.5 ) ○ Mild or moderate hepatic impairment; no information for severe hepatic impairment ( 2.6 , 8.8 ) Can be taken with or without food ( 2.3 ) Do not administer with liquids ( 2.3 ) 2.1 Dosing Information A daily dose of SYMPAZAN ® greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies (14) ]. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state. Table 1: Recommended Total Daily Dosing by Weight Group 30 kg or Less Body Weight Greater than 30 kg Body Weight Starting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg 2.2 Discontinuation or Dosage Reduction of SYMPAZAN To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue SYMPAZAN or reduce the dosage . Taper by decreasing the total daily dosage by 5-10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3) ]. 2.3 Important Administration Instructions Instruct patients and/or caregivers to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer SYMPAZAN ® oral films. Apply SYMPAZAN ® on top of the tongue where it adheres and dissolves. SYMPAZAN® oral film can be taken with or without food [see Clinical Pharmacology (12.3) ]. Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking. Only one oral film should be taken at a time; if a second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved. 2.4 Dosage Adjustments in Geriatric Patients Plasma concentrations at any given dose are generally higher in geriatric patients [see Clinical Pharmacology (12.3) ]. Therefore, the starting dosage should generally be 5 mg/day for all geriatric patients. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.5) ]. 2.5 Dosage Adjustments in CYP2C19 Poor Metabolizers In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased [see Clinical Pharmacology (12.5) ]. Therefore, the starting dosage should be 5 mg/day in patients known to be CYP2C19 poor metabolizers. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.6) ]. 2.6 Dosage Adjustments in Patients with Hepatic Impairment SYMPAZAN ® is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of SYMPAZAN ® . For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dosage should be 5 mg/day (regardless of weight). Then proceed slowly with dosing escalations; titrate patients according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21. There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment. Therefore, no dosing recommendation can be given for those patients [see Use in Specific Populations (8.8) , Clinical Pharmacology (12 .3) ].
Dosage forms and strengths
3 DOSAGE FORMS AND STRENGTHS SYMPAZAN ® Oral Film: Thin, white, rectangular, orally dissolving film strips: 5 mg imprinted with C5 10 mg imprinted with C10 20 mg imprinted with C20 Oral Film: 5 mg, 10 mg and 20 mg ( 3 )
Contraindications
4 CONTRAINDICATIONS SYMPAZAN ® is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions (5.6) ]. History of hypersensitivity to the drug or its ingredients ( 4 )
Warnings and precautions
Somnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants ( 5.4 , 5.5 ) Serious Dermatological Reactions (including Stevens-Johnson Syndrome and toxic epidermal necrolysis): Discontinue SYMPAZAN ® at first sign of rash unless the rash is clearly not drug-related ( 5.6 ) Drug Reaction with Eosinophilia and Systemic Symptoms (Dress)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.7 ) Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors ( 5.8 ) Neonatal Sedation and Withdrawal Syndrome: SYMPAZAN use during pregnancy can result in neonatal sedation and/or neonatal withdrawal ( 5.9 , 8.1 ) 5.1 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 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 (7.1) ]. 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including SYMPAZAN, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2) ]. Before prescribing SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of SYMPAZAN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SYMPAZAN along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) ]. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3) ]. Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3) ]. 5.4 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 (7.2) ]. 5.5 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 (6.1) ]. 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. 5.6 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 (4) ].
Side effects
Clinically significant adverse reactions that appear in other sections of the labeling include the following: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions (5.4) ] Somnolence or Sedation [see Warnings and Precautions (5.5) ] Serious Dermatological Reactions [see Contraindications (4) , Warnings and Precautions (5.6) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.7) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.8) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9) ] Adverse reactions that occurred at least 10% more frequently than placebo in any clobazam dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse events have been reported in clinical trials of patients treated with clobazam, the active ingredient of SYMPAZAN ® . During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more. The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2) [see Clinical Studies (14) ]. Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo. Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1) The adverse reactions associated with clobazam treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia. Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1) Table 3 lists the adverse reactions that occurred in ≥5% of clobazam-treated patients (at any dose), and at a rate greater than placebo-treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1). Table 3: Adverse Reactions Reported for ≥5% of Patients and More Frequently than Placebo in Any Treatment Group Clobazam Dose Level All Clobazam N=179 % Placebo N=59 % Low a N=58 % Medium b N=62 % High c N=59 % Gastrointestinal Disorders Vomiting 5 9 5 7 7 Constipation 0 2 2 10 5 Dysphagia 0 0 0 5 2 General Disorders and Administration Site Conditions Pyrexia 3 17 10 12 13 Irritability 5 3 11 5 7 Fatigue 2 5 5 3 5 Infections and Infestations Upper respiratory tract infection 10 10 13 14 12 Pneumonia 2 3 3 7 4 Urinary tract infection 0 2 5 5 4 Bronchitis 0 2 0 5 2 Metabolism and Nutrition Disorders Decreased appetite 3 3 0 7 3 Increased appetite 0 2 3 5 3 Nervous System Disorders Somnolence or Sedation 15 17 27 32 26 Somnolence 12 16 24 25 22 Sedation 3 2 3 9 5 Lethargy 5 10 5 15 10 Drooling 3 0 13 14 9 Ataxia 3 3 2 10 5 Psychomotor hyperactivity 3 3 3 5 4 Dysarthria 0 2 2 5 3 Psychiatric Disorders Aggression 5 3 8 14 8 Insomnia 2 2 5 7 5 Respiratory Disorders Cough 0 3 5 7 5 a Maximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight b Maximum daily dose of 10 mg for ≤30 kg body weight; 20 mg for >30 kg body weight c Maximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clobazam tablets. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class. Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia Eye Disorders: Diplopia, vision blurred Gastrointestinal Disorders: Abdominal distention General Disorders and Administration Site Conditions: Hypothermia Investigations: Hepatic enzyme increased Musculoskeletal: Muscle spasms Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucination Renal and Urinary Disorders: Urinary retention Respiratory Disorders: Aspiration, respiratory depression Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema
Drug interactions
Alcohol: Increases blood levels of clobazam by about 50% ( 7.2 ) Drugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with SYMPAZAN ® ( 7.3 ) Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of SYMPAZAN ® may be necessary ( 7.4 ) Cannabidiol: May increase risk of SYMPAZAN-related adverse reactions; consider dosage adjustment if this occurs ( 7.4 ) 7.1 Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1) ]. 7.2 CNS Depressants and Alcohol Concomitant use of SYMPAZAN ® with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions (5.4) ]. Alcohol, as a CNS depressant, will interact with SYMPAZAN ® in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated [see Warnings and Precautions (5.4) ]. 7.3 Effect of SYMPAZAN ® on Other Drugs Hormonal Contraceptives SYMPAZAN ® is a weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with SYMPAZAN ® . Additional non-hormonal forms of contraception are recommended when using SYMPAZAN ® [see Clinical Pharmacology (12.3) , Patient Counseling Information (17) ]. Drugs Metabolized by CYP2D6 SYMPAZAN ® inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology (12.3) ]. 7.4 Effect of Other Drugs on SYMPAZAN ® Strong and Moderate Inhibitors of CYP2C19 Coadministration with strong or moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of clobazam. This may increase the risk of dose-related adverse reactions. Dosage adjustment of SYMPAZAN ® may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) [see Clinical Pharmacology (12.3) ]. Effect of Cannabidiol on SYMPAZAN ® Coadministration of cannabidiol, a CYP3A4 and CYP2C19 substrate and a CYP2C19 inhibitor, with clobazam may increase the risk of clobazam-related adverse reactions [ see Warnings and Precautions (5.4, 5.5) , Clinical Pharmacology (12.3) ]. Consider a reduction in dosage of cannabidiol or clobazam if adverse reactions known to occur with SYMPAZAN are experienced.
Use in specific populations
Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN ® , during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN ® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/ Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.9) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15% -20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data 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 N-desmethylclobazam 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 preand 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. 8.2 Lactation Risk Summary SYMPAZAN ® is excreted in human milk (see Data). There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of clobazam on milk production. 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. Clinical Considerations Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Infants exposed to SYMPAZAN through breast milk should be monitored for sedation, poor feeding and poor weight gain. Data Scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk. 8.3 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 (13.1) ].
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN ® , during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN ® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/ Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.9) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15% -20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data 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 N-desmethylclobazam 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 preand 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.
Pediatric use
8.4 Pediatric Use 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 (14) ]. 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.
Geriatric use
8.5 Geriatric Use 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 (2.4) , Clinical Pharmacology (12.3) ].
Overdosage
Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2) ]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Description
11 DESCRIPTION SYMPAZAN ® contains clobazam, a benzodiazepine derivative, which is chemically known as 7-Chloro-1-methyl-5-phenyl-1 H -1,5 benzodiazepine-2,4( 3H , 5H )-dione with a molecular formula of C 16 H 13 ClN 2 O 2 , molecular weight of 300.74, and it has the following structural formula: Clobazam is a white or almost white, crystalline powder with a slightly bitter taste. It is slightly soluble in water and sparingly soluble in ethanol. Each SYMPAZAN ® Oral Film contains 5 mg, 10 mg or 20 mg of clobazam and the following inactive ingredients: artificial cooling flavor, citric acid, glycerol monooleate, hypromellose, maltitol, natural and artificial bitter masker, natural raspberry type flavor, polyethylene oxide, purified water, sodium phosphate dibasic, and sucralose. The following structural formula for SYMPAZANTM contains -clobazam,a benzodiazepine derivative, which is chemically known as 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione with a molecular formula of C16H13 ClN2O2 , molecular weight of 300.74.
Mechanism of action
12.1 Mechanism of Action The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor.
How supplied
Each SYMPAZAN ® oral film is a white rectangular film that contains 5 mg, 10 mg or 20 mg of clobazam and printed in black ink either "C5,” "C10" or "C20" on the strip according to their respective strengths and each film is packaged in a pouch (sachet). NDC 10094-205-60: 5 mg oral film, Package of 60 NDC 10094-210-60: 10 mg oral film, Package of 60 NDC 10094-220-60: 20 mg oral film, Package of 60 Store SYMPAZAN ® oral film pouches (sachets) at 20°C to 25°C (68°F to 77°F); Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature].
Patient 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 (5.1) , Drug Interactions (7.1) ]. Abuse, Misuse, and Addiction Inform patients that the use of SYMPAZAN, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances . Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2) ]. Withdrawal Reactions Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure. Inform patients that the continued use of SYMPAZAN may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SYMPAZAN may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of SYMPAZAN may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3) ]. 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 (5.4 , 5.5) ]. 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). Hypersensitivity 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 (5.6) ]. 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 (7.3) , Clinical Pharmacology (12.3) ]. 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 (5.6) ]. DRESS/Multiorgan Hypersensitivity Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. SYMPAZAN should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions ( 5.7) ] . 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 (5.8) ]. Pregnancy Advise pregnant females that the use of SYMPAZAN ® late in pregnancy can result in in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1) ]. Instruct patients to notify their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while taking SYMPAZAN. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Counsel patients that clobazam, the active ingredient in SYMPAZAN ® , is excreted in breast milk. Instruct patients to notify their healthcare provider if they are breast feeding or intend to breastfeed. Instruct breastfeeding patients who take SYMPAZAN to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2) ]. Manufactured by: Aquestive Therapeutics Warren, NJ 07059
Label text from the FDA structured product label by Aquestive Therapeutics (revised Dec 1, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Clobazam in 3 products
Sympazan NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 10094-205 | Clobazam 5 mg/1 Film | Aquestive Therapeutics | NDA · DEA CIV |
| 10094-210 | Clobazam 10 mg/1 Film | Aquestive Therapeutics | NDA · DEA CIV |
| 10094-220 | Clobazam 20 mg/1 Film | Aquestive Therapeutics | NDA · DEA CIV |
Frequently asked questions
What is Sympazan used for?
1 INDICATIONS AND USAGE SYMPAZAN ® is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older. SYMPAZAN ® is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older ( 1 ).
What are the side effects of Sympazan?
Clinically significant adverse reactions that appear in other sections of the labeling include the following: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Potentiation of Sedation from Concomitant Use with Central Nervous… See the full label for the complete list.
Who makes Sympazan?
Sympazan is listed by 1 labeler in the FDA NDC directory, including Aquestive Therapeutics.