ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. 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 )] Suicidal Behavior and Ideation [see Warnings and Precautions 5.7 )] 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 )] Suicidal Behavior and Ideation [see Warnings and Precautions 5.7 )] 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 Aquestive Therapeutics at 1-877-394-5045 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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(R).During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with 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 and 2) [see Clinical Studies 14 )]. Only Study included 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 lists the adverse reactions that occurred in >=5% of clobazam-treated patients (at any dose), and at 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 GroupClobazam Dose LevelAll ClobazamN=179%PlaceboN=59%LowaN=58% MediumbN=62% HighcN=59% Gastrointestinal DisordersVomiting 9 7 Constipation 2 10 Dysphagia 0 5 General Disorders and Administration Site ConditionsPyrexia 17 10 12 13 Irritability 3 11 7 Fatigue 5 3 Infections and InfestationsUpper respiratory tract infection 10 10 13 14 12 Pneumonia 3 7 Urinary tract infection 2 5 Bronchitis 2 5 Metabolism and Nutrition DisordersDecreased appetite 3 7 Increased appetite 2 5 Nervous System DisordersSomnolence or Sedation 15 17 27 32 26 Somnolence 12 16 24 25 22 Sedation 2 9 Lethargy 10 15 10 Drooling 0 13 14 Ataxia 3 10 Psychomotor hyperactivity 3 5 Dysarthria 2 5 Psychiatric DisordersAggression 3 14 Insomnia 2 7 Respiratory DisordersCough 3 7 a Maximum daily dose of mg for <=30 kg body weight; 10 mg for >30 kg body weight Maximum daily dose of 10 mg for <=30 kg body weight; 20 mg for >30 kg body weight Maximum daily dose of 20 mg for <=30 kg body weight; 40 mg for >30 kg body weight. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of clobazam tablets. These reactions are reported voluntarily from population of uncertain size; therefore, it is not possible to estimate their frequency or establish 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 retentionRespiratory Disorders: Aspiration, respiratory depression Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema.

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; AND DEPENDENCE AND WITHDRAWAL REACTIONS. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1), and Drug Interactions (7.1)].The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing SYMPAZAN and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1), and Drug Interactions (7.1)].. The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing SYMPAZAN and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].. The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS;ABUSE, MISUSE, AND ADDICTION; AND DEPENDENCE AND WITHDRAWAL REACTIONSSee full prescribing information for complete boxed warning.Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. (5.1, 7.1). The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SYMPAZAN and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2).Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue SYMPAZAN or reduce the dosage (2.2, 5.3).. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. (5.1, 7.1). The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SYMPAZAN and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2).. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue SYMPAZAN or reduce the dosage (2.2, 5.3).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. The exact mechanism of action for clobazam, 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 GABAA receptor.. 12.2Pharmacodynamics. Effects on ElectrocardiogramThe effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.. 12.3Pharmacokinetics. SYMPAZAN(R) Oral Films at single doses of 10 mg and 20 mg clobazam have been shown to be bioequivalent (Cm x and AUC) to clobazam tablets at equivalent doses. Following single-dose administration of SYMPAZAN(R), peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-20 mg. Based on population pharmacokinetic analysis with clobazam tablets, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t1/2) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.AbsorptionThe time to peak concentrations (Tm x) of SYMPAZAN(R) clobazam oral film under fasted conditions ranged from 0.33 to 4.0 hours after single-dose administration. The administration of clobazam tablets with food does not affect absorption. Although not studied, the oral bioavailability of SYMPAZAN(R) oral film is unlikely to be affected under fed conditions.DistributionClobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.Metabolism and ExcretionClobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethyl clobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam [see Clinical Pharmacology 12.4 )]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.Pharmacokinetics in Specific PopulationsAgePopulation pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages less than 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].SexPopulation pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.RacePopulation pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.Renal ImpairmentThe effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day. There were insignificant changes in Cmax (3-24%) and AUC (<=13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function. Patients with severe renal impairment or ESRD were not included in this study.Hepatic ImpairmentThere are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. In small study, the pharmacokinetics of 20 mg single oral dose of clobazam in patients with liver impairment were compared to healthy controls (N=6). The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls. The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment [see Dosage and Administration (2.6)].Drug Interaction StudiesIn vitro studies:Clobazam did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro. N-desmethylclobazam showed weak inhibition of CYP2C9, UGT1A4, UGT1A6 and UGT2B4.Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in concentration-dependent manner. Clobazam and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels. The potential for clobazam or N-desmethylclobazam to induce CYP2B6 and CYP2C8 has not been evaluated.Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.In vivo studies:Potential for Clobazam to Affect Other DrugsThe effect of repeated 40 mg once-daily doses of clobazam on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as drug cocktail (N=18).Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo. Drugs metabolized by CYP2D6 may require dose adjustment when used with clobazam.Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively. This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with clobazam. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with SYMPAZAN(R) [see Drug Interactions 7.3 )]. Repeated clobazam doses had no effect on caffeine and tolbutamide.A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).Potential for Other Drugs to Affect SYMPAZAN(R)Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax. There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18). Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data [see Clinical Pharmacology 12.4 )]. Dosage adjustment of SYMPAZAN(R) may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions 7.4 )].Coadministration of cannabidiol (a CYP3A4 and CYP2C19 substrate; an inhibitor of CYP2C19) produced 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19). This may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions 5.4 5.5 , Drug Interaction ( 7.4 )].The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C19 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials. Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with SYMPAZAN(R) [see Warnings and Precautions 5.4 ), Drug Interactions 7.2 )].. 12.4Pharmacogenomics. The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N-desmethyl-clobazam. Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3-5 times higher in poor metabolizers (e.g., subjects with 2/2 genotype) and times higher in intermediate metabolizers (e.g., subjects with 1/2 genotype). The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background. Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted [see Dosage and Administration 2.5 )].The systemic exposure of clobazam is similar for both CYP2C19 poor and extensive metabolizers.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. Figure 1:Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1). Figure 2:Drop Seizure Response by Category for Clobazam and Placebo (Study 1). 14.1Demonstration of Pharmacokinetic Equivalence Between SYMPAZAN(R) and Clobazam Tablets. The efficacy of SYMPAZAN(R) is based upon bioavailability studies comparing clobazam tablets to SYMPAZAN(R) [see Clinical Pharmacology 12.3 )]. 14.2Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS). The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome was established in two multicenter controlled studies (Study and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.Study 1Study (N=238) was randomized, double-blind, placebo-controlled study consisting of 4-week baseline period followed by 3-week titration period and 12-week maintenance period. Patients age 2-54 years with current or prior diagnosis of LGS were stratified into weight groups (12.5 kg to <=30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 4.Table 4: Study Total Daily Dose<=30 kg Body Weight>30 kg Body Weight Low Dose mg daily 10 mg daily Medium Dose 10 mg daily 20 mg daily High Dose 20 mg daily 40 mg daily Doses above mg/day were administered in two divided doses.The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of clobazam were statistically superior (p<=0.05) to the placebo group. This effect appeared to be dose dependent.Figure 1: Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1)Figure shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as worse. Patients in whom the seizure frequency decreased are shown in five categories.Figure 2: Drop Seizure Response by Category for Clobazam and Placebo (Study 1)There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period.Study 2Study (N=68) was randomized, double-blind comparison study of high- and low-dose clobazam, consisting of 4-week baseline period followed by 3-week titration period and 4-week maintenance period. Patients age 2-25 years with current or prior diagnosis of LGS were stratified by weight, then randomized to either low or high dose of clobazam, and then entered 3-week titration period.The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. For doses above mg/day, administer in two divided doses (2.1) Patients weighing 30 kg or less: Initiate at 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). For doses above mg/day, administer in two divided doses (2.1) Patients weighing 30 kg or less: Initiate at 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). 2.1Dosing Information. daily dose of SYMPAZAN(R) greater than mg should be administered in divided doses twice daily; 5 mg daily dose can be administered as 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 (e.g., 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 and days, respectively, to reach steady-state.Table 1: Recommended Total Daily Dosing by Weight Group30 kg or Less Body WeightGreater than 30 kg Body WeightStarting Dose mg10 mgStarting Day 10 mg20 mgStarting Day 14 20 mg40 mg. 2.2Discontinuation or Dosage Reduction of SYMPAZAN. To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use gradual taper to discontinue SYMPAZAN or reduce the dosage. Taper by decreasing the total daily dosage by 5-10 mg/day on weekly basis until discontinued. If 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 )].. 2.3Important 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(R) oral films.Apply SYMPAZAN(R) on top of the tongue where it adheres and dissolves. SYMPAZAN(R) 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 normal manner, but the patient should refrain from chewing, spitting or talking.Only one oral film should be taken at time; if second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved.. 2.4Dosage 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 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 )].. 2.5Dosage Adjustments in CYP2C19 Poor Metabolizers. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazams active metabolite, will be increased [see Clinical Pharmacology 12.4 )]. Therefore, the starting dosage should be 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 )].. 2.6Dosage Adjustments in Patients with Hepatic Impairment. SYMPAZAN(R) is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of SYMPAZAN(R) For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dosage should be 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 )].

DRUG ABUSE AND DEPENDENCE SECTION.

9DRUG ABUSE AND DEPENDENCE. 9.1Controlled Substance. SYMPAZAN(R) contains clobazam, Schedule IV controlled substance.. 9.2Abuse. SYMPAZAN is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions 5.2 )].The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam.. 9.3Dependence. Physical DependenceSYMPAZAN may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions 5.3 )]. To reduce the risk of withdrawal reactions, use gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration 2.2 and Warnings and Precautions 5.3 )]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.Protracted Withdrawal SyndromeProtracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.ToleranceTolerance to SYMPAZAN may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of SYMPAZAN may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DRUG INTERACTIONS SECTION.

7DRUG 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(R) (7.3) Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of SYMPAZAN(R) may be necessary (7.4) Cannabidiol: May increase risk of SYMPAZAN-related adverse reactions; consider dosage adjustment if this occurs (7.4). 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(R) (7.3) Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of SYMPAZAN(R) may be necessary (7.4) Cannabidiol: May increase risk of SYMPAZAN-related adverse reactions; consider dosage adjustment if this occurs (7.4). 7.1Opioids. 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 GABAA 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 )].. 7.2CNS Depressants and Alcohol. Concomitant use of SYMPAZAN(R) with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions 5.4 )].Alcohol, as CNS depressant, will interact with SYMPAZAN(R) in similar way and also increases clobazams 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 )].. 7.3Effect of SYMPAZAN(R) on Other Drugs. Hormonal ContraceptivesSYMPAZAN(R) is weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with SYMPAZAN(R). Additional non-hormonal forms of contraception are recommended when using SYMPAZAN(R) [see Clinical Pharmacology 12.3 ), Patient Counseling Information 17 )].Drugs Metabolized by CYP2D6SYMPAZAN(R) 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(R). Strong and Moderate Inhibitors of CYP2C19Coadministration 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(R) 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(R)Coadministration of cannabidiol, CYP3A4 and CYP2C19 substrate and 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 reduction in dosage of cannabidiol or clobazam if adverse reactions known to occur with SYMPAZAN are experienced.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).Risks from Concomitant Use with OpioidsInform patients and caregivers that potentially fatal additive effects may occur if SYMPAZAN(R) is used with opioids and not to use such drugs concomitantly unless supervised by 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 ReactionsAdvise 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 protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of SYMPAZAN may require slow taper [see Warnings and Precautions 5.3 and Drug Abuse and Dependence 9.3 )]. Somnolence or SedationAdvise patients or caregivers to check with their healthcare provider before SYMPAZAN(R) 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(R) does not affect them adversely (e.g., impair judgment, thinking or motor skills).HypersensitivityInform patients or caregivers that SYMPAZAN(R) is contraindicated in patients with history of hypersensitivity to the drug or its ingredients [see Warnings and Precautions 5.6 Interactions with Hormonal ContraceptivesCounsel women to also use non-hormonal methods of contraception when SYMPAZAN(R) is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing SYMPAZAN(R) to ensure contraceptive reliability [see Drug Interactions 7.3 ), Clinical Pharmacology 12.3 )].Serious Dermatological ReactionsAdvise 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 hospital and may be life-threatening. If skin reaction occurs while taking SYMPAZAN(R), patients or caregivers should consult with healthcare providers immediately [see Warnings and Precautions 5.6 )].Suicidal Thinking and BehaviorCounsel patients, their caregivers, and their families that AEDs, including SYMPAZAN(R), 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 (5.7)].Use in PregnancyAdvise pregnant women and women of childbearing potential that the use of SYMPAZAN(R) 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 pregnancy registry that collects information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations 8.1 )].Use in LactationCounsel patients that SYMPAZAN(R) 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 8.2 )].Manufactured by: Aquestive TherapeuticsWarren, NJ 07059.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. SYMPAZAN(R) Oral Films at single doses of 10 mg and 20 mg clobazam have been shown to be bioequivalent (Cm x and AUC) to clobazam tablets at equivalent doses. Following single-dose administration of SYMPAZAN(R), peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-20 mg. Based on population pharmacokinetic analysis with clobazam tablets, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t1/2) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.AbsorptionThe time to peak concentrations (Tm x) of SYMPAZAN(R) clobazam oral film under fasted conditions ranged from 0.33 to 4.0 hours after single-dose administration. The administration of clobazam tablets with food does not affect absorption. Although not studied, the oral bioavailability of SYMPAZAN(R) oral film is unlikely to be affected under fed conditions.DistributionClobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.Metabolism and ExcretionClobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethyl clobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam [see Clinical Pharmacology 12.4 )]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.Pharmacokinetics in Specific PopulationsAgePopulation pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages less than 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].SexPopulation pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.RacePopulation pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.Renal ImpairmentThe effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day. There were insignificant changes in Cmax (3-24%) and AUC (<=13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function. Patients with severe renal impairment or ESRD were not included in this study.Hepatic ImpairmentThere are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. In small study, the pharmacokinetics of 20 mg single oral dose of clobazam in patients with liver impairment were compared to healthy controls (N=6). The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls. The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment [see Dosage and Administration (2.6)].Drug Interaction StudiesIn vitro studies:Clobazam did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro. N-desmethylclobazam showed weak inhibition of CYP2C9, UGT1A4, UGT1A6 and UGT2B4.Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in concentration-dependent manner. Clobazam and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels. The potential for clobazam or N-desmethylclobazam to induce CYP2B6 and CYP2C8 has not been evaluated.Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.In vivo studies:Potential for Clobazam to Affect Other DrugsThe effect of repeated 40 mg once-daily doses of clobazam on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as drug cocktail (N=18).Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo. Drugs metabolized by CYP2D6 may require dose adjustment when used with clobazam.Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively. This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with clobazam. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with SYMPAZAN(R) [see Drug Interactions 7.3 )]. Repeated clobazam doses had no effect on caffeine and tolbutamide.A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).Potential for Other Drugs to Affect SYMPAZAN(R)Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax. There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18). Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data [see Clinical Pharmacology 12.4 )]. Dosage adjustment of SYMPAZAN(R) may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions 7.4 )].Coadministration of cannabidiol (a CYP3A4 and CYP2C19 substrate; an inhibitor of CYP2C19) produced 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19). This may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions 5.4 5.5 , Drug Interaction ( 7.4 )].The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C19 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials. Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with SYMPAZAN(R) [see Warnings and Precautions 5.4 ), Drug Interactions 7.2 )].

PREGNANCY SECTION.

8.1Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN(R), during pregnancy. Physicians are advised to recommend that pregnant patients taking SYMPAZAN(R) 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/.Risk SummaryThere are no adequate and well-controlled studies of SYMPAZAN(R) 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 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(R) 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 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 15% -20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.Clinical Considerations 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 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(R) 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 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.DataHuman Data Congenital Anomalies Although there are no adequate and well controlled studies of SYMPAZAN(R) in pregnant women, there is information about benzodiazepines as class. Dolovich et al. published meta-analysis 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. follow up to that meta-analysis included 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.Animal DataIn 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 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.

SPL MEDGUIDE SECTION.

MEDICATION GUIDESYMPAZAN(R)(SYM-pa-zan)(clobazam)oral film, CIVWhat is the most important information should know about SYMPAZANSYMPAZAN is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants(including street drugs)can cause severe drowsiness, breathingproblems(respiratorydepression),coma,anddeath.Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation)Do not drive or operate heavy machinery until you know how taking SYMPAZAN with opioids affects you. Risk of abuse, misuse, and addiction. There is risk for abuse, misuse, and addiction with benzodiazepines, including SYMPAZAN, which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including SYMPAZAN. These serious side effects may also includedelirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take SYMPAZAN as prescribed by your healthcare provider. Take SYMPAZAN exactly as your healthcare provider prescribed. Do not share your SYMPAZAN with other people. Keep SYMPAZAN in safe place and away from children. Physical dependence and withdrawal reactions. SYMPAZAN can cause physical dependence and withdrawal reactions. Do not suddenly stop taking SYMPAZAN. Stopping SYMPAZAN suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning, or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more SYMPAZAN than prescribed or take SYMPAZAN for longer than prescribed. SYMPAZAN can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how SYMPAZAN affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking SYMPAZAN without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, SYMPAZAN may make your sleepiness or dizziness much worse. Serious skin reactions have been seen when SYMPAZAN is taken with other medicines and may requirestoppingitsuse.Do not stop taking SYMPAZAN without first talking to your healthcare provider. serious skin reaction can happen at any time during your treatment with SYMPAZAN, but is more likely to happen within the first weeks of treatment. These skin reactions may need to be treated right away. Call your healthcare provider immediately if you have skin blisters, rash, sores in mouth, hives or any other allergic reaction. Likeotherantiepilepticmedicines,SYMPAZANmaycausesuicidalthoughtsoractionsinaverysmall number of people, about in500.Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thought about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety or irritability feeling agitated or restless an extreme increase in activity and talking (mania) trouble sleeping (insomnia) new or worse panic attacks acting aggressive, being angry or violent acting on dangerous impulses other unusual changes in behavior or mood How can watch for early symptoms of suicidal thoughts and actionsPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.Stopping seizure medicine suddenly in patient who has epilepsy can cause seizures that will not stop (status epilepticus).Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.What is SYMPAZANSYMPAZAN is prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut Syndrome in people years of age or older. SYMPAZAN is federally controlled substance (C-IV) because it contains clobazam that can be abused or lead to dependence. Keep SYMPAZAN in safe place to prevent misuse and abuse. Selling or giving away SYMPAZAN may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.It is not known if SYMPAZAN is safe and effective in children less than years old.Do not take SYMPAZAN if you:are allergic to clobazam or any of the ingredients in SYMPAZAN. See the end of this Medication Guide for complete list of ingredients in SYMPAZAN. Before you take SYMPAZAN, tell your healthcare provider about all of your medical conditions, including if you:have liver or kidney problems have lung problems (respiratory disease) have or have had depression, mood problems, or suicidal thoughts or behavior use birth control medicine. SYMPAZAN may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use. are pregnant or plan to become pregnant. SYMPAZAN may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking SYMPAZAN. You and your healthcare provider will decide if you should take SYMPAZAN while you are pregnant. Babies born to mothers receiving benzodiazepine medications (including SYMPAZAN) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms. If you become pregnant while taking SYMPAZAN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. SYMPAZAN can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take SYMPAZAN. You and your healthcare provider should decide if you will take SYMPAZAN or breast feed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. Taking SYMPAZAN with certain other medicines cancause side effects or affect how well SYMPAZAN or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.How should take SYMPAZANTake SYMPAZAN exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much SYMPAZAN to take and when to take it. Place the entire SYMPAZAN oral film on top of the tongue. SYMPAZAN oral films can be taken with or without food. Do not take liquids with SYMPAZAN oral films. Take only SYMPAZAN oral film at time. Read the Instructions for Use at the end of this Medication Guide for information on the right way to take SYMPAZAN oral films. Your healthcare provider may change your dose if needed. Do not change your dose of SYMPAZAN without talking to your healthcare provider. Do not stop taking SYMPAZAN without first talking to your healthcare provider. Stopping SYMPAZAN suddenly can cause serious problems. If you take too much SYMPAZAN, call your healthcare provider or go to the nearest hospital emergency room right away. What should avoid while taking SYMPAZANSee What is the most important information should know about SYMPAZANWhat are the possible side effects of SYMPAZANSYMPAZAN may cause serious side effects, including: See What is the most important information should know about SYMPAZANThe most common side effects of SYMPAZAN include: sleepiness drooling constipation cough pain with urination fever acting aggressive, being angry, or violent difficulty sleeping slurred speech tiredness problems with breathingThese are not all the possible side effects of SYMPAZAN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SYMPAZANStore SYMPAZAN oral film at room temperature between 68F to 77F (20C to 25C). Keep SYMPAZAN and all medicines out of the reach of children.General Information about the safe and effective use of SYMPAZAN.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use SYMPAZAN for condition for which it was not prescribed. Do not give SYMPAZAN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SYMPAZAN that is written for health professionals.What are the ingredients in SYMPAZANActive ingredient: clobazamInactive 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.Manufactured by:Aquestive Therapeutics Warren, NJ 07059 SYMPAZAN(R) is registered trademark of Aquestive Therapeutics For more information, go to www.SYMPAZAN.com or call the Aquestive Therapeutics Rx Patient and Caregiver Support Line at 1-833-AQUESTV (1-833-278- 3788). This Medication Guide has been approved by the U.S. Food and Drug Administration Revision Date::3/2021. SYMPAZAN is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants(including street drugs)can cause severe drowsiness, breathingproblems(respiratorydepression),coma,anddeath.Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation)Do not drive or operate heavy machinery until you know how taking SYMPAZAN with opioids affects you. Risk of abuse, misuse, and addiction. There is risk for abuse, misuse, and addiction with benzodiazepines, including SYMPAZAN, which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including SYMPAZAN. These serious side effects may also includedelirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take SYMPAZAN as prescribed by your healthcare provider. Take SYMPAZAN exactly as your healthcare provider prescribed. Do not share your SYMPAZAN with other people. Keep SYMPAZAN in safe place and away from children. Physical dependence and withdrawal reactions. SYMPAZAN can cause physical dependence and withdrawal reactions. Do not suddenly stop taking SYMPAZAN. Stopping SYMPAZAN suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning, or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more SYMPAZAN than prescribed or take SYMPAZAN for longer than prescribed. SYMPAZAN can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how SYMPAZAN affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking SYMPAZAN without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, SYMPAZAN may make your sleepiness or dizziness much worse. Serious skin reactions have been seen when SYMPAZAN is taken with other medicines and may requirestoppingitsuse.Do not stop taking SYMPAZAN without first talking to your healthcare provider. serious skin reaction can happen at any time during your treatment with SYMPAZAN, but is more likely to happen within the first weeks of treatment. These skin reactions may need to be treated right away. Call your healthcare provider immediately if you have skin blisters, rash, sores in mouth, hives or any other allergic reaction. Likeotherantiepilepticmedicines,SYMPAZANmaycausesuicidalthoughtsoractionsinaverysmall number of people, about in500.. Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. SYMPAZAN is prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut Syndrome in people years of age or older. SYMPAZAN is federally controlled substance (C-IV) because it contains clobazam that can be abused or lead to dependence. Keep SYMPAZAN in safe place to prevent misuse and abuse. Selling or giving away SYMPAZAN may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.. are allergic to clobazam or any of the ingredients in SYMPAZAN. See the end of this Medication Guide for complete list of ingredients in SYMPAZAN. have liver or kidney problems have lung problems (respiratory disease) have or have had depression, mood problems, or suicidal thoughts or behavior use birth control medicine. SYMPAZAN may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use. are pregnant or plan to become pregnant. SYMPAZAN may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking SYMPAZAN. You and your healthcare provider will decide if you should take SYMPAZAN while you are pregnant. Babies born to mothers receiving benzodiazepine medications (including SYMPAZAN) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms. If you become pregnant while taking SYMPAZAN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. SYMPAZAN can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take SYMPAZAN. You and your healthcare provider should decide if you will take SYMPAZAN or breast feed. You should not do both. Take SYMPAZAN exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much SYMPAZAN to take and when to take it. Place the entire SYMPAZAN oral film on top of the tongue. SYMPAZAN oral films can be taken with or without food. Do not take liquids with SYMPAZAN oral films. Take only SYMPAZAN oral film at time. Read the Instructions for Use at the end of this Medication Guide for information on the right way to take SYMPAZAN oral films. Your healthcare provider may change your dose if needed. Do not change your dose of SYMPAZAN without talking to your healthcare provider. Do not stop taking SYMPAZAN without first talking to your healthcare provider. Stopping SYMPAZAN suddenly can cause serious problems. If you take too much SYMPAZAN, call your healthcare provider or go to the nearest hospital emergency room right away. See What is the most important information should know about SYMPAZAN. Store SYMPAZAN oral film at room temperature between 68F to 77F (20C to 25C).

SPL PATIENT PACKAGE INSERT SECTION.

Instructions for UseSYMPAZAN(R) (SIM-pa-zan)(clobazam) oral film, CIVRead this Instructions for Usebefore you start using SYMPAZAN and each time you get refill. There may be new information. The information does not take the place of talking with your healthcare provider about your medical condition or treatment. Important Information for Patient and Caregiver: Do not take SYMPAZAN until: you have read and understand these instructions. you have reviewed the steps with your healthcare provider on how to take it. you know the right time, how often, and the dose to take. you feel comfortable with how to use SYMPAZAN. If you are not sure about giving treatment or when to give treatment, call your healthcare provider before using SYMPAZAN How should store SYMPAZANStore SYMPAZAN at room temperature between 68F to 77F (20C to 25C). Keep SYMPAZAN in the foil pouch until you are ready to use. Use right away after opening foil pouch. Keep SYMPAZAN and all medicines out of the reach ofchildren.How to Use SYMPAZAN:Take only SYMPAZAN film at time unless instructed differently by your healthcare provider. If second film is needed to get full dose of SYMPAZAN, do not take the second film until the first film has completely dissolved. Place the entire SYMPAZAN oral film on top of the tongue. Check your prescription or contact your healthcare provider if you are not sure about the amount to take. Make sure your hands are clean and dry before handling the SYMPAZAN film. Check the expiration date printed on the foil pouch. Do not use SYMPAZAN if expired.Step 1. Open PouchFold foil pouch along solid line. Note where the slit is and carefully tear it to open pouch.Step 2. Remove FilmRemove the SYMPAZAN from the foil pouch. Step 3. Place on TonguePlace SYMPAZAN on top of the tongue. The film will stick to the tongue and begin to dissolve.Step 4. Close Mouth and Swallow Saliva NormallyClose mouth. Swallow saliva normally as SYMPAZAN dissolves. Do not take with liquids. Do not chew, spit, or talk while SYMPAZAN dissolves.Wash your hands after taking SYMPAZAN.Throw away the empty foil pouch in the regular trash.Manufactured by:Aquestive TherapeuticsWarren, NJ 07059For more information or support about SYMPAZAN: Call 1-833-AQUESTV (1-833-278-3788).This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revision Date: 11/2018. Do not take SYMPAZAN until: you have read and understand these instructions. you have reviewed the steps with your healthcare provider on how to take it. you know the right time, how often, and the dose to take. you feel comfortable with how to use SYMPAZAN. If you are not sure about giving treatment or when to give treatment, call your healthcare provider before using SYMPAZAN . Store SYMPAZAN at room temperature between 68F to 77F (20C to 25C). Keep SYMPAZAN in the foil pouch until you are ready to use. Use right away after opening foil pouch. Keep SYMPAZAN and all medicines out of the reach ofchildren.. Take only SYMPAZAN film at time unless instructed differently by your healthcare provider. If second film is needed to get full dose of SYMPAZAN, do not take the second film until the first film has completely dissolved. Place the entire SYMPAZAN oral film on top of the tongue. Check your prescription or contact your healthcare provider if you are not sure about the amount to take. Make sure your hands are clean and dry before handling the SYMPAZAN film. Check the expiration date printed on the foil pouch. Do not use SYMPAZAN if expired.. Fold foil pouch along solid line. Note where the slit is and carefully tear it to open pouch.. Remove the SYMPAZAN from the foil pouch. Place SYMPAZAN on top of the tongue. The film will stick to the tongue and begin to dissolve.. Close mouth. Swallow saliva normally as SYMPAZAN dissolves. Do not take with liquids. Do not chew, spit, or talk while SYMPAZAN dissolves.. Wash your hands after taking SYMPAZAN.. Throw away the empty foil pouch in the regular trash.. Step 1. Open Pouch. Step 2. Remove Film. Step 3. Place on Tongue. Step 4. Close Mouth and Swallow Saliva Normally.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN(R), during pregnancy. Physicians are advised to recommend that pregnant patients taking SYMPAZAN(R) 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/.Risk SummaryThere are no adequate and well-controlled studies of SYMPAZAN(R) 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 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(R) 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 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 15% -20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.Clinical Considerations 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 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(R) 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 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.DataHuman Data Congenital Anomalies Although there are no adequate and well controlled studies of SYMPAZAN(R) in pregnant women, there is information about benzodiazepines as class. Dolovich et al. published meta-analysis 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. follow up to that meta-analysis included 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.Animal DataIn 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 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.. 8.2Lactation. Risk SummarySYMPAZAN(R) is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as SYMPAZAN(R), may have effects of lethargy, somnolence and poor sucking. The effect of SYMPAZAN(R) on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for SYMPAZAN(R) and any potential adverse effects on the breastfed infant from SYMPAZAN(R) or from the underlying maternal condition. If exposing breastfed infant to SYMPAZAN(R), observe for any potential adverse effects. Clinical Considerations Monitoring for Adverse ReactionsAdverse 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 in scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.. 8.3Females 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 )]. 8.4Pediatric Use. Safety and effectiveness for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients 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 years of age have not been established.Juvenile Animal DataIn 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.. 8.5Geriatric 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 )].. 8.6CYP2C19 Poor Metabolizers. Concentrations of clobazams 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 2.5 ), Clinical Pharmacology 12.3 )].. 8.7Renal Impairment. 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(R) in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethyl-clobazam, is dialyzable [see Clinical Pharmacology 12.3 )].. 8.8Hepatic Impairment. SYMPAZAN(R) 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 2.6 )]. There is inadequate information about metabolism of SYMPAZAN(R) in patients with severe hepatic impairment [see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS 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(R) at first sign of rash unless the rash is clearly not drug-related (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors (5.7) 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(R) at first sign of rash unless the rash is clearly not drug-related (5.5) Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors (5.7) 5.1Risks from Concomitant Use with Opioids. Concomitant use of benzodiazepines, including SYMPAZAN(R), 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 decision is made to prescribe SYMPAZAN(R) 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(R) is used with opioids [see Drug Interactions 7.1 )]. 5.2Abuse, 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 patients risk for abuse, misuse, and addiction (e.g., using 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 substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.. 5.3Dependence and Withdrawal Reactions. To reduce the risk of withdrawal reactions, use 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 ReactionsThe 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 SyndromeIn some cases, benzodiazepine users have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence 9.3 )]. 5.4Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants. Since SYMPAZAN(R) has 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 )].. 5.5Somnolence or Sedation. SYMPAZAN(R) 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(R) is known. 5.6Serious 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 weeks of treatment initiation or when re-introducing therapy. SYMPAZAN(R) 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 )].. 5.7Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including SYMPAZAN(R), 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 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 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 shows absolute and relative risk by indication for all evaluated AEDs.Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled AnalysisIndicationPlaceboPatients with Events per 1000PatientsDrug Patients with Events per 1000PatientsRelative Risk: Incidenceof DrugEvents in DrugPatients/Incidencein Placebo PatientsRisk Difference:AdditionalDrug Patients with Eventsper 1000 PatientsEpilepsy1.03.43.52.4Psychiatric 5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The 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(R) 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.