MECHANISM OF ACTION SECTION.

12.1 Mechanism 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.

ABUSE SECTION.

9.2 Abuse Clobazam oral suspension 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS oClinically significant adverse reactions that appear in other sections of the labeling include the following:oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]oPotentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions (5.4)]oSomnolence or Sedation [see Warnings and Precautions (5.5)]oSerious Dermatological Reactions [see Contraindications (4), Warnings and Precautions (5.6) ]oSuicidal Behavior and Ideation [see Warnings and Precautions (5.7)]. oClinically significant adverse reactions that appear in other sections of the labeling include the following:. oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]. oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]. oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]. oPotentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions (5.4)]. oSomnolence or Sedation [see Warnings and Precautions (5.5)]. oSerious Dermatological Reactions [see Contraindications (4), Warnings and Precautions (5.6) ]. oSuicidal 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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.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 GroupPlaceboN 59%Clobazam Dose LevelAll ClobazamN 179%LowMaximum daily dose of mg for <= 30 kg body weight; 10 mg for 30 kg body weightN 58%MediumMaximum daily dose of 10 mg for <= 30 kg body weight; 20 mg for 30 kg body weightN 62%HighMaximum daily dose of 20 mg for <= 30 kg body weight; 40 mg for 30 kg body weightN 59%Gastrointestinal Disorders Vomiting59577 Constipation022105 Dysphagia00052General Disorders and Administration Site Conditions Pyrexia317101213 Irritability531157 Fatigue25535Infections and Infestations Upper respiratory tract infection1010131412 Pneumonia23374 Urinary tract infection02554 Bronchitis02052Metabolism and Nutrition Disorders Decreased appetite33073 Increased appetite02353Nervous System Disorders Somnolence or Sedation1517273226 Somnolence1216242522 Sedation32395 Lethargy51051510 Drooling3013149 Ataxia332105 Psychomotor hyperactivity33354 Dysarthria02253Psychiatric Disorders Aggression538148 Insomnia22575Respiratory Disorders Cough03575. 6.2Postmarketing Experience 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, thrombocytopeniaEye Disorders: Diplopia, vision blurredGastrointestinal Disorders: Abdominal distentionGeneral Disorders and Administration Site Conditions: HypothermiaInvestigations: Hepatic enzyme increasedMusculoskeletal: Muscle spasmsPsychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucinationRenal and Urinary Disorders: Urinary retentionRespiratory Disorders: Aspiration, respiratory depressionSkin 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 oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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), Drug Interactions (7.1)].oThe use of benzodiazepines, including clobazam oral suspension, 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 clobazam oral suspension and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].oThe continued use of benzodiazepines, including clobazam oral suspension, 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 clobazam oral suspension 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 clobazam oral suspension or reduce the dosage [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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), Drug Interactions (7.1)].. oThe use of benzodiazepines, including clobazam oral suspension, 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 clobazam oral suspension and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].. oThe continued use of benzodiazepines, including clobazam oral suspension, 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 clobazam oral suspension 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 clobazam oral suspension 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 REACTIONS See full prescribing information for complete boxed warning.oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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). oThe use of benzodiazepines, including clobazam oral suspension, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing clobazam oral suspension and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2). oAbrupt discontinuation or rapid dosage reduction of clobazam oral suspension 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 clobazam oral suspension or reduce the dosage (2.2, 5.3). oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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). oThe use of benzodiazepines, including clobazam oral suspension, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing clobazam oral suspension and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2). oAbrupt discontinuation or rapid dosage reduction of clobazam oral suspension 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 clobazam oral suspension or reduce the dosage (2.2, 5.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for years did not result in an increase in tumors. The highest dose tested was approximately times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2).In rats, oral administration of clobazam for years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD.. Mutagenesis. Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.. Impairment of Fertility. In fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84 and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40 mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism 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.. 12.2 Pharmacodynamics Effects on Electrocardiogram. The 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. 12.3 Pharmacokinetics The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10 to 80 mg following single- or multiple-dose administration of clobazam. Based on population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from to 160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t 1/2 of clobazam and N-desmethylclobazam were 36 to 42 hours and 71 to 82 hours, respectively.. Absorption. Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to hours. Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and oral suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.. Distribution. Clobazam 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 to 90% and 70%, respectively.. Metabolism and Excretion. Clobazam 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 to 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-desmethylclobazam 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 (12.5)]. 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 Populations. Age Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages to 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].. Sex Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.. Race Population 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 Impairment The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] 50 to 80 mL/min; = 6) and moderate (CLCR 30 to 50 mL/min; = 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 to 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 Impairment There 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 (2.7)].. Drug Interaction Studies. In 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 Drugs. The 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 clobazam [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 Clobazam. 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 (12.5)]. Dosage adjustment of clobazam may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions (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 clobazam [see Warnings and Precautions (5.4) Drug Interactions (7.2)].. 12.5Pharmacogenomics The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N-desmethylclobazam. Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately to 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.

14 CLINICAL STUDIES 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 1: Study (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 to 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 5.Table 5. Study Total Daily Dose<= 30 kg Body Weight> 30 kg Body WeightLow Dose5 mg daily10 mg dailyMedium Dose10 mg daily20 mg dailyHigh Dose20 mg daily40 mg dailyDoses 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 2: Study (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 to 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%; < 0.05).. 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).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Clobazam oral suspension is contraindicated in patients with history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions (5.6) ].. History of hypersensitivity to the drug or its ingredients (4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance Clobazam oral suspension contains clobazam, Schedule IV controlled substance.

DEPENDENCE SECTION.

9.3 Dependence Physical Dependence. Clobazam oral suspension 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)]. In clinical trials, cases of dependency were reported following abrupt discontinuation of clobazam oral suspension. To reduce the risk of withdrawal reactions, use gradual taper to discontinue clobazam oral suspension 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.. Tolerance. Tolerance to clobazam oral suspension 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 clobazam oral suspension may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DESCRIPTION SECTION.

11 DESCRIPTION Table 4. DescriptionEstablished Name:Clobazam Oral SuspensionDosage Form:Oral SuspensionRoute of Administration:OralEstablished Pharmacologic Class of Drug:BenzodiazepineChemical Name:7-Chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dioneStructural Formula:Clobazam is white or almost white, crystalline powder with slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride. The melting range of clobazam is from 183oC to 184oC. The molecular formula is C16H13ClN2O2 and the molecular weight is 300.7.Clobazam is available for oral administration as white to off-white liquid suspension containing clobazam at concentration of 2.5 mg/mL. Inactive ingredients include citric acid monohydrate, dibasic sodium phosphate, magnesium aluminum silicate, maltitol solution, methylparaben, mixed berry flavor, nitrogen, polysorbate 80, propylene glycol, propylparaben, purified water, simethicone emulsion, sucralose and xanthan gum. Clobazam Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oFor doses above mg/day administer in two divided doses (2.1)oPatients <= 30 kg body weight: Initiate at mg daily and titrate as tolerated up to 20 mg daily (2.1) oPatients 30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily (2.1) oDosage adjustment needed in following groups:oGeriatric patients (2.4, 8.5)oKnown CYP2C19 poor metabolizers (2.5)oMild or moderate hepatic impairment; no information for severe hepatic impairment (2.7, 8.8)oMeasure prescribed amount of oral suspension using provided adapter and dosing syringe (2.3)oOral suspension: Can be taken with or without food (2.3). oFor doses above mg/day administer in two divided doses (2.1). oPatients <= 30 kg body weight: Initiate at mg daily and titrate as tolerated up to 20 mg daily (2.1) oPatients 30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily (2.1) oDosage adjustment needed in following groups:oGeriatric patients (2.4, 8.5)oKnown CYP2C19 poor metabolizers (2.5)oMild or moderate hepatic impairment; no information for severe hepatic impairment (2.7, 8.8). oGeriatric patients (2.4, 8.5). oKnown CYP2C19 poor metabolizers (2.5). oMild or moderate hepatic impairment; no information for severe hepatic impairment (2.7, 8.8). oMeasure prescribed amount of oral suspension using provided adapter and dosing syringe (2.3). oOral suspension: Can be taken with or without food (2.3). 2.1Dosing Information A daily dose of clobazam oral suspension 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 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 Group<= 30 kg Body Weight> 30 kg Body WeightStarting Dose5 mg10 mgStarting Day 710 mg20 mgStarting Day 14 20 mg40 mg. 2.2Discontinuation or Dosage Reduction of Clobazam Oral Suspension To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use gradual taper to discontinue clobazam oral suspension or reduce the dosage. Taper by decreasing the total daily dose by to 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 to read the Instructions for Use carefully for complete directions on how to properly dose and administer clobazam oral suspension.. Clobazam Oral Suspension Oral Administration. Clobazam oral suspension can be taken with or without food [see Clinical Pharmacology (12.3) ].Shake clobazam oral suspension well before every administration. When administering the oral suspension, use only the oral dosing syringe provided with the product. Each carton includes two syringes, but only one syringe should be used for dosing. The second oral syringe is reserved as replacement in case the first syringe is damaged or lost. Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose. After removing the syringe from the bottle adapter, slowly squirt clobazam oral suspension into the corner of the patients mouth. Replace the cap after each use. The cap fits over the adapter when the adapter is properly placed. See clobazam oral suspension Instructions for Use for complete instruction on how to properly dose and administer the clobazam oral suspension.. 2.4Dosage Adjustments in Geriatric Patients Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation. The starting dose should be mg/day for all elderly patients. Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (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. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.5)].. 2.6Patients with Renal Impairment No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with clobazam oral suspension in patients with severe renal impairment or end stage renal disease (ESRD). It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) ].. 2.7Dosage Adjustments in Patients with Hepatic Impairment Clobazam oral suspension is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam oral suspension. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score to 9), the starting dose should be mg/day in both weight groups. Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of clobazam oral suspension in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Clobazam Oral Suspension is mixed berry flavored, white to off-white liquid suspension supplied in bottle with child-resistant closure. The oral suspension is packaged with dispenser set which contains two calibrated oral dosing syringes and bottle adapter. Each bottle contains 120 mL of white to off-white liquid suspension containing 2.5 mg/mL of clobazam for oral administration.. oOral Suspension: 2.5 mg/mL in 120 mL bottles (3). oOral Suspension: 2.5 mg/mL in 120 mL bottles (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Clobazam oral suspension contains clobazam, Schedule IV controlled substance.. 9.2 Abuse Clobazam oral suspension 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.. 9.3 Dependence Physical Dependence. Clobazam oral suspension 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)]. In clinical trials, cases of dependency were reported following abrupt discontinuation of clobazam oral suspension. To reduce the risk of withdrawal reactions, use gradual taper to discontinue clobazam oral suspension 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.. Tolerance. Tolerance to clobazam oral suspension 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 clobazam oral suspension may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oAlcohol: Increases blood levels of clobazam by about 50% (7.2)oDrugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with clobazam (7.3)oStrong or Moderate CYP2C19 Inhibitors: Dosage adjustment of clobazam may be necessary (7.4). oAlcohol: Increases blood levels of clobazam by about 50% (7.2). oDrugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with clobazam (7.3). oStrong or Moderate CYP2C19 Inhibitors: Dosage adjustment of clobazam may be necessary (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 clobazam 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 clobazam 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 Clobazam on Other Drugs Hormonal Contraceptives. Clobazam is weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with clobazam. Additional non-hormonal forms of contraception are recommended when using clobazam [see Clinical Pharmacology (12.3) Patient Counseling Information (17)].. Drugs Metabolized by CYP2D6. Clobazam inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology (12.3)].. 7.4Effect of Other Drugs on Clobazam Strong and Moderate Inhibitors of CYP2C19. Strong and 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 clobazam 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) ].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be mg/day. Patients should be titrated initially to 10 to 20 mg/day. Patients may be titrated further to maximum daily dose of 40 mg if tolerated [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Clobazam Oral Suspension is mixed berry flavored, white to off-white liquid suspension supplied in bottle with child-resistant closure. The oral suspension is packaged with dispenser set which contains two calibrated oral dosing syringes and bottle adapter.Store and dispense clobazam oral suspension in its original bottle in an upright position. Use within 90 days of first opening the bottle, then discard any remainder.NDC 0378-8043-212.5 mg/mL supplied in bottle containing 120 mL of liquid suspensionStore oral suspension at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]PHARMACIST: Dispense Medication Guide and Instructions for Use with each prescription.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Clobazam oral suspension is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients years of age or older.. Clobazam oral suspension is benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients years of age or older (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).Risks from Concomitant Use with Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if clobazam oral suspension 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 clobazam oral suspension, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].Withdrawal Reactions: Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure. Inform patients that the continued use of clobazam oral suspension may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of clobazam oral suspension 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 clobazam oral suspension may require slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].Somnolence or Sedation: Advise patients or caregivers to check with their healthcare provider before clobazam oral suspension 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 clobazam oral suspension does not affect them adversely (e.g., impair judgment, thinking or motor skills).Hypersensitivity: Inform patients or caregivers that clobazam oral suspension is contraindicated in patients with history of hypersensitivity to the drug or its ingredients [see Warnings and Precautions (5.6)].Interactions with Hormonal Contraceptives: Counsel women to also use non-hormonal methods of contraception when clobazam oral suspension is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing clobazam oral suspension to ensure contraceptive reliability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].Serious Dermatological Reactions: Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam oral suspension. Serious skin reactions, including SJS/TEN, may need to be treated in hospital and may be life-threatening. If skin reaction occurs while taking clobazam oral suspension, patients or caregivers should consult with healthcare providers immediately [see Warnings and Precautions (5.6) ].Suicidal Thinking and Behavior: Counsel patients, their caregivers, and their families that AEDs, including clobazam oral suspension, 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)].Pregnancy: Advise pregnant women and women of childbearing potential that the use of clobazam 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 exposure registry that collects information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].Nursing: Counsel patients that clobazam 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)].

LABOR & DELIVERY SECTION.

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.

LACTATION SECTION.

8.2 Lactation Risk Summary. Clobazam is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as clobazam oral suspension, may have effects of lethargy, somnolence and poor sucking. The effect of clobazam on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for clobazam and any potential adverse effects on the breastfed infant from clobazam or from the underlying maternal condition. If exposing breastfed infant to clobazam, observe for any potential adverse effects. Clinical Considerations. Monitoring for Adverse Reactions Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Monitor breastfed infants for possible sedation and poor sucking. Data. Scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for years did not result in an increase in tumors. The highest dose tested was approximately times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2).In rats, oral administration of clobazam for years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD.. Mutagenesis. Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.. Impairment of Fertility. In fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84 and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40 mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.

OVERDOSAGE SECTION.

10 OVERDOSAGE 10.1Signs and Symptoms of Overdosage Overdose and intoxication with benzodiazepines, including clobazam oral suspension, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of fatal outcome is increased in cases of combined poisoning with other CNS depressants, including opioids and alcohol.. 10.2Management of Overdosage The management of clobazam overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs. Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in clobazam overdose has not been assessed. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 120 mL NDC 0378-8043-21ClobazamOral Suspension CIV2.5 mg/mLFOR ORALADMINISTRATION ONLY.PHARMACIST: Dispense the accompanyingMedication Guide and Instructions for Useto each patient.Rx only 120 mLStore at 20 to 25C (68 to77F). [See USP ControlledRoom Temperature.]STORE AND DISPENSE ORALSUSPENSION IN ORIGINALCONTAINER IN AN UPRIGHTPOSITION.Use within 90 days of firstopening, then discard anyremainder.Shake the bottle well beforeeach use.FOR ORAL ADMINISTRATIONONLY.Keep this and all medicationout of the reach of children.This product is an oralsuspension liquid and issupplied with two 10 mL oralsyringes for administration.Each mL contains:Clobazam 2.5 mgUsual Dosage: Seeaccompanying prescribinginformation.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.DPT:8043:21:1C:R3117654-0321Mylan.com. Clobazam Oral Suspension 2.5 mg/mL Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness in patients less than years of age have not been established.In 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Effects on Electrocardiogram. The 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10 to 80 mg following single- or multiple-dose administration of clobazam. Based on population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from to 160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t 1/2 of clobazam and N-desmethylclobazam were 36 to 42 hours and 71 to 82 hours, respectively.. Absorption. Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to hours. Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and oral suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.. Distribution. Clobazam 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 to 90% and 70%, respectively.. Metabolism and Excretion. Clobazam 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 to 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-desmethylclobazam 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 (12.5)]. 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 Populations. Age Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages to 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].. Sex Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.. Race Population 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 Impairment The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] 50 to 80 mL/min; = 6) and moderate (CLCR 30 to 50 mL/min; = 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 to 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 Impairment There 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 (2.7)].. Drug Interaction Studies. In 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 Drugs. The 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 clobazam [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 Clobazam. 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 (12.5)]. Dosage adjustment of clobazam may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions (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 clobazam [see Warnings and Precautions (5.4) Drug Interactions (7.2)].

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as clobazam, during pregnancy. Physicians are advised to recommend that pregnant patients taking clobazam 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 Summary. There are no adequate and well-controlled studies of clobazam 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. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise pregnant woman 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 to 4% and 15 to 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 clobazam 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.. Data. Human Data Congenital Anomalies. Although there are no adequate and well controlled studies of clobazam 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 Data In 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.

RECENT MAJOR CHANGES SECTION.

oBoxed Warning 2/2021oDosage and Administration (2.2) 2/2021oWarnings and Precautions (5.2, 5.3) 2/2021. oBoxed Warning 2/2021. oDosage and Administration (2.2) 2/2021. oWarnings and Precautions (5.2, 5.3) 2/2021.

RISKS.

Risk Summary. There are no adequate and well-controlled studies of clobazam 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. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise pregnant woman 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 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

SPL MEDGUIDE SECTION.

Medication Guide Clobazam Oral Suspension CIV(kloe ba zam)What is the most important information should know about clobazam oral suspensionoClobazam oral suspension is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death. Get emergency help right away if any of the following happens: oshallow or slowed breathing obreathing stops (which may lead to the heart stopping) oexcessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking clobazam oral suspension with opioids affects you. oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including clobazam oral suspension, which can lead to overdose and serious side effects including coma and death. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including clobazam oral suspension. These serious side effects may also include delirium, 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. oYou can develop an addiction even if you take clobazam oral suspension as prescribed by your healthcare provider. oTake clobazam oral suspension exactly as your healthcare provider prescribed. oDo not share your clobazam oral suspension with other people. oKeep clobazam oral suspension in safe place and away from children. oPhysical dependence and withdrawal reactions. Clobazam oral suspension can cause physical dependence and withdrawal reactions. oDo not suddenly stop taking clobazam oral suspension. Stopping clobazam oral suspension 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. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks tomore 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. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more clobazam oral suspension than prescribed or take clobazam oral suspension for longer than prescribed. oClobazam oral suspension can make you sleepy or dizzy and can slow your thinking and motor skills. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how clobazam oral suspension affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clobazam oral suspension without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, clobazam oral suspension may make your sleepiness or dizziness much worse. oSerious skin reactions have been seen when clobazam oral suspension is taken with other medicines and may require stopping its use. Do not stop taking clobazam oral suspension without first talking to your healthcare provider.oA serious skin reaction can happen at any time during your treatment with clobazam oral suspension, but is more likely to happen within the first weeks of treatment. These skin reactions may need to be treated right away.oCall your healthcare provider immediately if you have skin blisters, rash, sores in the mouth, hives or any other allergic reaction.oLike other antiepileptic medicines, clobazam oral suspension may cause suicidal thoughts or actions in very small number of people, about in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:othoughts about suicide or dyingonew or worse depressionofeeling agitated or restlessotrouble sleeping (insomnia)oacting aggressive, being angry or violentoother unusual changes in behavior or moodoattempts to commit suicideonew or worse anxiety or irritability oan extreme increase in activity and talking (mania)onew or worse panic attacksoacting on dangerous impulsesHow can watch for early symptoms of suicidal thoughts and actionsoPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.oKeep 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 clobazam oral suspensionoClobazam oral suspension is prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut syndrome in people years of age or older. oClobazam oral suspension is federally controlled substance (C-IV) because it contains clobazam that can be abused or lead to dependence. Keep clobazam oral suspension in safe place to prevent misuse and abuse. Selling or giving away clobazam oral suspension 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 clobazam oral suspension is safe and effective in children less than years old.Do not take clobazam oral suspension if you:oare allergic to clobazam or any of the ingredients in clobazam oral suspension. See the end of this Medication Guide for complete list of ingredients in clobazam oral suspension.Before you take clobazam oral suspension, tell your healthcare provider about all your medical conditions, including if you:ohave liver or kidney problemsohave lung problems (respiratory disease)ohave or have had depression, mood problems, or suicidal thoughts or behaviorouse birth control medicine. Clobazam oral suspension may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use.oare pregnant or plan to become pregnant. Clobazam oral suspension may harm your unborn baby.oTell your healthcare provider right away if you become pregnant while taking clobazam oral suspension. You and your healthcare provider will decide if you should take clobazam oral suspension while you are pregnant.oBabies born to mothers receiving benzodiazepine medications (including clobazam oral suspension) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms.oIf you become pregnant while taking clobazam oral suspension, 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.oClobazam can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take clobazam oral suspension. You and your healthcare provider should decide if you will take clobazam oral suspension or breastfeed. 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 clobazam oral suspension with certain other medicines can cause side effects or affect how well clobazam oral suspension or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.How should take clobazam oral suspensionoTake clobazam oral suspension exactly as your healthcare provider tells you to take it.oYour healthcare provider will tell you how much clobazam oral suspension to take and when to take it.oClobazam oral suspension can be taken with or without food.oShake the bottle of clobazam oral suspension right before you take each dose.oMeasure your dose of clobazam oral suspension using the bottle adapter and dosing syringes that come with your clobazam oral suspension.oRead the Instructions for Use at the end of this Medication Guide for information on the right way to use clobazam oral suspension.oYour healthcare provider may change your dose if needed. Do not change your dose of clobazam oral suspension without talking to your healthcare provider.oDo not stop taking clobazam oral suspension without first talking to your healthcare provider.oStopping clobazam oral suspension suddenly can cause serious problems.oIf you take too much clobazam oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking clobazam oral suspensionSee What is the most important information should know about clobazam oral suspension What are the possible side effects of clobazam oral suspensionClobazam oral suspension may cause serious side effects, including: See What is the most important information should know about clobazam oral suspension The most common side effects of clobazam oral suspension include:osleepinessocoughoacting aggressive, being angry or violentotirednessodroolingopain with urinationodifficulty sleepingoproblems with breathingoconstipationofeveroslurred speechThese are not all the possible side effects of clobazam oral suspension. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store clobazam oral suspensionoStore clobazam oral suspension between 20 to 25C (68 to 77F).Oral SuspensionoReplace the cap securely after opening.oStore and dispense the oral suspension in its original bottle in an upright position. Use clobazam oral suspension within 90 days of first opening the bottle.oAfter 90 days safely throw away any clobazam oral suspension that has not been used.oKeep clobazam oral suspension and all medicines out of the reach of children.General information about the safe and effective use of clobazam oral suspension. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use clobazam oral suspension for condition for which it was not prescribed. Do not give clobazam oral suspension 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 clobazam oral suspension that is written for health professionals.What are the ingredients in clobazam oral suspension Oral SuspensionActive ingredient: clobazamInactive ingredients: citric acid monohydrate, dibasic sodium phosphate, magnesium aluminum silicate, maltitol solution, methylparaben, mixed berry flavor, nitrogen, polysorbate 80, propylene glycol, propylparaben, purified water, simethicone emulsion, sucralose and xanthan gum. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.For more information about clobazam oral suspension, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration. Instructions for UseClobazam Oral Suspension CIV(kloe ba zam)Read this Instructions for Use before using clobazam oral suspension and each time you get refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.Prepare Clobazam Oral Suspension DoseYou will need the following supplies: See Figure oClobazam oral suspension bottleoBottle adapteroOral dosing syringe (2 dosing oral syringes are included in the clobazam oral suspension box).oUse only oral syringe to take your dose of clobazam oral suspension. If you lose or damage the oral syringe, or cannot read the markings, use the other oral syringe.Figure AStep 1. Remove the clobazam oral suspension bottle, bottle adapter, and oral syringe from the box.Step 2. Shake the bottle well before each use. See Figure BFigure BStep 3. Uncap the bottle and firmly insert the bottle adapter into the bottle until the adapter top is even with the bottle top. See Figure CFigure COnce the bottle adapter is in place, it should not be removed.Step 4. Check your dose in milliliters (mL) as prescribed by your healthcare provider. Find this number on the oral syringe. Do not take more than the prescribed total dose in day. See Figure DFigure DStep 5. Push the plunger all the way down and then insert the oral syringe into the upright bottle through the opening in the bottle adapter. See Figure EFigure EStep 6. With the oral syringe in place, turn the bottle upside down. Pull the plunger to the number of mLs needed (the amount of liquid medicine in Step 4). See Figure FFigure FMeasure the mLs of medicine using the end of the blue plunger. See Figure Figure GStep 7. Remove the oral syringe from the bottle adapter. Slowly squirt clobazam oral suspension directly into the corner of your mouth or your childs mouth until all of the liquid medicine in the oral syringe is given. See Figure Figure HStep 8. Cap the bottle tightly with the adapter in place. If the cap does not fit securely, check to see if the adapter is fully inserted. See Figure IoStore and dispense clobazam oral suspension in its original bottle in an upright position at 20 to 25C (68 to 77F).oUse clobazam oral suspension within 90 days of first opening bottle.oAfter 90 days safely throw away any clobazam oral suspension that has not been used.Figure IStep 9. Wash the oral syringe after each use.oTo clean the oral syringe, take apart by removing the plunger completely. Pull plunger straight out of the barrel.oThe barrel and plunger can be washed with soap and water, rinsed, and allowed to dry.oDo not wash the oral syringe in the dishwasher.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: DPT Laboratories, Ltd. San Antonio, TX 78215 U.S.A.141199-0321Revised: 3/2021DPT:CLOBOS:R6. oClobazam oral suspension is benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death. Get emergency help right away if any of the following happens: oshallow or slowed breathing obreathing stops (which may lead to the heart stopping) oexcessive sleepiness (sedation) oshallow or slowed breathing obreathing stops (which may lead to the heart stopping) oexcessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking clobazam oral suspension with opioids affects you. oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including clobazam oral suspension, which can lead to overdose and serious side effects including coma and death. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including clobazam oral suspension. These serious side effects may also include delirium, 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. oYou can develop an addiction even if you take clobazam oral suspension as prescribed by your healthcare provider. oTake clobazam oral suspension exactly as your healthcare provider prescribed. oDo not share your clobazam oral suspension with other people. oKeep clobazam oral suspension in safe place and away from children. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including clobazam oral suspension. These serious side effects may also include delirium, 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. oYou can develop an addiction even if you take clobazam oral suspension as prescribed by your healthcare provider. oTake clobazam oral suspension exactly as your healthcare provider prescribed. oDo not share your clobazam oral suspension with other people. oKeep clobazam oral suspension in safe place and away from children. oPhysical dependence and withdrawal reactions. Clobazam oral suspension can cause physical dependence and withdrawal reactions. oDo not suddenly stop taking clobazam oral suspension. Stopping clobazam oral suspension 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. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks tomore 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. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more clobazam oral suspension than prescribed or take clobazam oral suspension for longer than prescribed. oDo not suddenly stop taking clobazam oral suspension. Stopping clobazam oral suspension 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. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks tomore 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. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. oDo not take more clobazam oral suspension than prescribed or take clobazam oral suspension for longer than prescribed. oClobazam oral suspension can make you sleepy or dizzy and can slow your thinking and motor skills. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how clobazam oral suspension affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clobazam oral suspension without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, clobazam oral suspension may make your sleepiness or dizziness much worse. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how clobazam oral suspension affects you. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clobazam oral suspension without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, clobazam oral suspension may make your sleepiness or dizziness much worse. oSerious skin reactions have been seen when clobazam oral suspension is taken with other medicines and may require stopping its use. Do not stop taking clobazam oral suspension without first talking to your healthcare provider.oA serious skin reaction can happen at any time during your treatment with clobazam oral suspension, but is more likely to happen within the first weeks of treatment. These skin reactions may need to be treated right away.oCall your healthcare provider immediately if you have skin blisters, rash, sores in the mouth, hives or any other allergic reaction.. oA serious skin reaction can happen at any time during your treatment with clobazam oral suspension, but is more likely to happen within the first weeks of treatment. These skin reactions may need to be treated right away.. oCall your healthcare provider immediately if you have skin blisters, rash, sores in the mouth, hives or any other allergic reaction.. oLike other antiepileptic medicines, clobazam oral suspension may cause suicidal thoughts or actions in very small number of people, about in 500.. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:. othoughts about suicide or dying. onew or worse depression. ofeeling agitated or restless. otrouble sleeping (insomnia). oacting aggressive, being angry or violent. oother unusual changes in behavior or mood. oattempts to commit suicide. onew or worse anxiety or irritability oan extreme increase in activity and talking (mania). onew or worse panic attacks. oacting on dangerous impulses. oPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.. oKeep 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.. oClobazam oral suspension is prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut syndrome in people years of age or older. oClobazam oral suspension is federally controlled substance (C-IV) because it contains clobazam that can be abused or lead to dependence. Keep clobazam oral suspension in safe place to prevent misuse and abuse. Selling or giving away clobazam oral suspension 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.. oare allergic to clobazam or any of the ingredients in clobazam oral suspension. See the end of this Medication Guide for complete list of ingredients in clobazam oral suspension.. ohave liver or kidney problems. ohave lung problems (respiratory disease). ohave or have had depression, mood problems, or suicidal thoughts or behavior. ouse birth control medicine. Clobazam oral suspension may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use.. oare pregnant or plan to become pregnant. Clobazam oral suspension may harm your unborn baby.oTell your healthcare provider right away if you become pregnant while taking clobazam oral suspension. You and your healthcare provider will decide if you should take clobazam oral suspension while you are pregnant.oBabies born to mothers receiving benzodiazepine medications (including clobazam oral suspension) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms.. oTell your healthcare provider right away if you become pregnant while taking clobazam oral suspension. You and your healthcare provider will decide if you should take clobazam oral suspension while you are pregnant.. oBabies born to mothers receiving benzodiazepine medications (including clobazam oral suspension) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms.. oIf you become pregnant while taking clobazam oral suspension, 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.. oClobazam can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take clobazam oral suspension. You and your healthcare provider should decide if you will take clobazam oral suspension or breastfeed. You should not do both.. oTake clobazam oral suspension exactly as your healthcare provider tells you to take it.. oYour healthcare provider will tell you how much clobazam oral suspension to take and when to take it.. oClobazam oral suspension can be taken with or without food.. oShake the bottle of clobazam oral suspension right before you take each dose.. oMeasure your dose of clobazam oral suspension using the bottle adapter and dosing syringes that come with your clobazam oral suspension.. oRead the Instructions for Use at the end of this Medication Guide for information on the right way to use clobazam oral suspension.. oYour healthcare provider may change your dose if needed. Do not change your dose of clobazam oral suspension without talking to your healthcare provider.. oDo not stop taking clobazam oral suspension without first talking to your healthcare provider.. oStopping clobazam oral suspension suddenly can cause serious problems.. oIf you take too much clobazam oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away.. osleepiness. ocough. oacting aggressive, being angry or violent. otiredness. odrooling. opain with urination. odifficulty sleeping. oproblems with breathing. oconstipation. ofever. oslurred speech. oStore clobazam oral suspension between 20 to 25C (68 to 77F).. oReplace the cap securely after opening.. oStore and dispense the oral suspension in its original bottle in an upright position. Use clobazam oral suspension within 90 days of first opening the bottle.. oAfter 90 days safely throw away any clobazam oral suspension that has not been used.. oKeep clobazam oral suspension and all medicines out of the reach of children.. oClobazam oral suspension bottle. oBottle adapter. oOral dosing syringe (2 dosing oral syringes are included in the clobazam oral suspension box).. oUse only oral syringe to take your dose of clobazam oral suspension. If you lose or damage the oral syringe, or cannot read the markings, use the other oral syringe.. oStore and dispense clobazam oral suspension in its original bottle in an upright position at 20 to 25C (68 to 77F).. oUse clobazam oral suspension within 90 days of first opening bottle.. oAfter 90 days safely throw away any clobazam oral suspension that has not been used.. oTo clean the oral syringe, take apart by removing the plunger completely. Pull plunger straight out of the barrel.. oThe barrel and plunger can be washed with soap and water, rinsed, and allowed to dry.. oDo not wash the oral syringe in the dishwasher.. Instructions for Use Figure A. Instructions for Use Figure B. Instructions for Use Figure C. Instructions for Use Figure D. Instructions for Use Figure E. Instructions for Use Figure F. Instructions for Use Figure G. Instructions for Use Figure H. Instructions for Use Figure I.

SPL UNCLASSIFIED SECTION.

2.1Dosing Information A daily dose of clobazam oral suspension 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 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 Group<= 30 kg Body Weight> 30 kg Body WeightStarting Dose5 mg10 mgStarting Day 710 mg20 mgStarting Day 14 20 mg40 mg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Pregnancy Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as clobazam, during pregnancy. Physicians are advised to recommend that pregnant patients taking clobazam 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 Summary. There are no adequate and well-controlled studies of clobazam 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. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise pregnant woman 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 to 4% and 15 to 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 clobazam 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.. Data. Human Data Congenital Anomalies. Although there are no adequate and well controlled studies of clobazam 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 Data In 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.. 8.2 Lactation Risk Summary. Clobazam is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as clobazam oral suspension, may have effects of lethargy, somnolence and poor sucking. The effect of clobazam on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for clobazam and any potential adverse effects on the breastfed infant from clobazam or from the underlying maternal condition. If exposing breastfed infant to clobazam, observe for any potential adverse effects. Clinical Considerations. Monitoring for Adverse Reactions Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Monitor breastfed infants for possible sedation and poor sucking. Data. Scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.. 8.3 Females and Males of Reproductive Potential Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in patients less than years of age have not been established.In 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.. 8.5 Geriatric Use Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be mg/day. Patients should be titrated initially to 10 to 20 mg/day. Patients may be titrated further to maximum daily dose of 40 mg if tolerated [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].. 8.6 CYP2C19 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) ].. 8.7 Renal 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 clobazam in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].. 8.8 Hepatic Impairment Clobazam 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 to 9). There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oSomnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants (5.4, 5.5)oSerious Dermatological Reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis): Discontinue clobazam at first sign of rash unless the rash is clearly not drug-related (5.6)oSuicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors (5.7). oSomnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants (5.4, 5.5). oSerious Dermatological Reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis): Discontinue clobazam at first sign of rash unless the rash is clearly not drug-related (5.6). oSuicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors (5.7). 5.1Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including clobazam oral suspension, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for 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 clobazam 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 clobazam is used with opioids [see Drug Interactions (7.1)].. 5.2Abuse, Misuse, and Addiction The use of benzodiazepines, including clobazam oral suspension, 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 clobazam oral suspension and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of clobazam oral suspension, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clobazam oral suspension 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 clobazam oral suspension or reduce the dosage [see Dosage and Administration (2.2)]. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions. The continued use of benzodiazepines, including clobazam oral suspension, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of clobazam oral suspension after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)] . Protracted Withdrawal Syndrome. In some cases, benzodiazepine users have developed 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 clobazam 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 Clobazam causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of clobazam 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 postmarketing 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. Clobazam 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 clobazam, 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 to 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 AnalysisIndicationPlacebo Patients with Events per 1,000 PatientsDrug Patients with Events per 1,000 PatientsRelative Risk:Incidence of Drug Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events per 1,000 PatientsEpilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The 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 clobazam or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.