clobazam 5 MG Oral Film [Sympazan]

INDICATIONS AND USAGE Clobazam oral suspension is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Clobazam oral suspension is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. ( 1 )

DOSAGE AND ADMINISTRATION For doses above 5 mg/day administer in two divided doses ( 2.1 ) Patients ≤30 kg body weight: Initiate at 5 mg daily and titrate as tolerated up to 20 mg daily ( 2.1 ) Patients greater than 30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily ( 2.1 ) Dosage adjustment needed in following groups: o Geriatric patients ( 2.4 , 8.5 ) o Known CYP2C19 poor metabolizers ( 2.5 ) o Mild or moderate hepatic impairment; no information for severe hepatic impairment ( 2.7 , 8.8 ) Measure prescribed amount of oral suspension using provided adapter and dosing syringe ( 2.3 ) Oral suspension: Can be taken with or without food ( 2.3 ) 2.1 Dosing Information A daily dose of clobazam oral suspension greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in ≤30 kg weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies ( 14 )]. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state. Table 1. Recommended Total Daily Dosing by Weight Group ≤30 kg Body Weight Greater than 30 kg Body Weight Starting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg 2.2 Discontinuation or Dosage Reduction of Clobazam Oral Suspension To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clobazam oral suspension or reduce the dosage. Taper by decreasing the total daily dose by 5 to 10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions ( 5.3 ) and Drug Abuse and Dependence ( 9.3 )] . 2.3 Important Administration Instructions Instruct patients 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 a 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 patient’s 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. 2.4 Dosage 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 5 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 )]. 2.5 Dosage Adjustments in CYP2C19 Poor Metabolizers In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 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 )]. 2.6 Patients 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 )]. 2.7 Dosage 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 5 to 9), the starting dose should be 5 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 )].

WARNINGS AND PRECAUTIONS Somnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants ( 5.4 , 5.5 ) Serious Dermatological Reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis): Discontinue clobazam oral suspension at first sign of rash unless the rash is clearly not drug-related ( 5.6 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.7 ) Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors ( 5.8 ) Neonatal Sedation and Withdrawal Syndrome: Clobazam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal ( 5.9 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including 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 a decision is made to prescribe clobazam oral suspension 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 oral suspension is used with opioids [see Drug Interactions ( 7.1 )]. 5.2 Abuse, 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue 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 a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence ( 9.3 )]. 5.4 Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants Since clobazam oral suspension has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated [see Drug Interactions ( 7.2 )] . 5.5 Somnolence or Sedation Clobazam oral suspension 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 oral suspension is known. 5.6 Serious Dermatological Reactions Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam oral suspension 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 8 weeks of treatment initiation or when re-introducing therapy. Clobazam oral suspension 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 )]. 5.7 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including clobazam oral suspension. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Clobazam oral suspension should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications ( 4 )]. 5.8 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including clobazam oral suspension, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment d

CONTRAINDICATIONS Clobazam oral suspension is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions ( 5.6 , 5.7) ] . History of hypersensitivity to the drug or its ingredients ( 4 )

Mechanism of Action The exact mechanism of action for clobazam, a 1, 5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor.