Sympazan - Drug Monograph

Introduction

Sympazan (clobazam) is a benzodiazepine derivative approved by the U.S. Food and Drug Administration (FDA) in 2018 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older. It is available as an oral film formulation, offering an alternative administration method for patients who have difficulty swallowing conventional tablets or capsules.

Mechanism of Action

Sympazan exerts its therapeutic effects through potentiation of gamma-aminobutyric acid (GABA)-mediated neurotransmission. As a benzodiazepine, it binds to specific sites on the GABA-A receptor complex, enhancing the inhibitory effects of GABA. This binding increases chloride ion channel opening frequency, resulting in neuronal hyperpolarization and reduced neuronal excitability. Clobazam demonstrates preferential affinity for α2-containing GABA-A receptors over α1-containing receptors, which may contribute to its apparently better tolerability profile compared to classical benzodiazepines.

Indications

• Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older

Dosage and Administration

• Patients ≤30 kg: Start at 5 mg/day
• Patients >30 kg: Start at 10 mg/day
• Divide total daily dose into two administrations

• May increase dosage weekly based on response and tolerability
• Maximum recommended dosage:

- Patients ≤30 kg: 20 mg/day - Patients >30 kg: 40 mg/day

• Geriatric patients: Use lowest effective dose
• Renal impairment: Use caution; consider dose reduction
• Hepatic impairment: Use caution; consider dose reduction
• CYP2C19 poor metabolizers: Maximum recommended dose is 20 mg/day for patients >30 kg

• Place film on top of tongue where it will dissolve
• May administer with or without water
• Do not cut or split the film

Pharmacokinetics

• Rapidly absorbed with peak concentrations occurring at approximately 0.5-4 hours
• Absolute bioavailability approximately 100%
• Food does not significantly affect absorption

• Protein binding: 80-90%
• Volume of distribution: Approximately 100 L
• Crosses blood-brain barrier and placenta

• Extensive hepatic metabolism primarily via CYP3A4 and CYP2C19
• N-desmethylclobazam (active metabolite) formed via CYP2C19, CYP3A4, and CYP2B6
• N-desmethylclobazam has approximately 1/5 the activity of parent compound

• Terminal elimination half-life:

- Clobazam: 36-42 hours - N-desmethylclobazam: 71-82 hours

• Primarily excreted in urine (80%) and feces (11%)

Contraindications

• Hypersensitivity to clobazam or any component of the formulation
• Acute narrow-angle glaucoma
• Significant respiratory depression
• Severe hepatic impairment

Warnings and Precautions

• May cause sedation, somnolence, and impaired coordination
• Caution patients against operating machinery or driving
• Effects potentiated by alcohol and other CNS depressants

• Risk of dependence with prolonged use
• Abrupt discontinuation may cause withdrawal symptoms including seizures
• Taper gradually when discontinuing therapy

• Antiepileptic drugs may increase risk of suicidal thoughts and behavior
• Monitor for emergence or worsening of depression

• Use with caution in patients with pulmonary disease or respiratory compromise
• Risk increased with concomitant opioid use

• Common side effects that may impair cognitive and motor functions
• Typically most pronounced during initial therapy and after dose increases

Drug Interactions

• Omeprazole, fluvoxamine, fluoxetine: May increase levels of N-desmethylclobazam
• Consider dose reduction of Sympazan

• Carbamazepine, phenytoin, rifampin: May decrease clobazam levels
• May require dose adjustment

• Alcohol, opioids, barbiturates: Additive CNS depression
• Use with extreme caution

• May decrease efficacy of hormonal contraceptives
• Recommend additional non-hormonal contraception

Adverse Effects

• Somnolence (32%)
• Sedation (25%)
• Pyrexia (17%)
• Lethargy (15%)
• Drooling (13%)
• Aggression (12%)
• Insomnia (11%)
• Irritability (11%)

• Respiratory depression
• Suicidal ideation and behavior
• Physical dependence and withdrawal
• Severe dermatological reactions
• Hematological abnormalities

Monitoring Parameters

• Seizure frequency and characteristics
• Sedation and cognitive function
• Respiratory status, especially in patients with pulmonary compromise
• Signs of depression or suicidal ideation
• Complete blood count and liver function tests periodically
• Withdrawal symptoms during dose reduction or discontinuation
• Growth parameters in pediatric patients

Patient Education

• Demonstrate proper placement of oral film on tongue
• Do not chew, swallow, or cut the film
• May be taken with or without water

• Avoid alcohol and other sedating substances
• Do not drive or operate machinery until effects are known
• Report increased sedation, confusion, or respiratory changes
• Never stop medication abruptly without medical supervision

• Discuss pregnancy planning with healthcare provider
• Registry available for pregnant patients taking AEDs
• Clobazam excreted in human milk; discuss risks and benefits

• Store at room temperature (20-25°C)
• Keep in original packaging until use
• Keep out of reach of children

References

1. FDA Prescribing Information: Sympazan (clobazam) oral film. 2018. 2. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77(15):1473-1481. 3. Conry JA, Ng YT, Kernitsky L, et al. Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia. 2014;55(4):558-567. 4. Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246-1251. 5. Gastaut H, Low MD. Antiepileptic properties of clobazam, a 1,5-benzodiazepine, in man. Epilepsia. 1979;20(4):437-446. 6. Sankar R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs. 2011;25(3):229-244.