SYMPAZAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYMPAZAN (SYMPAZAN).
SYMPAZAN (clobazam) is a benzodiazepine that potentiates GABAergic inhibition via binding to the GABA-A receptor at the benzodiazepine site, enhancing chloride ion influx and neuronal hyperpolarization.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2C19 to N-desmethylclobazam, an active metabolite. N-desmethylclobazam is further metabolized by CYP2C19. |
| Excretion | Primarily renal excretion of unchanged drug (approximately 60-70%), with minor fecal elimination (10-15%) and metabolism. |
| Half-life | Terminal elimination half-life is approximately 20-30 minutes sublingually, prolonged to 2-3 hours in hepatic impairment. Clinical context: Short t½ necessitates repeated dosing for seizure clusters. |
| Protein binding | Approximately 90-95% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd is 1-2 L/kg, indicating extensive tissue distribution beyond plasma volume. |
| Bioavailability | Sublingual and buccal: 100% bioequivalent to intravenous; intranasal: approximately 80%. |
| Onset of Action | Sublingual: 2-5 minutes; buccal: 2-5 minutes; intranasal: 3-5 minutes. Rapid onset due to high bioavailability. |
| Duration of Action | Duration is 1-2 hours for acute seizure control, with possible prolonged effect up to 6 hours. Clinical note: Short duration limits use to seizure clusters rather than maintenance. |
| Molecular Weight | 300.74 |
10-20 mg orally three times daily (maximum 60 mg/day). If switching from another benzodiazepine, use equivalent dose.
| Dosage form | FILM |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. For severe renal impairment (CrCl <30 mL/min), use with caution and consider dose reduction; specific guidelines not established. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B), reduce dose by 50% or administer with caution, as clobazam is extensively metabolized in the liver. |
| Pediatric use | Based on body weight: 5 mg orally once daily for <30 kg, increase to 10 mg daily after 2 weeks if needed (max 20 mg/day). For ≥30 kg, 5-10 mg once daily initially, titrate to 20 mg/day (max 40 mg/day). |
| Geriatric use | Initiate at 5 mg once daily, titrate slowly due to increased sensitivity to benzodiazepines and risk of falls. Maximum dose generally not to exceed 20 mg/day. |
| 1st trimester | Benzodiazepines are generally avoided in the first trimester due to potential increased risk of congenital malformations, particularly oral clefts, although data for clobazam specifically are limited. Use only if clearly needed. |
| 2nd trimester | Consider risk-benefit; may be used if benefit outweighs risk. Monitor for neonatal withdrawal if used near term. |
| 3rd trimester | Avoid in late third trimester due to risk of neonatal sedation, withdrawal, and floppy infant syndrome. |
Clinical note
Comprehensive clinical and safety monograph for SYMPAZAN (SYMPAZAN).
| Placental transfer | Clobazam crosses the placenta. Data from other benzodiazepines indicate significant placental transfer; specific degree for clobazam is limited. |
| Breastfeeding | Clobazam and its active metabolite N-desmethylclobazam are excreted into breast milk. Monitor infant for sedation, poor feeding, and weight gain. If possible, use lowest effective dose and avoid prolonged use. |
■ FDA Black Box Warning
Concomitant use of benzodiazepines with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate.
| Serious Effects |
Hypersensitivity to clobazam or any benzodiazepineSevere hepatic impairmentNarrow-angle glaucomaMyasthenia gravisSevere respiratory insufficiencySleep apnea syndrome
| Precautions | Respiratory depression, Sedation and somnolence, Risk of abuse, misuse, and addiction, Dependence and withdrawal reactions, Suicidal thoughts or behavior |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase levels of clobazam and its active metabolite. No other significant food interactions known. |
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| Lactation Rating | L3 (Moderately Safe) - limited data suggest potential adverse effects in nursing infants; consider risk-benefit. |
| Teratogenic Risk | Benzodiazepines are generally associated with increased risk of oral clefts when used in the first trimester. Use in the third trimester may cause neonatal sedation, withdrawal, or floppy infant syndrome. Specific fetal risk data for clobazam (Sympazan) are limited. |
| Fetal Monitoring | Fetal ultrasound monitoring for growth restriction, assessment of neonatal adaptation at birth, and monitoring for signs of withdrawal or sedation in the neonate. |
| Fertility Effects | No specific studies. Benzodiazepines may cause menstrual irregularities in women; impact on fertility is unknown. |
| Clinical Pearls | Clobazam oral film (SYMPAZAN) is a benzodiazepine approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is available as a rapidly dissolving film that can be placed on the tongue. The active metabolite N-desmethylclobazam is primarily renally excreted; adjust dose in renal impairment. Avoid abrupt discontinuation due to risk of withdrawal seizures. CYP2C19 poor metabolizers have significantly higher exposure to the active metabolite; consider dose reduction. Can cause sedation, dizziness, and somnolence; monitor for respiratory depression especially with other CNS depressants. Abuse potential exists; use with caution in patients with history of substance abuse. |
| Patient Advice | Place the film on your tongue where it will dissolve quickly; do not chew or swallow it whole. · Take this medication exactly as prescribed; do not increase the dose or stop suddenly without talking to your doctor to avoid withdrawal seizures. · Avoid driving or operating heavy machinery until you know how this drug affects you, as it may cause drowsiness, dizziness, or blurred vision. · Avoid alcohol and other sedating medications while taking SYMPAZAN, as they can increase the risk of severe drowsiness and breathing problems. · Tell your doctor if you have kidney or liver disease, or if you have a history of substance abuse or depression. · If you miss a dose, take it as soon as you remember; if it is close to the next dose, skip the missed dose and continue your regular schedule. Do not double the dose. · Store the film at room temperature away from moisture and heat; keep each film in its sealed pouch until ready to use. |