Version July 2025
Concomitant 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.
The use of benzodiazepines, including clobazam, 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 and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.
The continued use of benzodiazepines, including clobazam, 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 after continued use may precipitate acute withdrawal reactions, which can be life threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clobazam or reduce the dosage.
Dosage guidance:
Safety: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise) (Ref). Avoid use in patients with a history of substance use, misuse of medications, or depression (Ref).
Anxiety disorders (off-label use):
Note: Generally used short-term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks, followed by tapering). Long-term, low-dose therapy may be considered in select patients only when other treatments are ineffective or poorly tolerated (Ref). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may cause cognitive changes (Ref).
Oral: 20 to 30 mg/day in 2 to 3 divided doses; may gradually increase based on response and tolerability to 80 mg/day (Ref).
Catamenial epilepsy (off-label use): Oral: 20 to 30 mg daily for 10 days during the perimenstrual period (Ref).
Lennox-Gastaut (adjunctive): Oral: Initial: 5 mg twice daily for ≥1 week, then increase based on response and tolerability to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter.
CYP2C19 poor metabolizers : Oral: Initial: 5 mg once daily for ≥1 week; based on response and tolerability may increase to 5 mg twice daily for ≥1 week; based on response and tolerability may increase to 10 mg twice daily for ≥1 week; if further dose increases are needed based on response and tolerability may increase to 20 mg twice daily starting ≥21 days after initial dose.
Seizures, treatment refractory (adjunctive; off-label): Oral: Initial: 5 to 15 mg/day; may gradually increase based on response and tolerability to 40 mg/day (Ref). Alternatively, a maximum dose of 80 mg/day has also been recommended (Ref). Daily doses of up to 30 mg may be taken as a single dose at bedtime; higher doses should be divided (Ref).
CYP2C19 poor metabolizers: Initiate at lowest recommended doses; titrate slowly as tolerated to half of usual recommended maximum dose. If needed, dose may be further increased as tolerated to usual recommended maximum dose beginning day 21 (Ref).
Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms (Ref).
Low or moderate dose, no concerns for benzodiazepine use disorder: Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Ref).
Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by ~25% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Ref). Reduce dose more rapidly in the beginning, and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Ref). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Mild to moderate impairment: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily based on patient tolerability and response; maximum: 40 mg/day.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Use with caution; undergoes extensive hepatic metabolism.
Lennox-Gastaut (adjunctive): Oral: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily based on patient tolerability and response; maximum 40 mg/day.
Discontinuation of therapy: See adult dosing.
(For additional information see "Clobazam: Pediatric drug information")
Dosage guidance:
Dosage form information: Oral film and tablet dosage forms are bioequivalent.
Dravet syndrome: Limited data available:
Note: Clobazam or valproic acid are considered optimal first-line medications; initiate with either agent as monotherapy; if response suboptimal the other agent should be added; continued management should be guided by expert recommendations (Ref).
Infants, Children, and Adolescents: Oral: Initial: 0.2 to 0.3 mg/kg/day typically administered in divided doses twice daily; titrate up to common target range: 0.5 to 2 mg/kg/day (Ref).
Lennox-Gastaut syndrome: Note: Titrate dose based on patient tolerability and response.
Children ≥2 years and Adolescents:
≤30 kg: Oral: Initial: 5 mg once daily for ≥1 week, may then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily thereafter; usual maximum daily dose: 20 mg/day; however, in a long-term, open-label extension study, doses up to 2 mg/kg/day were associated with improved seizure control (Ref).
>30 kg: Oral: Initial: 5 mg twice daily for ≥1 week, may then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter; usual maximum daily dose: 40 mg/day; however, in a long-term, open-label extension study, doses up to 2 mg/kg/day (maximum daily dose: 80 mg/day) were associated with improved seizure control (Ref).
Seizures, refractory; generalized or partial, monotherapy or adjunctive therapy: Limited data available. Note: Titrate dose based on patient tolerability and response.
Infants and Children <2 years: Oral: Initial: 0.5 to 1 mg/kg/day usually in divided doses twice daily; maximum initial daily dose: 5 mg/day; may increase dosage slowly (not more often than every 5 to 7 days); maximum daily dose: 10 mg/day.
Children 2 to 16 years: Oral: Initial: 5 mg once daily; may increase dosage slowly (not more often than every 5 days), usual range: 10 to 20 mg/day or 0.3 to 1 mg/kg/day in divided doses twice daily; maximum daily dose: 40 mg/day; a retrospective review of 108 pediatric patients (mean age: 8.66 years; range: 0.62 to 17.9 years) reported a mean initial dose of 0.88 mg/kg/day (range: 0.23 to 2.17 mg/kg/day) and at initial response, the reported mean dose was 1.05 mg/kg/day (range: 0.23 to 4.66 mg/kg/day) (Ref).
Discontinuation of therapy: Children ≥2 years and Adolescents: Oral: Withdraw gradually by decreasing the total daily dosage by 5 to 10 mg/day on a weekly basis until discontinued. Consider pausing a taper or increasing the dosage of a previous tapered dosage level if withdrawal reactions occur; further dose tapering should be done more slowly.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for CYP2C19 poor metabolizers:
Children ≥2 years and Adolescents:
≤30 kg: Oral: Initial: 5 mg once daily for 1 week, titrate slowly; based on response and tolerability, may increase to 5 mg twice daily for ≥1 week; if further increases are needed based on response and tolerability, may increase to 10 mg twice daily starting ≥21 days after initial dose.
>30 kg: Oral: Initial: 5 mg once daily for 1 week; based on response and tolerability, may increase to 5 mg twice daily for ≥1 week; based on response and tolerability, may then increase to 10 mg twice daily for ≥1 week; if further dose increases are needed based on response and tolerability, may increase to 20 mg twice daily starting ≥21 days after initial dose.
Children and Adolescents:
CrCl ≥30 mL/minute: Oral: No dosage adjustment required.
CrCl <30 mL/minute: Oral: Use with caution; has not been studied.
Children ≥2 years and Adolescents:
Mild to moderate impairment:
≤30 kg: Oral: Initial: 5 mg once daily for 1 week, titrate slowly; based on response and tolerability, may increase to 5 mg twice daily for ≥1 week; if further increases are needed based on response and tolerability, may increase to 10 mg twice daily starting ≥21 days after initial dose.
>30 kg: Oral: Initial: 5 mg once daily for 1 week, titrate slowly; based on response and tolerability, may increase to 5 mg twice daily for ≥1 week; based on response and tolerability, may then increase to 10 mg twice daily for ≥1 week; if further dose increases are needed based on response and tolerability, may increase to 20 mg twice daily starting ≥21 days after initial dose.
Severe impairment: There are no dosage adjustments provided in manufacturer's labeling; there is inadequate information about hepatic metabolism and the pharmacokinetics in patients with severe impairment. Use with extreme caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Central nervous system: Drowsiness (16% to 25%), lethargy (10% to 15%), drooling (13% to 14%), aggressive behavior (8% to 14%), irritability (11%)
Respiratory: Upper respiratory tract infection (13% to 14%)
Miscellaneous: Fever (10% to 17%)
1% to 10%:
Central nervous system: Ataxia (10%), sedation (9%), insomnia (5% to 7%), psychomotor agitation (5%), fatigue (3% to 5%), dysarthria (2% to 5%)
Gastrointestinal: Constipation (2% to 10%), vomiting (7% to 9%), decreased appetite (7%), increased appetite (2% to 5%), dysphagia (5%)
Genitourinary: Urinary tract infection (2% to 5%)
Respiratory: Cough (3% to 7%), pneumonia (3% to 7%), bronchitis (2% to 5%)
Postmarketing and/or case reports: Abdominal distention, agitation, anemia, angioedema, anxiety, apathy, behavioral changes, blurred vision, confusion, delirium, delusions, depression, diplopia, DRESS syndrome (Dang 2015), eosinophilia, facial edema, hallucination, hypothermia, increased liver enzymes, leukopenia, lip edema, mood changes, muscle spasm, pulmonary aspiration, respiratory depression, skin rash, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, thrombocytopenia, toxic epidermal necrolysis, urinary retention, urticaria, withdrawal syndrome
Hypersensitivity to clobazam or any component of the formulation.
Canadian labeling: Additional contraindications (not in US labeling): Myasthenia gravis; narrow-angle glaucoma; severe hepatic or respiratory disease; sleep apnea; history of substance abuse; use in the first trimester of pregnancy; breast-feeding
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Multiorgan hypersensitivity reactions: Potentially serious, sometimes life-threatening or fatal multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms) have been reported with some antiseizure drugs, including clobazam. Symptoms typically include fever, rash, lymphadenopathy, and/or facial swelling, in association with organ involvement such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; may sometimes resemble an acute viral infection. Discontinue therapy if evidence of multiorgan hypersensitivity occurs.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).
• Skin reactions: Serious reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported. Monitor patients closely for signs and symptoms (eg, burning sensation, pleomorphic rash, petechiae, vesicles, bullae) especially during the first 8 weeks or when reintroducing therapy. Permanently discontinue immediately if rash is suggestive of SJS/TEN.
• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).
• Suicidal ideation: Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.
Disease-related concerns:
• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be necessary.
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.
Special populations:
• Older adult: Lower doses are recommended. Older adult patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older adult dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).
• Poor CYP2C19 metabolizers: Concentrations of the active metabolite N-desmethylclobazam are 3 to 5 times higher in patients who are known CYP2C19 poor metabolizers compared to CYP2C19 extensive metabolizers. Dose adjustment is needed in patients who are poor CYP2C19 metabolizers.
Other warnings/precautions:
• Abuse, misuse, and substance use disorder: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and substance use disorder. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• Chronic use: Tolerance to antiseizure effects and loss of seizure control have been reported with chronic administration, although this risk may be lower than with other benzodiazepines; a long-term trial evaluating 200 patients (age range: 2 to 60 years of age) treated for Lennox-Gastaut syndrome did not show evidence of tolerance over 2 years of treatment (Gidal 2016).
• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
May cause CNS depression and dose-related somnolence and sedation (incidence: 32% with high doses); onset of somnolence and sedation occurs within first month of therapy and may lessen with continued treatment. Decreased bone density and bone length and alterations in behavior have been reported in juvenile animal studies at levels of exposure greater than therapeutic doses; adverse bone effects were reversible upon discontinuation. Administration of high doses to rats for 2 years was associated with an increase in thyroid follicular cell adenomas; implications for human use are uncertain.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Film, Oral:
Sympazan: 5 mg (1 ea, 60 ea); 10 mg (1 ea, 60 ea); 20 mg (1 ea, 60 ea)
Suspension, Oral:
Onfi: 2.5 mg/mL (120 mL) [contains methylparaben, polysorbate 80, propylene glycol, propylparaben; berry flavor]
Generic: 2.5 mg/mL (120 mL)
Tablet, Oral:
Onfi: 10 mg, 20 mg [scored; contains corn starch]
Generic: 10 mg, 20 mg
May be product dependent
Film (Sympazan Oral)
5 mg (per each): $20.17
10 mg (per each): $40.36
20 mg (per each): $80.72
Suspension (cloBAZam Oral)
2.5 mg/mL (per mL): $0.35 - $9.14
Suspension (Onfi Oral)
2.5 mg/mL (per mL): $15.67
Tablets (cloBAZam Oral)
10 mg (per each): $2.29 - $20.87
20 mg (per each): $4.58 - $41.74
Tablets (Onfi Oral)
10 mg (per each): $37.57
20 mg (per each): $75.14
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 10 mg
C-IV
Administer with or without food. Daily doses >5 mg should be divided and administered twice daily.
Oral film: Apply one oral film on top of tongue where it dissolves. Do not take more than one film at a time. If a second film is needed, apply on top of tongue after the first film completely dissolves. Do not administer with liquids; swallow in a normal manner as the film dissolves; do not chew, spit, or talk as the film dissolves.
Suspension: Shake suspension well before using; only use the oral dosing syringe supplied with the suspension.
Tablets: Tablets can be broken in half or crushed and mixed in applesauce.
Oral: May be administered with or without food.
Oral film: Apply 1 oral film on top of tongue and let dissolve. Do not take more than 1 film at a time. If a second film is needed, apply on top of tongue after the first film completely dissolves. Do not administer with liquids; swallow in a normal manner as the film dissolves; do not chew, spit, or talk as the film dissolves.
Oral suspension: Shake well before use. Measure dosage with manufacturer-provided oral dosing syringe and bottle adapter.
Tablets: May be administered whole, broken in half along score, or crushed and mixed in applesauce.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Onfi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202067s007,203993s009lbl.pdf
Sympazan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210833s004lbl.pdf
Lennox-Gastaut syndrome: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients ≥2 years
Anxiety disorders; Catamenial epilepsy; Seizures, treatment refractory (adjunctive)
CloBAZam may be confused with clonazePAM
Beers Criteria: Clobazam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients ≥65 years of age due to risk of abuse, misuse, physical dependence, and addiction. In addition, older adults have increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use, and slower metabolism of long-acting benzodiazepines (eg, clobazam); however, benzodiazepines may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorder, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2023]).
Substrate of CYP2B6 (Minor), CYP2C19 (Major with inhibitors), CYP2C19 (Minor with inducers), CYP3A4 (Major with inducers), CYP3A4 (Minor with inhibitors), P-glycoprotein (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (Weak); Induces CYP3A4 (Weak);
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): May increase CNS depressant effects of CloBAZam. Alcohol (Ethyl) may increase serum concentration of CloBAZam. Management: Patients taking clobazam should avoid alcohol consumption. If combined, patients should be informed that the CNS depressant effects of alcohol and clobazam may be potentiated. Risk D: Consider Therapy Modification
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
ARIPiprazole Lauroxil: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole Lauroxil may increase hypotensive effects of Benzodiazepines. Specifically, the risk of orthostatic hypotension may be increased. Risk C: Monitor
ARIPiprazole: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole may increase hypotensive effects of Benzodiazepines. Specifically, orthostatic hypotension may be increased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Atogepant: CYP3A4 Inducers (Weak) may decrease serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Beta-Acetyldigoxin: Benzodiazepines may increase serum concentration of Beta-Acetyldigoxin. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabidiol: CloBAZam may increase hepatotoxic effects of Cannabidiol. Cannabidiol may increase serum concentration of CloBAZam. Cannabidiol may increase active metabolite exposure of CloBAZam. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
CarBAMazepine: CYP3A4 Inducers (Weak) may decrease serum concentration of CarBAMazepine. Risk C: Monitor
Cenobamate: May increase active metabolite exposure of CloBAZam. Cenobamate may increase serum concentration of CloBAZam. Risk C: Monitor
Certoparin: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CloZAPine: Benzodiazepines may increase adverse/toxic effects of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider Therapy Modification
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Corticosteroids (Orally Inhaled): Benzodiazepines may increase adverse/toxic effects of Corticosteroids (Orally Inhaled). Specifically, the risk of pneumonia may be increased. Risk C: Monitor
CYP2C19 Inhibitors (Moderate): May increase active metabolite exposure of CloBAZam. CYP2C19 Inhibitors (Moderate) may increase serum concentration of CloBAZam. Risk C: Monitor
CYP2C19 Inhibitors (Strong): May increase active metabolite exposure of CloBAZam. CYP2C19 Inhibitors (Strong) may increase serum concentration of CloBAZam. Risk C: Monitor
CYP2C19 Inhibitors (Weak): May increase serum concentration of CloBAZam. CYP2C19 Inhibitors (Weak) may increase active metabolite exposure of CloBAZam. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Fenfluramine: CloBAZam may increase serum concentration of Fenfluramine. Management: Limit the fenfluramine dose to a maximum daily dosage of 0.2 mg/kg twice daily (17 mg/day) when used in combination with stiripentol and clobazam. Risk D: Consider Therapy Modification
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider Therapy Modification
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ilaprazole: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melatonin: May increase sedative effects of Benzodiazepines. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: Benzodiazepines may increase CNS depressant effects of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider Therapy Modification
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
NiMODipine: CYP3A4 Inducers (Weak) may decrease serum concentration of NiMODipine. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Benzodiazepines may increase adverse/toxic effects of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: Benzodiazepines may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Phenobarbital-Primidone: May increase CNS depressant effects of CloBAZam. Phenobarbital-Primidone may decrease serum concentration of CloBAZam. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Selpercatinib: CYP3A4 Inducers (Weak) may decrease serum concentration of Selpercatinib. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease serum concentration of Sirolimus (Conventional). Risk C: Monitor
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease serum concentration of Sirolimus (Protein Bound). Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Teduglutide: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Theophylline Derivatives: May decrease therapeutic effects of Benzodiazepines. Risk C: Monitor
Thioridazine: CYP2D6 Inhibitors (Weak) may increase serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider Therapy Modification
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ubrogepant: CYP3A4 Inducers (Weak) may decrease serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider Therapy Modification
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valproic Acid and Derivatives: May increase CNS depressant effects of CloBAZam. CloBAZam may increase serum concentration of Valproic Acid and Derivatives. Risk C: Monitor
Yohimbine: May decrease therapeutic effects of Antianxiety Agents. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Ethanol: Concomitant administration may increase bioavailability of clobazam by 50%. Management: Monitor for increased effects with coadministration.
Manage epilepsy in patients who could become pregnant based on a shared decision-making process that optimizes seizure control and considers the possibility of pregnancy during treatment (Pack 2024). Regularly discuss age-specific and developmental needs, including pregnancy planning and contraceptive options during the patient’s reproductive lifespan (ACOG 2020; NICE 2022). Obtain reference concentrations of total and unbound clobazam and N-desmethylclobazam twice prior to pregnancy while patient has stable seizure control and is on a minimal dose (Arfman 2020).
Clobazam is not a first-line medication to treat anxiety disorders prior to conception in patients who are treatment naive or who do not have a history of effective treatment with a specific medication. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist. Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]).
Clobazam crosses the placenta (Nandakumaran 1982).
In-utero exposure to benzodiazepines has the potential to cause harm to the fetus. Teratogenic effects have been observed in some studies; however, a clear association has not been reported and additional data are needed (Bellantuono 2013; Chuang 2024; Freeman 2018; Grigoriadis 2019; Tinker 2019; Wu 2024). Data are insufficient to evaluate the risk of specific major congenital malformations following in utero exposure to clobazam (Pack 2024). Exposure to a benzodiazepine late in pregnancy may cause neonatal sedation (hypotonia, lethargy, respiratory depression) and/or symptoms of neonatal withdrawal (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, and tremors). Data related to long-term effects on neurodevelopment following maternal use of benzodiazepines are inconclusive (Andrade 2024; Radojčić 2017; Sundbakk 2025; Wang 2022) and data are insufficient to evaluate the risk of neurodevelopmental outcomes (IQ scores or autism spectrum disorder) in children following in utero exposure to clobazam (Pack 2024). Newborns exposed to clobazam in utero should be monitored for adverse events. Screen for major congenital malformations and monitor fetal growth when antiseizure medications are used during pregnancy. Conduct age-appropriate developmental screening in children with previous in utero exposure to antiseizure medications (Pack 2024).
Data are insufficient to evaluate possible pregnancy-induced physiologic changes related to the pharmacokinetics of clobazam (Arfman 2020). Monitor total and unbound trough levels of clobazam and N-desmethylclobazam when necessary during pregnancy and adjust doses based on decreasing levels or seizure control (Arfman 2020; Pack 2024). Formulate a plan to return to prepregnancy doses after delivery (NICE 2022).
Epilepsy is associated with adverse maternal and fetal outcomes (Kuang 2024; Mazzone 2023). Convulsive seizures should be minimized to reduce risks to the fetus and pregnant patient. Use caution if removing or replacing an effective seizure medication in patients who become pregnant during therapy. Folic acid supplementation prior to and during pregnancy minimizes the risk of congenital malformations and poor neurodevelopment (Pack 2024).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Anxiety disorders during pregnancy are associated with low birth weight, preterm birth, and adverse behavioral outcomes in the offspring. Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process. Agents other than clobazam may be preferred when treatment for anxiety is initiated for the first-time during pregnancy. The use of benzodiazepines for the treatment of perinatal anxiety should be avoided or used sparingly until preferred therapy is initiated and effective, or when preferred therapy is not effective. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy outcomes following exposure to antiepileptic drugs is ongoing. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334 or http://www.aedpregnancyregistry.org).
Clobazam and its active metabolite N-desmethylclobazam are present in breast milk.
• Breast milk was sampled 2 hours after each dose following administration of clobazam 10 mg at 7 AM and 20 mg at 3 PM to six patients (postpartum age not provided). The average morning clobazam and N-desmethylclobazam concentrations after 2 days of therapy were 0.125 mg/L (breast milk) and 0.418 mg/L (maternal plasma). After 5 days of therapy, average morning clobazam and N-desmethylclobazam concentrations were 0.152 mg/L (breast milk) and 1.22 mg/L (maternal plasma) (Bennett 1996).
Drowsiness, lethargy, or weight loss in breastfeeding infants have been observed in case reports following maternal use of some benzodiazepines (Iqbal 2002).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to clobazam via breast milk should be monitored for feeding problems, respiratory depression, and poor weight gain. A benzodiazepine with a short half-life can be considered for the treatment of anxiety in patients who are breastfeeding. Avoid benzodiazepines with long half-life or multiple active metabolites (Eleftheriou 2024).
Gradual dose adjustments over the first 21 days postpartum and maternal therapeutic drug monitoring are recommended after delivery if the dose of clobazam was changed during pregnancy (Arfman 2020).
Respiratory and mental status/suicidality (eg, suicidal thoughts, depression, behavioral changes); serious skin reactions (Stevens Johnson Syndrome, toxic epidermal necrolysis) during treatment initiation or reintroduction of therapy; signs and symptoms of multiorgan hypersensitivity reactions.
Long-acting benzodiazepine (Griffin 2013). Clobazam is a 1,5 benzodiazepine which binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors (Vinkers 2012).
Onset: Maximum effect: 5 to 9 days.
Duration of action: Adults: Classified as a long-acting benzodiazepine; classification based on benzodiazepines with half-life >40 hours (Griffin 2013).
Absorption: Rapid and extensive; not affected by food or crushing tablet.
Distribution: 100 L.
Protein binding: Clobazam: 80% to 90%; N-desmethylclobazam (NCLB): 70%.
Metabolism: Hepatic via CYP3A4 and to a lesser extent via CYP2C19 and 2B6 (N-demethylation to active metabolite [N-desmethyl] with ~20% activity of clobazam). CYP2C19 primarily mediates subsequent hydroxylation of the N-desmethyl metabolite; metabolic rate increased in children (53% to 69%) (Ng 2007). Plasma concentrations of NCLB are 5 times higher in CYP2C19 poor metabolizers versus extensive metabolizers.
Bioavailability: 87% (Ng 2007).
Half-life elimination: Children: Clobazam: 16 hours (Ng 2007); Adults: Clobazam: 36 to 42 hours; N-desmethyl (active): 71 to 82 hours.
Time to peak: Oral film: 0.33 to 4 hours; Tablet: 0.5 to 4 hours; Oral suspension: 0.5 to 2 hours.
Excretion: Urine (~82%; unchanged drug: 2%, NCLB and other metabolites: ~94%); feces (~11%; 1% unchanged drug).
Older adult: Clearance is lower in elderly patients.
CYP2C19 poor metabolizers: AUC and Cmax of active metabolite are ~3 to 5 times higher in poor metabolizers compared with extensive metabolizers and ~2 times higher in intermediate metabolizers.
