Version May 2024
The FDA has issued a drug safety communication warning that clobazam (Onfi, Sympazan) can cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a rare but serious hypersensitivity reaction that can be life-threatening if not diagnosed and treated quickly. The onset of DRESS typically occurs 2 to 8 weeks after starting clobazam; symptoms may include rash, fever, or swollen lymph nodes but can quickly progress, resulting in injury to organs including the liver, kidney, lungs, heart, or pancreas, the need for hospitalization, and death. The FDA is requiring warnings about this risk to be added to the prescribing information and Medication Guide. Health care providers should advise patients of the signs and symptoms of DRESS and to stop taking their medication and seek immediate medical attention if DRESS is suspected during treatment with clobazam.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-rare-serious-drug-reaction-antiseizure-medicines-levetiracetam-keppra-keppra-xr-elepsia-xr
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 worsen symptoms (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:
Dosing: Dosage should be titrated according to patient tolerability and response.
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: 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:
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: Oral:
≤30 kg: 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: 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: No dosage adjustment required
CrCl <30 mL/minute: Use with caution, has not been studied
Children ≥2 years and Adolescents: Oral:
Mild to moderate impairment:
≤30 kg: 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: 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).
• 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): $19.06
10 mg (per each): $38.11
20 mg (per each): $76.24
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): $35.78
20 mg (per each): $71.56
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.
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#page=29
Sympazan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210833s004lbl.pdf#page=26
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), CYP3A4 (major), P-glycoprotein/ABCB1 (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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of CloBAZam. Alcohol (Ethyl) may increase the 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Atogepant: CYP3A4 Inducers (Weak) may decrease the 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 enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect 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
Cannabidiol: CloBAZam may enhance the hepatotoxic effect of Cannabidiol. Cannabidiol may increase serum concentrations of the active metabolite(s) of CloBAZam. Cannabidiol may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect 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 enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Strong) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
CYP2C19 Inhibitors (Weak): May increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect 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 enhance the CNS depressant effect 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect 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
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fenfluramine: CloBAZam may increase the 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 enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 the 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 enhance the CNS depressant effect 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 the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect 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
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy
Methadone: Benzodiazepines may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect 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 therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect 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
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect 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 the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Thioridazine: CYP2D6 Inhibitors (Weak) may increase the 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: May enhance the CNS depressant effect of CloBAZam. CloBAZam may increase the serum concentration of Valproate Products. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect 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.
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; Freeman 2018; Grigoriadis 2019; Noh 2022; Szpunar 2022; Tinker 2019; Wikner 2007). 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 are inconclusive (Chen 2022; Radojčić 2017; Sundbakk 2022; Wang 2022). Newborns exposed to clobazam in utero should be monitored for feeding problems, respiratory depression, sedation, and withdrawal.
When treating pregnant patients for epilepsy, monotherapy with the lowest effective dose and avoidance medications known to have a high incidence of teratogenic effects is recommended (Harden 2009; Wlodarczyk 2012).
Data collection to monitor pregnancy and infant outcomes following exposure to clobazam is ongoing. Patients exposed to clobazam during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Clobazam and its active metabolite are present in breast milk.
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.
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.
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.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
