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.
Note: Dosage should be titrated according to patient tolerability and response. 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 (Wirrell 2017).
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 (Knupp 2018; Wirrell 2016).
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 (Isojarvi 2018).
>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 (Isojarvi 2018).
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) (Canadian Study Group 1998; Frisium prescribing information [UK 2020, Health Canada 2017]; Ng 2007; Perry 2013).
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 (Child-Pugh Score 5 to 9):
≤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.
Severe impairment: Use with extreme caution; has not been studied; undergoes extensive hepatic metabolism.
(For additional information see "Clobazam: Drug information")
Catamenial epilepsy (off-label use): Oral: 20 to 30 mg daily for 10 days during the perimenstrual period (Feely 1984).
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 (Koeppen 1987; Schmidt 1986). Alternatively, a maximum dose of 80 mg/day has also been recommended (Canadian manufacturer's labeling). Daily doses of up to 30 mg may be taken as a single dose at bedtime; higher doses should be divided (Allen 1983; Canadian manufacturer's labeling).
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 (Canadian manufacturer's labeling).
Discontinuation of therapy: In patients receiving extended- or higher-dose benzodiazepine therapy, unless safety concerns require a more rapid withdrawal, gradually withdraw to detect reemerging symptoms and minimize rebound and withdrawal symptoms. Taper total daily dose by 10% to 50% every 1 to 2 weeks based on response and tolerability (Bystritsky 2021; Park 2021; VA/DoD 2015). The optimal taper rate and duration will vary; durations up to 6 months may be necessary for some patients. For patients on high doses, taper more rapidly in the beginning and slow the reduction rate as the taper progresses. For example, reduce the dose weekly by 25% until half of the dose remains. Thereafter, continue to reduce by ~12% every 4 to 7 days (VA/DoD 2015).
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.
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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Frisium: 10 mg [DSC]
Generic: 10 mg
C-IV
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/2018/202067s005,203993s007lbl.pdf#page=29
Sympazan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210833s002lbl.pdf#page=27
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.
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 film: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Suspension, tablet: Store at 20°C to 25°C (68°F to 77°F). Dispose of unused suspension 90 days after opening bottle.
Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (FDA approved in ages ≥2 years and adults); has also been used as monotherapy and adjunctive treatment for other forms of epilepsy; has also been used in the management of seizures associated with Dravet syndrome (severe myoclonic epilepsy of infancy).
CloBAZam may be confused with clonazePAM
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 (Mancusco 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 antiepileptics (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:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be necessary.
Special populations:
• Elderly: Lower doses are recommended. Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly 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 addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. 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 anticonvulsive 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).
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)
Alcohol (Ethyl): May enhance the CNS depressant effect of CloBAZam. Alcohol (Ethyl) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
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
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. 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
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: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. 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
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
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
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. Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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
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
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
Ethanol: Concomitant administration may increase bioavailability of clobazam by 50%. Management: Monitor for increased effects with coadministration.
Clobazam crosses the placenta.
An increased risk of fetal malformations may be associated with first trimester benzodiazepine exposure (data not consistent). Exposure to benzodiazepines immediately prior to or during birth may result in hypothermia, hypotonia, respiratory depression, and difficulty feeding in the neonate; neonates exposed to benzodiazepines late in pregnancy may develop dependence and withdrawal. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Wikner 2007). A combination of factors influences the potential teratogenicity of anticonvulsant therapy. When treating women with 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).
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.
Respiratory and mental status/suicidality (eg, suicidal thoughts, depression, behavioral changes); CBC, liver function, and renal function; some recommend periodic thyroid function tests
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
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)
Geriatric: 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.
Film (Sympazan Oral)
5 mg (per each): $18.17
10 mg (per each): $36.34
20 mg (per each): $72.67
Suspension (cloBAZam Oral)
2.5 mg/mL (per mL): $0.80 - $9.14
Suspension (Onfi Oral)
2.5 mg/mL (per mL): $13.31
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): $30.39
20 mg (per each): $60.79
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