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Clobazam

Medically reviewed by Drugs.com. Last updated on Jul 23, 2020.

Pronunciation

(KLOE ba zam)

Dosage Forms

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

Brand Names: U.S.

  • Onfi
  • Sympazan

Pharmacologic Category

  • Anticonvulsant, Benzodiazepine
  • Benzodiazepine

Pharmacology

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).

Absorption

Rapid and extensive; not affected by food or crushing tablet

Distribution

100 L

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.

Excretion

Urine (~82%; unchanged drug: 2%, NCLB and other metabolites: ~94%); feces (~11%; 1% unchanged drug)

Onset of Action

Maximum effect: 5 to 9 days

Time to Peak

Oral film: 0.33 to 4 hours; Tablet: 0.5 to 4 hours; Oral suspension: 0.5 to 2 hours

Half-Life Elimination

Children: Clobazam: 16 hours (Ng 2007); Adults: Clobazam: 36 to 42 hours; N-desmethyl (active): 71 to 82 hours

Protein Binding

Clobazam: 80% to 90%; N-desmethylclobazam (NCLB): 70%

Special Populations: Elderly

Clearance is lower in elderly patients.

Special Populations Note

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.

Use: Labeled Indications

Lennox-Gastaut syndrome: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients ≥2 years

Off Label Uses

Catamenial epilepsy

Data from a limited number of patients studied suggest that clobazam may be beneficial for the treatment of catamenial epilepsy [Feely 1984]. Additional data may be necessary to further define the role of clobazam in this condition.

Seizures, treatment refractory (adjunctive)

Data from a limited number of patients studied in 4 randomized, double-blind, placebo-controlled cross-over trials support the use of clobazam as an adjunctive therapy in treatment refractory epilepsy. More data exist to support use in patients with focal (partial)-onset seizures than for patients with generalized onset seizures [Michael 2008].

Based on the American Academy of Neurology and the American Epilepsy Society practice guideline update summary on the efficacy and tolerability of the new antiepileptic drugs II: treatment-resistant epilepsy, clobazam is possibly effective as add-on therapy for treatment-resistant adult focal epilepsy.

Contraindications

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

Dosing: Adult

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: Initial: 5 mg once daily for ≥1 week, then increase based on response and tolerability 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.

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: Withdraw gradually by decreasing the total daily dosage by 5 to 10 mg/day on a weekly basis until discontinued.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

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.

Dosing: Pediatric

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.

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, then increase to 5 mg twice daily for ≥1 week, may then increase to 10 mg twice daily based on patient tolerability and response.

>30 kg: 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 for ≥1 week, may then increase to 20 mg twice daily based on patient tolerability and response.

Administration

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.

Storage

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.

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of CloBAZam. Alcohol (Ethyl) may increase the serum concentration of CloBAZam. Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). 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. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. 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. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. 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. 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. 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. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Estrogen Derivatives (Contraceptive): CloBAZam may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use additional non-hormonal forms of contraception in patients treated with clobazam due to the potential for reduced contraceptive efficacy. Consider therapy modification

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. 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. Consider therapy modification

Fosphenytoin: Benzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. 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. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. 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. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. 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. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. 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. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Progestins (Contraceptive): CloBAZam may decrease the serum concentration of Progestins (Contraceptive). Management: Use additional non-hormonal forms of contraception in patients treated with clobazam due to the potential for reduced contraceptive efficacy. Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. 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. Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. 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. Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. 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. Consider therapy modification

Adverse Reactions

>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, 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

ALERT: U.S. Boxed Warning

Risks from concomitant use of benzodiazepines and opioids:

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in 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.

Warnings/Precautions

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 which require mental alertness (eg, operating machinery or 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:

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Psychological and physical dependence, as well as tolerance to sedative and anticonvulsive effects, may occur with prolonged use (Vinkers 2012).

• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be necessary.

Concurrent drug therapy issues:

• Benzodiazepines and opioids: [US Boxed Warning]: The concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in 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.

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:

• 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) treated for Lennox-Gastaut syndrome did not show evidence of tolerance over 2 years of treatment (Gidal 2016).

• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly (eg, decrease weekly by 5 to 10 mg/day) and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Monitoring Parameters

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.

Pregnancy Considerations

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.

Patient Education

What is this drug used for?

• It is used to help control certain kinds of seizures.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Drooling

• Constipation

• Lack of appetite

• Increased appetite

• Common cold symptoms

• Trouble sleeping

• Cough

• Vomiting

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Shortness of breath

• Change in balance

• Confusion

• Severe loss of strength and energy

• Slurred speech

• Seizures

• Passing out

• Severe dizziness

• Severe fatigue

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• Agitation

• Irritability

• Panic attacks

• Mood changes

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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