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Clobazam

Pronunciation

Pronunciation

(KLOE ba zam)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Oral:

Onfi: 2.5 mg/mL (120 mL) [contains methylparaben, polysorbate 80, propylene glycol, propylparaben; berry flavor]

Tablet, Oral:

Onfi: 5 mg [DSC]

Onfi: 10 mg, 20 mg [scored]

Brand Names: U.S.

  • Onfi

Pharmacologic Category

  • 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.

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: 5-9 days

Time to Peak

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

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

Canadian labeling: Epilepsy: Adjunctive treatment of epilepsy

Use: Unlabeled

Catamenial 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

US labeling:

Lennox-Gastaut (adjunctive): Oral: Note: Dose should be titrated according to 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 thereafter

>30 kg: Initial: 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter

CYP2C19 poor metabolizers:

≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may increase to 10 mg twice daily

>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; after ≥1 week may increase to 20 mg twice daily

Canadian labeling:

Epilepsy (adjunctive): Oral: Initial: 5 to 15 mg/day; dosage may be gradually adjusted (based on tolerance and seizure control) to a maximum of 80 mg/day. Note: Daily doses of up to 30 mg may be taken as a single dose at bedtime; higher doses should be divided.

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.

Catamenial epilepsy (off-label use): Oral: 20 to 30 mg daily for 10 days during the perimenstrual period (Feely, 1984)

Dosing: Geriatric

US labeling:

Lennox-Gastaut (adjunctive): Oral:

≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may 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; after ≥1 week may increase to 20 mg twice daily based on patient tolerability and response

Canadian labeling.

Epilepsy (adjunctive): Oral: Refer to adult dosing. Initiate therapy at lowest possible dose and titrate slowly; monitor closely.

Dosing: Pediatric

US labeling:

Lennox-Gastaut (adjunctive): Children ≥2 years and Adolescents: Oral: Refer to adult dosing.

Canadian labeling:

Epilepsy (adjunctive):

Children <2 years: Oral: Initial 0.5 to 1 mg/kg/day

Children 2 to 16 years: Oral: Initial: 5 mg daily; may be increased (no more frequently than every 5 days) to a maximum of 40 mg daily. Note: Daily doses of up to 30 mg may be taken as a single dose at bedtime; higher doses should be divided.

CYP2C19 poor metabolizers: Initiate at lowest recommended doses; titrate slowly as tolerated to half of usual recommended age-based maximum dose. If needed, dose may be further increased as tolerated to recommended age-based maximum dose beginning day 21.

Epilepsy (monotherapy) (off-label use): Children 2 to 16 years: Oral: Initial: Titrate slowly over 1 to 3 weeks to target dose of ~0.5 mg/kg/day in 2 divided doses (Canadian Study Group, 1998)

Dosing: Renal Impairment

US labeling:

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.

Canadian labeling: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a reduced dosage is recommended.

Dosing: Hepatic Impairment

US labeling:

Mild to moderate impairment:

≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may 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; after ≥1 week may increase to 20 mg twice daily based on patient tolerability and response

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution; undergoes extensive hepatic metabolism.

Canadian labeling:

Mild to moderate impairment: Initiate at lowest recommended doses; titrate slowly as tolerated to half of usual recommended age-based maximum dose. If needed, dose may be further increased as tolerated to usual recommended age-based maximum dose beginning day 21.

Severe impairment: Use is contraindicated.

Administration

Oral: May be administered with or without food. Tablets can be crushed and mixed in applesauce. Shake suspension well before using; only use the oral dosing syringe supplied with the suspension. Daily doses greater than 5 mg should be divided and administered twice daily.

Storage

Tablets and suspension: 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

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

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. Consider therapy modification

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant 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

Contraceptives (Estrogens): CloBAZam may decrease the serum concentration of Contraceptives (Estrogens). Consider therapy modification

Contraceptives (Progestins): CloBAZam may decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dimethindene: 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 (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C19 Substrates. Monitor therapy

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

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

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

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. 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

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. 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

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

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

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

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Stiripentol: CloBAZam may increase the serum concentration of Stiripentol. Stiripentol may increase the serum concentration of CloBAZam. 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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

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

Tetrahydrocannabinol: 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. Consider therapy modification

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

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%), aggressive behavior (8% to 14%), irritability (3% to 11%)

Gastrointestinal: Sialorrhea (13% to 14%)

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%), 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 (Limited to important or life-threatening): Angioedema, aspiration, behavioral changes, blurred vision, confusion, delirium, delusions, depression, diplopia, eosinophilia, hallucination, hypothermia, leukopenia, lip edema, mood changes, respiratory depression, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, thrombocytopenia, toxic epidermal necrolysis, urinary retention, withdrawal syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• 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, particularly in adolescent/pediatric or psychiatric patients.

• 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.

• 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 healthcare 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. Tolerance, psychological and physical dependence may occur with prolonged use.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be necessary. The Canadian labeling contraindicates use in severe impairment.

• Muscle weakness/coordination: Use with caution in patients with preexisting muscle weakness or ataxia; may cause muscle weakness. The Canadian labeling contraindicates use in myasthenia gravis.

• Psychiatric disease: Where possible, avoid use in patients with psychiatric disease (eg, depression, psychosis).

• Respiratory disease: Use with caution in patients with respiratory disease. The Canadian labeling contraindicates use in severe respiratory insufficiency or sleep apnea syndrome.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in debilitated patients; lower doses are recommended.

• Elderly: Lower doses are recommended.

• Poor CYP2C19 metabolizers: Concentrations of the active metabolite 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 and loss of seizure control have been reported with chronic administration.

• 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 5-10 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). The Canadian labeling recommends periodic CBC, liver function, renal function and thyroid function tests.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Clobazam crosses the placenta. An increased risk of fetal malformations may be associated with first trimester exposure. The Canadian labeling contraindicates use in the first trimester. 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience drooling, constipation, cough, or vomiting. Have patient report immediately to prescriber shortness of breath, change in balance, confusion, severe loss of strength and energy, pain with urination, slurred speech, seizures, insomnia, passing out, severe dizziness, severe fatigue, signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), agitation, irritability, panic attacks, mood changes, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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