clobazam (Rx)

Brand and Other Names:ONFI, Sympazan
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

scored tablet (ONFI, generic): Schedule IV

  • 10mg
  • 20mg

oral suspension (ONFI, generic): Schedule IV

  • 2.5mg/mL

oral soluble film (Sympazan): Schedule IV

  • 5mg
  • 10mg
  • 20mg
more...

Seizures

Indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS)

Initiate at 5 mg PO q12hr; may titrate as tolerated up to 40 mg/day divided q12hr

Dose escalation should not proceed more rapidly than once weekly

CYP2C19 poor metabolizers

  • In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased
  • Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose
  • Additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21

Dosage Modifications

Renal impairment

  • Mild or moderate: No dose adjustment required
  • Severe or ESRD: No experience
  • Dialyzable: Unknown if clobazam or active metabolite is dialyzable

Hepatic impairment

  • Limited data to characterize the effect of hepatic impairment on the pharmacokinetics; proceed with low and slow titration
  • Mild-to-moderate (Child-Pugh 5-9): Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose; additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group may be started on day 21
  • Severe: Not recommended

Dosage Forms & Strengths

scored tablet (ONFI, generic): Schedule IV

  • 10mg
  • 20mg

oral suspension (ONFI, generic): Schedule IV

  • 2.5mg/mL

oral soluble film (Sympazan): Schedule IV

  • 5mg
  • 10mg
  • 20mg
more...

Seizures

Indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years or older

≤30 kg

  • Starting dose: 5 mg PO qDay; titrate as tolerated up to 20 mg PO daily
  • After 7 days, may increase to 5 mg PO q12hr; if needed, may increase to 10 mg PO q12hr after an additional 7 days

>30 kg

  • Starting dose: 5 mg PO q12hr; titrate as tolerated up to 40 mg PO daily
  • After 7 days, may increase to 10 mg PO q12hr; if needed, may increase to 20 mg PO q12hr after an additional 7 days

CYP2C19 poor metabolizers

  • In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased
  • Starting dose should be 5 mg/day and titrated according to weight, but to half the typical dose
  • Additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21

Dosage Modifications

Renal impairment

  • Mild or moderate: No dose adjustment required
  • Severe or ESRD: No experience
  • Dialyzable: Unknown if clobazam or active metabolite is dialyzable

Hepatic impairment

  • Limited data to characterize the effect of hepatic impairment on the pharmacokinetics; proceed with low and slow titration
  • Mild-to-moderate (Child-Pugh 5-9): Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose; additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21
  • Severe hepatic impairment: Not recommended

Plasma concentrations at any given dose are generally higher in the elderly; proceed slowly with dose escalation

Starting dose should be 5 mg/day for all elderly patients and titrated according to weight, but to half the typical adult dose

Additional titration to the maximum daily dose (depending on weight either 20 mg/day or 40 mg/day) may be started on day 21

Administer daily doses >5 mg in divided doses q12hr

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Interactions

Interaction Checker

and clobazam

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            Adverse Effects

            >10%

            Somnolence or sedation (26%)

            Somnolence (22%)

            Pyrexia (13%)

            Upper respiratory tract infection (12%)

            1-10%

            Drooling (9%)

            Aggression (8%)

            Irritability (7%)

            Vomiting (7%)

            Insomnia (5%)

            Ataxia (5%)

            Sedation (5%)

            Constipation (5%)

            Fatigue (5%)

            Cough (5%)

            Psychomotor hyperactivity (4%)

            Pneumonia (4%)

            Urinary tract infection (4%)

            Dysarthria (3%)

            Decreased appetite (3%)

            Increased appetite (3%)

            Bronchitis (2%)

            Dysphagia (2%)

            Postmarketing Reports

            Hypothermia

            Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia

            Eye Disorders: Diplopia, vision blurred

            Gastrointestinal Disorders: Abdominal distention

            GU disorders: Urinary retention

            Lab: Hepatic enzyme increased

            Musculoskeletal: Muscle spasms

            Respiratory Disorders: Aspiration, respiratory depression

            Skin and Subcutaneous Tissue Disorders: Rash, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), urticaria

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            Warnings

            Black Box Warnings

            Concomitant use of benzodiazepines and opioids may result in profound respiratory depression, coma, and death; administer concomitantly when there are no alternative options; limit dosages and durations to minimum required; monitor for signs and symptoms of respiratory depression and sedation

            Contraindications

            History of hypersensitivity to drug or ingredients

            Cautions

            Somnolence or sedation; generally occurs within the first month of treatment and may diminish with continued treatment; caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy does not affect them adversely (eg, impair judgment, thinking or motor skills)

            Serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported in both children and adults; monitor closely, especially during the first 8 weeks of treatment initiation or when reintroducing therapy; discontinue at the first sign of drug-related rash and do not resume

            Consider history of substance abuse because of predisposition of such patients to physical and/or psychological dependence

            Antiepileptic drugs increase the risk of suicidal thoughts or behavior

            Avoid simultaneous use of other CNS depressants or alcohol; effects may be potentiated; alcohol increases clobazam blood levels by about 50%

            CYP2C19 substrate; dose adjustment may be required when coadministered with strong or moderate CYP2C19 inhibitors (may result in increased systemic exposure to active metabolite, N-desmethlclobazam)

            CYP2D6 inhibitor; lower doses of major CYP2D6 substrates may be required

            Weak CYP3A4 inducer; may diminish effectiveness of combination oral contraceptives

            Withdrawal

            • As with all antiepileptic drugs, withdraw gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus
            • Avoid abrupt discontinuation; taper by decreasing dose each week by 5-10 mg/day until discontinued
            • Withdrawal symptoms (eg, convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) occur following abrupt discontinuation, risk is greater with higher doses
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            Pregnancy & Lactation

            Pregnancy

            Encourage pregnant patients (or their caregivers) to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; toll free number 1-888-233-2334; http://www.aedpregnancyregistry.org

            There are no adequate and well-controlled studies in pregnant women; available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies; although some early epidemiological studies suggested a relationship between benzodiazepine drug use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations; more recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies; there is insufficient evidence to assess effect of benzodiazepine pregnancy exposure on neurodevelopment

            There are clinical considerations regarding exposure to benzodiazepines during second and third trimester of pregnancy or immediately prior to or during childbirth; these risks include decreased fetal movement and/or fetal heart rate variability, “floppy infant syndrome,” dependence, and withdrawal

            Administration of clobazam to pregnant rats and rabbits during period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients; data for other benzodiazepines suggest possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses; drug should be used during pregnancy only if potential benefit to mother justifies potential risk to fetus; advise a pregnant woman and women of childbearing age of potential risk to a fetus

            Infants born to mothers who have taken benzodiazepines during later stages of pregnancy can develop dependence, and subsequently withdrawal, during postnatal period; clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting; these complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months depending on degree of dependence and pharmacokinetic profile of the benzodiazepine; symptoms may be mild and transient or severe; standard management for neonatal withdrawal syndrome has not yet been defined; observe newborns who are exposed to drug in utero during later stages of pregnancy for symptoms of withdrawal and manage accordingly

            Laber and delivery

            • Administration of benzodiazepines immediately prior to or during childbirth can result in a floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding; floppy infant syndrome occurs mainly within first hours after birth and may last up to 14 days; observe exposed newborns for these symptoms and manage accordingly

            Lactation

            Drug is excreted in human milk; postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, may have effects of lethargy, somnolence and poor sucking; effect of drug on milk production is unknown; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from drug or from underlying maternal condition; if exposing a breastfed infant to drug, observe for any potential adverse effects

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            A 1,5-benzodiazepine, exact mechanism of action not fully understood; thought to potentiate GABAergic neurotransmission resulting from binding to GABA-A receptor

            Pharmacokinetics

            Bioavailability: 100%

            Peak Plasma Time: 0.5-4 hr

            Peak Plasma Concentration: Dose-proportional (linear)

            AUC: Dose-proportional (linear)

            Protein Bound: 80-90% (clobazam); 70% (N-desmethylclobazam)

            Vd: 100 L

            Half-life: 36-42 hr (clobazam); 72-82 hr (N-desmethylclobazam)

            Dialyzable: Unknown

            Excretion: 11% as metabolites feces (1% unchanged drug), 82% as metabolites urine (2% unchanged drug)

            Metabolism

            • Metabolized extensively by N-demethylation in the liver, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6; active metabolite is extensively metabolized by CYP2C19
            • Metabolites: N-desmethylclobazam is the major circulating active metabolite; at therapeutic doses, plasma concentration is 3-5 times higher than those of clobazam
            • Enzyme substrate: CYP2C19 (active metabolite)
            • Inhibitor: CYP2D6
            • Inducer: Weak inhibitor of CYP3A4

            Pharmacogenomics

            Polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active metabolite N-desmethylclobazam

            Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3-5 times higher in poor metabolizers (eg, subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (eg, subjects with *1/*2 genotype)

            The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background

            Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted

            Systemic exposure for the parent drug, clobazam, is similar for both CYP2C19 poor and extensive metabolizers

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            Administration

            Oral Administration

            Individualize weight-based dose according to clinical efficacy and tolerability

            Doses above 5 mg/day should be administered in divided doses twice daily (5 mg dose can be administered as a single daily dose)

            When discontinuing, withdraw gradually; taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued

            Oral tablet

            • May take with or without food
            • Tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce

            Oral suspension

            • May take with or without food
            • Shake suspension well before every administration
            • When administering, use only the oral dosing syringe provided with the product
            • Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle; to withdraw dose, insert dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose
            • After removing syringe from bottle adapter, slowly squirt oral suspension into the corner of the patient’s mouth

            Oral soluble film

            • May take with or without food
            • Do not administer with liquids
            • Apply film on top of the tongue where it adheres and dissolves
            • As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking
            • Only 1 oral film should be taken at a time; if a second film is needed to complete the dose, it should not be taken until the first film has completely dissolved

            Storage

            Tablets, oral suspension: Store at controlled room temperature 20-25°C (68-77°F)

            Oral film: Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Oral suspension

            • Store and dispense in original bottle in an upright position
            • Use within 90 days of first opening the bottle; discard remaining suspension after 90 days
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.