Class: Benzodiazepines
VA Class: CN400
Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
Molecular Formula: C₁₆H₁₃ClN₂O₂
CAS Number: 22316-47-8
Brands: Onfi

Medically reviewed on Nov 13, 2017

Introduction

Anticonvulsant that also demonstrates anxiolytic properties; a 1,5-benzodiazepine.^{1 2 3 6 7 9 14 19 34 36 44}

Uses for Clobazam

Seizure Disorders

Management (in combination with other anticonvulsants) of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients ≥2 years of age.^{1 2 3 5 6 9 17 19 22 36} Designated an orphan drug by FDA for use in this condition.^{5 9 19}

Also has been used as adjunctive therapy in many other seizure disorders, sometimes refractory, including partial, generalized, and myoclonic seizures†.^{6 13 14 23 24 25 26 41 44} Has been used with some success in partial onset seizures; additional studies needed to more clearly determine role in the adjunctive treatment of other refractory seizure disorders.^{14 24}

Anxiety Disorders

Has been used for short-term (2–4 weeks) treatment of anxiety disorders† in some countries outside the US.^{6 13 36 42 44} Currently not FDA-labeled for the treatment of anxiety disorders in the US.¹

Clobazam Dosage and Administration

General

• Withdraw clobazam gradually; avoid abrupt discontinuance to minimize risk of precipitating or exacerbating seizures, status epilepticus, or withdrawal symptoms.^{1 4} (See Dosage under Dosage and Administration and also see Discontinuance of Therapy under Cautions.)

• Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.^{1 4} (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer orally as tablets or oral suspension.¹ Administer daily dosages >5 mg in divided doses twice daily; may administer 5-mg daily dosage as a single daily dose.^{1 19}

May administer tablets or oral suspension without regard to meals.¹

Tablets may be swallowed whole, broken in half, or crushed and mixed in applesauce.¹

Shake oral suspension well prior to administration.¹ Administer suspension using bottle adapter and calibrated oral dosing syringe supplied by manufacturer.¹ Firmly insert bottle adapter into neck of bottle before first use and keep in place for duration of use (up to 90 days).¹ To dispense dose, insert oral dosing syringe into adapter, then invert bottle and withdraw appropriate dose into syringe.¹ Administer dose slowly and directly into corner of patient's mouth.¹ Replace cap over bottle adapter after each use.¹ Consult manufacturer's prescribing information for more detailed instructions.¹

Dosage

Pediatric Patients

Seizure Disorders

Adjunctive Therapy in Lennox-Gastaut Syndrome

Oral

Individualize dosage based on patient response and tolerability.¹ Although all recommended dosages have demonstrated efficacy, efficacy is dose related;^{1 2 3 13} titrate to maximum tolerability until adequate seizure control attained.¹³ Increase dosage no more frequently than once a week to allow sufficient time for steady-state concentrations to be achieved at each dosage level.¹

Children ≥2 years of age weighing ≤30 kg: Initially, 5 mg daily as a single daily dose.¹ May increase to 10 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 20 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.¹

Children ≥2 years of age weighing >30 kg: Initially, 10 mg daily in 2 divided doses.¹ May increase to 20 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 40 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.¹

Reduce dosage gradually (by decreasing total daily dosage by 5–10 mg at weekly intervals) if discontinuing therapy.¹ (See Discontinuance of Therapy under Cautions.)

Adults

Seizure Disorders

Adjunctive Therapy in Lennox-Gastaut Syndrome

Oral

Individualize dosage based on patient response and tolerability.¹ Although all recommended dosages have demonstrated efficacy, efficacy is dose related;^{1 2 3 13} titrate to maximum tolerability until adequate seizure control attained.¹³ Increase dosage no more frequently than once a week to allow sufficient time for steady-state concentrations to be achieved at each dosage level.¹

Patients weighing ≤30 kg: Initially, 5 mg daily as a single daily dose.¹ May increase to 10 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 20 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.¹

Patients weighing >30 kg: Initially, 10 mg daily in 2 divided doses.¹ May increase to 20 mg daily (in 2 divided doses) after 7 days, and to recommended maximum of 40 mg daily (in 2 divided doses) after an additional 7 days if clinically indicated and tolerated.¹

Reduce dosage gradually (by decreasing total daily dosage by 5–10 mg at weekly intervals) if discontinuing therapy.¹ (See Discontinuance of Therapy under Cautions.)

Anxiety Disorders†

Short-term Treatment of Severe, Disabling, or Intolerable Anxiety†

Oral

Usual dosage: 20–30 mg daily in divided doses or as a single dose in the evening.⁴⁴ Dosages of up to 60 mg daily have been used for severe anxiety in hospitalized patients.⁴⁴

Prescribing Limits

Pediatric Patients

Seizure Disorders

Adjunctive Therapy in Lennox-Gastaut Syndrome

Oral

Children ≥2 years of age: Maximum 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg.¹

Adults

Seizure Disorders

Adjunctive Therapy in Lennox-Gastaut Syndrome

Oral

Maximum 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg.¹

Special Populations

Hepatic Impairment

Adjunctive Therapy in Lennox-Gastaut Syndrome

Limited pharmacokinetic data; titrate dosage slowly.¹

Mild to moderate hepatic impairment (Child-Pugh class A or B): Initially, 5 mg daily regardless of body weight.¹ Subsequently titrate dosage according to weight, but to half of the usual recommended dosage as tolerated.¹ May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response.¹ (See Hepatic Impairment under Cautions.)

Severe hepatic impairment (Child-Pugh class C): Data currently insufficient to make dosage recommendations.¹

Renal Impairment

Adjunctive Therapy in Lennox-Gastaut Syndrome

Mild or moderate renal impairment (Cl_cr 30–80 mL/minute): No dosage adjustment necessary.¹

Severe renal impairment or end-stage renal disease: Not systematically evaluated.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Adjunctive Therapy in Lennox-Gastaut Syndrome

Initially, 5 mg daily regardless of body weight.¹ Subsequently titrate dosage slowly according to weight, but to half of the usual recommended dosage as tolerated.¹ May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response.¹ (See Geriatric Use under Cautions.)

Poor CYP2C19 Metabolizers

Adjunctive Therapy in Lennox-Gastaut Syndrome

Initially, 5 mg daily regardless of body weight.¹ (See Poor CYP2C19 Metabolizers under Cautions.) Subsequently titrate dosage slowly according to weight, but to half of the usual recommended dosage as tolerated.¹ May initiate an additional titration to maximum dosage of 20 mg daily (in patients weighing ≤30 kg) or 40 mg daily (in patients weighing >30 kg) at 3 weeks if necessary and based on clinical response.¹

Cautions for Clobazam

Contraindications

• None.¹

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clobazam, and opiates may result in profound sedation, respiratory depression, coma, and death.^{700 701 703 705 706 707} Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.^{700 701 705 706 707 711}

Reserve concomitant use of clobazam and opiates for patients in whom alternative treatment options are inadequate.^{700 703} (See Specific Drugs under Interactions.)

Other Warnings and Precautions

Concomitant Use of CNS Depressants

Risk of potentiated CNS depressant effects.^{1 4} (See Concomitant Use with Opiates and also Somnolence and Sedation under Cautions.)

Somnolence and Sedation

Somnolence and sedation commonly occur.^{1 2 3 6 19} Generally occur within first month of treatment and may diminish with continued therapy.^{1 6 19} Observed at all clinically effective dosages and appear to be dose related.^{1 2}

Monitor for somnolence and sedation, particularly during concomitant use of other CNS depressants (e.g., alcohol, opiate agonists, tricyclic antidepressants [TCAs], sedating antihistamines, other benzodiazepines).¹ (See Concomitant Use with Opiates under Cautions and also see Advice to Patients.)

Discontinuance of Therapy

Avoid abrupt discontinuance and rapid dosage reduction to minimize the risk of precipitating or exacerbating seizures and status epilepticus.¹

Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorders, tremor, anxiety, irritability, dysphoria, insomnia, headache, palpitations, diarrhea) also can occur following abrupt discontinuance; risk of withdrawal symptoms is greater with increasing dosage and duration of treatment.^{1 36}

When discontinuing therapy, decrease dosage gradually (i.e., by 5–10 mg daily at weekly intervals).¹

Serious Dermatologic Reactions

Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), reported rarely in pediatric and adult patients during postmarketing experience worldwide.^{1 47 48} May occur at any time during therapy, but risk is greater during first 8 weeks of therapy or when clobazam is discontinued and then reinitiated.⁴⁷ Hospitalization was required in all cases; one case resulted in blindness and at least one death occurred.⁴⁷

Closely monitor patients for signs and symptoms of SJS and TEN, particularly during the initial 8 weeks of treatment or when reinitiating therapy.^{1 47} Discontinue therapy at the first sign of a rash unless clearly not drug related (see Discontinuance of Therapy under Cautions); if manifestations suggest SJS or TEN, do not reinitiate clobazam and consider alternative therapies.^{1 47} When switching from one anticonvulsant to another, consider that other anticonvulsants also may be associated with serious dermatologic reactions.⁴⁷

Physical and Psychological Dependence

Possible physical and/or psychological dependence.^{1 36} While the risk is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use (i.e., a few weeks) at recommended dosages.¹

As with all benzodiazepines, tolerance to the therapeutic effects of clobazam reported, and may be a concern with long-term use.^{19 23 24 25 26 31 41}

Carefully monitor patients with a history of substance abuse because of their predisposition to habituation and dependence.¹

Avoid abrupt discontinuance or rapid dosage reduction, which can precipitate withdrawal symptoms in patients with physical dependence.¹ (See Discontinuance of Therapy under Cautions.)

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{1 10 11 12} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{1 10 11} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{1 10}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 10 11 12} Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.¹⁰

Balance risk of suicidality with risk of untreated illness.^{1 10} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{1 12} If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{1 12} (See Advice to Patients.)

Abuse Potential

Abuse potential expected to be similar to that of other benzodiazepines (e.g., diazepam).¹

Specific Populations

Pregnancy

Category C.¹

North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients or caregivers) at 888-233-2334 or [Web].^{1 4}

Lactation

Distributed into human milk.¹ Discontinue nursing or the drug.^{1 4}

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.^{1 4}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.¹

Because of the possibility of decreased clearance in geriatric patients, initiate therapy with a low dosage and titrate slowly.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Extensively metabolized by the liver; however, effects of hepatic impairment on pharmacokinetics of clobazam not fully characterized.^{1 13 45}

Initiate therapy at 5 mg daily (regardless of patient weight) and titrate slowly in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).^{1 36} Insufficient information in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure to clobazam or its active metabolite not substantially altered in patients with mild (Cl_cr >50–80 mL/minute) or moderate (Cl_cr 30–50 mL/minute) renal impairment.¹ No experience in patients with severe renal impairment or end-stage renal disease.¹

Not known whether clobazam or its active N-desmethylclobazam metabolite is dialyzable.¹ (See Renal Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Poor CYP2C19 Metabolizers

Genetic polymorphism of CYP2C19 can affect pharmacokinetic and pharmacodynamic response to clobazam.^{1 27 31 32 33} CYP2C19 is the principal enzyme involved in the metabolism of N-desmethylclobazam, the pharmacologically active metabolite of clobazam.¹ Plasma concentrations of N-desmethylclobazam are higher in poor CYP2C19 metabolizers compared with extensive CYP2C19 metabolizers.^{1 27 31 32 33}

Dosage adjustment necessary in known poor CYP2C19 metabolizers.¹ (See Poor CYP2C19 Metabolizers under Dosage and Administration.)

Common Adverse Effects

Adverse effects generally similar to those observed with other benzodiazepines.^{6 9 13 19}

Somnolence or sedation,^{1 2} lethargy,^{1 2} drooling,^{1 2} vomiting,¹ constipation,^{1 2} dysphagia,¹ decreased or increased appetite,¹ cough,¹ upper respiratory tract infection,¹ pneumonia,¹ bronchitis,¹ urinary tract infection,¹ aggression,¹ insomnia,¹ irritability,¹ ataxia,¹ psychomotor hyperactivity,¹ dysarthria,¹ pyrexia,^{1 2} fatigue.¹

Interactions for Clobazam

Metabolized principally by CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6.^{1 27 42} Clobazam's active metabolite, N-desmethylclobazam, is metabolized principally by CYP2C19.^{1 27}

Clobazam and N-desmethylclobazam induce CYP3A4 in a concentration-dependent manner; N-desmethylclobazam also is a weak inhibitor of CYP2C9.¹ Clobazam also appears to inhibit CYP2D6.¹

Does not inhibit CYP1A2, 2C8, 2C9, 2C19, and 3A4 nor substantially induce CYP1A2 and CYP2C19 in vitro.¹

Clobazam does not inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, or 2B4 in vitro.¹ N-desmethylclobazam is a weak inhibitor of UGT 1A4, 1A6, and 2B4.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Potential pharmacokinetic interaction (increased plasma concentrations of substrate); dosage adjustment of drugs metabolized by CYP2D6 may be necessary.^{1 36 42}

CYP3A4 substrates: Potential pharmacokinetic interaction (decreased plasma concentrations of substrate);^{1 42} however, manufacturer states dosage adjustment of drugs principally metabolized by CYP3A4 not necessary.¹

CYP1A2 substrates: Pharmacokinetic interaction not likely.^{1 42}

CYP2C9 substrates: Pharmacokinetic interaction not likely.^{1 42}

Drugs Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP2C19 inhibitors: Potential pharmacokinetic interaction (increased exposure to N-desmethylclobazam and possible toxicity); clobazam dosage adjustment may be necessary.^{1 36 42}

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased exposure to clobazam).^{1 42}

Specific Drugs

Clobazam Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration; peak plasma concentrations achieved within 0.5–4 hours after single- or multiple-dose administration of clobazam tablets under fasting conditions.^{1 6 13 19 25 36 39 42 45} Peak plasma concentrations achieved within 0.5–2 hours following single-dose administration of the oral suspension under fasting conditions.¹

Bioavailability of oral suspension similar to that of tablets under fasting conditions.¹

At therapeutic dosages, plasma concentrations of N-desmethylclobazam (an active metabolite) are approximately 3–5 times higher than those of clobazam.^{1 42}

Food

Food does not appear to substantially affect absorption from tablets; although not evaluated, food also unlikely to affect bioavailability of the oral suspension.^{1 6 13 19}

Special Populations

Limited data indicate no substantial pharmacokinetic differences between patients with hepatic impairment and healthy individuals.^{1 13 45}

No substantial pharmacokinetic differences between patients with mild (Cl_cr >50–80 mL/minute) or moderate (Cl_cr 30–50 mL/minute) renal impairment and those with normal renal function.¹ Not known if clobazam or N-desmethylclobazam is dialyzable;¹ limited evidence suggests clobazam concentrations are unaffected by hemodialysis.⁴⁰

Systemic exposure to N-desmethylclobazam is approximately 3–5 times higher in poor CYP2C19 metabolizers and approximately 2 times higher in intermediate CYP2C19 metabolizers than in those with normal CYP2C19 function (i.e., extensive metabolizers).¹

Distribution

Extent

Highly lipophilic and distributes rapidly throughout the body.^{1 25}

Crosses the blood-brain barrier.²⁵

Distributes into human milk.¹

Plasma Protein Binding

Clobazam: Approximately 80–90%.^{1 25}

N-desmethylclobazam: Approximately 70%.^{1 25}

Elimination

Metabolism

Extensively metabolized in liver, primarily via N-demethylation (principally by CYP3A4 and, to a lesser extent, by CYP2C19 and CYP2B6) to pharmacologically active metabolite, N-desmethylclobazam.^{1 13 27} Potency of N-desmethylclobazam may be similar to or somewhat less than parent drug; therefore, active metabolite may contribute to efficacy and safety.^{1 6 13 19 25 31 32 42}

N-Desmethylclobazam is further metabolized by CYP2C19 to an inactive derivative.^{1 6 9 27 31 32 33}

Metabolism is subject to genetic polymorphism of CYP2C19.^{1 6 9 27 31 32 33 42} (See Actions.)

Elimination Route

Eliminated mainly in urine (82%) as metabolites; only about 2% of dose is excreted as unchanged drug.¹

Half-life

Approximately 36–42 hours for clobazam and 71–82 hours for N-desmethylclobazam.^{1 13}

Special Populations

Some data suggest that clobazam may be more rapidly and extensively metabolized in children than in adults.^{6 19}

Decreased clearance observed in geriatric patients compared with younger age groups (ages 2–64).¹

Stability

Storage

Oral

Tablets

20–25°C.¹

Suspension

20–25°C.¹ Store bottle in upright position; use within 90 days of opening.¹

Actions

• 1,5-benzodiazepine with anticonvulsant and anxiolytic properties.^{1 2 3 6 9 14 19 34 36 44}

• Exact mechanism of anticonvulsant and anxiolytic actions unknown, but thought to involve allosteric binding of clobazam to the benzodiazepine site of the GABA type A (GABA_A) receptor, which in turn potentiates the inhibitory effects of GABA.^{1 6 9 19 34 36 46}

• Structurally similar to the 1,4-benzodiazepines (e.g., clonazepam, diazepam, lorazepam), but appears to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects).^{6 14 19 25 31 34 39}

• Metabolism of the drug is subject to genetic polymorphism of CYP2C19.^{1 6 9 27 31 32 33 42} Individuals with the CYP2C19*2/*2 genotype are described as poor metabolizers; those with the CYP2C19*1/*2 genotype are intermediate metabolizers, and those with CYP2C19*1/*1 are extensive metabolizers.^{1 33} Prevalence of poor CYP2C19 metabolizers in general population varies based on ethnic and racial background.^{1 9 27 31 33}

Advice to Patients

• Importance of providing patient or caregiver with copy of written patient information (medication guide) each time clobazam is dispensed.^{1 4} Importance of advising patients or caregivers to read the medication guide before start of therapy and each time the prescription is refilled.^{1 4}

• Importance of taking clobazam only as prescribed.^{1 4}

• Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly.^{700 703} Avoid concomitant use of opiate antitussives;^{700 704} also avoid concomitant use of opiate analgesics unless use is supervised by clinician.^{700 703}

• Risk of potentiated CNS depression with concurrent use of alcohol or other CNS depressants.^{1 4} Advise patients or caregivers to avoid concomitant use of alcohol⁷⁰⁰ and to check with their clinician before using clobazam concomitantly with other CNS depressants (e.g., other benzodiazepines, TCAs, sedating antihistamines).^{1 4}

• Risk of somnolence or sedation.^{1 4} Caution patients against driving or operating hazardous machinery until they are reasonably certain that clobazam does not adversely affect their judgment, thinking, or motor skills.^{1 4}

• Risk of rare but serious skin reactions, including SJS and TEN.^{1 47 48} Advise patient or caregivers to seek immediate medical attention at first appearance of a skin rash or other signs of hypersensitivity (e.g., blistering or peeling of skin, mouth sores, hives) while receiving clobazam.^{1 47} Drug discontinuance may be required; advise patients or caregivers not to discontinue without first consulting with their clinician.^{1 47}

• Risk of suicidality (anticonvulsants, including clobazam, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{1 4 10 12} Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).^{1 4 10}

• Importance of advising patients or caregivers to consult their clinician before increasing or decreasing the dosage or abruptly discontinuing the drug.^{1 4} Sudden discontinuance can cause serious problems (e.g., increased risk of seizures, withdrawal symptoms).^{1 4}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry (see Pregnancy under Cautions).^{1 4}

• Importance of informing women that clobazam may cause some hormonal contraceptives (e.g., oral contraceptives, patches, rings, implants, injections, intrauterine devices) to be less effective; importance of advising women to use additional nonhormonal forms of contraception during clobazam therapy and for 28 days after discontinuance of the drug.^{1 4}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., kidney or liver disease, respiratory problems, depression or other mood disorders).^{1 4}

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.¹

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