Onfi

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Keep all appointments with your doctor.

Do not let anyone else take your medication. Clobazam is a controlled substance. Prescriptions may be refilled only a limited number of times; ask your pharmacist if you have any questions.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Clobazam is a benzodiazepine (ben-zoe-dye-AZE-eh-peen). Clobazam affects chemicals in the brain that may be unbalanced in people with anxiety.

Clobazam is used in combination with other medications to treat seizures caused by Lennox-Gastaut syndrome, a severe form of childhood epilepsy that also causes developmental and behavior problems.

Clobazam may also be used for purposes not listed in this medication guide.

You may have thoughts about suicide while taking this medicine. Your doctor will need to check you at regular visits.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

You should not take clobazam if you are allergic to it.

To make sure clobazam is safe for you, tell your doctor if you have:

• liver or kidney disease;
• any type of breathing problem or lung disease;
• a history of depression or suicidal thoughts or behavior; or
• a history of drug or alcohol addiction.

Some young people have thoughts about suicide when first taking clobazam. Your doctor will need to check your progress at regular visits while you are using this medicine. Your family or other caregivers should also be alert to changes in your mood or symptoms.

It is not known whether clobazam will harm an unborn baby. Clobazam may cause breathing problems, feeding problems, and low body temperature in a newborn. Your baby could also become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant. Use effective birth control to prevent pregnancy while you are taking clobazam.

Clobazam can make birth control pills less effective. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while taking clobazam.

Clobazam can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Clobazam should not be given to a child younger than 2 years old.

The sedative effects of clobazam may last longer in older adults. Accidental falls are common in elderly patients who take benzodiazepines. Use caution to avoid falling or accidental injury while you are taking clobazam.

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Flumazenil
• Thioridazine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Amobarbital
• Anileridine
• Bromazepam
• Buprenorphine
• Butabarbital
• Butalbital
• Butorphanol
• Calcifediol
• Carbinoxamine
• Carisoprodol
• Chloral Hydrate
• Chlorzoxazone
• Clozapine
• Codeine
• Dantrolene
• Dihydrocodeine
• Donepezil
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Doxylamine
• Eliglustat
• Eslicarbazepine Acetate
• Ethchlorvynol
• Fentanyl
• Flibanserin
• Hydrocodone
• Hydromorphone
• Levorphanol
• Meperidine
• Mephenesin
• Mephobarbital
• Meprobamate
• Metaxalone
• Methadone
• Methocarbamol
• Methohexital
• Mirtazapine
• Morphine
• Morphine Sulfate Liposome
• Nifedipine
• Orlistat
• Oxycodone
• Oxymorphone
• Pentazocine
• Pentobarbital
• Periciazine
• Phenobarbital
• Piperaquine
• Primidone
• Propoxyphene
• Remifentanil
• Secobarbital
• Sodium Oxybate
• Sufentanil
• Tamoxifen
• Tapentadol
• Thiopental
• Tramadol
• Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Dextromethorphan
• Etravirine
• Felbamate
• Fosphenytoin
• Ginkgo
• Ketoconazole
• Phenytoin
• Theophylline

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients

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

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.)

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

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

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

Special Populations

Hepatic Impairment

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

Mild or moderate renal impairment (Clcr 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

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

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

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 (Clcr >50–80 mL/minute) or moderate (Clcr 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

Clobazam is used to help control seizures (convulsions) that occur with Lennox-Gastaut syndrome (LGS). It works in the brain to prevent seizures. This medicine will not cure LGS and will only control seizures for as long as you continue to take it.

Clobazam is a benzodiazepine. Benzodiazepines belong to the group of medicines called central nervous system (CNS) depressants, which are medicines that slow down the nervous system.

This medicine is available only with your doctor's prescription.

Onfi (clobazam) is a benzodiazepine (ben-zoe-dye-AZE-eh-peen). Clobazam affects chemicals in the brain that may be unbalanced in people with anxiety.

Onfi is used in combination with other medications to treat seizures caused by Lennox-Gastaut syndrome, a severe form of childhood epilepsy that also causes developmental and behavior problems.

Onfi may also be used for purposes not listed in this medication guide.

Taking this medicine with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Other drugs may interact with clobazam, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.