CLOBAZAM (Page 6 of 7)

12.5 Pharmacogenomics

The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N-desmethylclobazam. Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3 to 5 times higher in poor metabolizers (e.g., subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (e.g., 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 [see Dosage and Administration (2.5)].

The systemic exposure of clobazam is similar for both CYP2C19 poor and extensive metabolizers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In mice, oral administration of clobazam (0 mg/kg/day, 6 mg/kg/day, 12 mg/kg/day, or 24 mg/kg/day) for 2 years did not result in an increase in tumors. The highest dose tested was approximately 3 times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2).

In rats, oral administration of clobazam for 2 years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD.

M u tagenesis

Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

In a fertility study in which clobazam (50 mg/kg/day, 350 mg/kg/day, or 750 mg/kg/day, corresponding to 12 times, 84 times and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40 mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.

14 CLINICAL STUDIES

The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.

S tudy 1

Study 1 (N=238) was a randomized, doubleblind, placebo-controlled study consisting of a 4 week baseline period followed by a 3 week titration period and 12 week maintenance period. Patients age 2 years to 54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤ 30 kg or > 30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 5.

Table 5 Study 1 Total Daily Dose
30 kg Body Weight > 30 kg Body Weight
Low Dose 5 mg daily 10 mg daily
Medium Dose 10 mg daily 20 mg daily
High Dose 20 mg daily 40 mg daily

Doses above 5 mg/day were administered in two divided doses.

The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4 week baseline period to 12 week maintenance period.

The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of clobazam were statistically superior (p ≤ 0.05) to the placebo group. This effect appeared to be dose dependent.

Figure 1

M ea n Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1)

Image
(click image for full-size original)

Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in five categories.

Figure 2

Drop Seizure Response by Category for clobazam and Placebo (Study 1)

Image
(click image for full-size original)

There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3 month maintenance period.

S tudy 2

Study 2 (N=68) was a randomized, double-blind comparison study of high- and low- dose clobazam, consisting of a 4 week baseline period followed by a 3 week titration period and 4 week maintenance period. Patients age 2 years to 25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of clobazam, and then entered a 3 week titration period.

The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4 week baseline period to the 4 week maintenance period.

A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs. 29%; p < 0.05).

16 HOW SUPPLIED/STORAGE AND HANDLING

Clobazam Tablets, 10 mg are white to off-white, modified capsule-shaped, biconvex tablet, debossed with ’13’ and ’25’ on either side of functional scoreline on one side and plain on other side and are supplied as follows:

NDC 70710-1325-1: scored tablet, in bottles of 100 tablets with child-resistant closure.

Clobazam Tablets, 20 mg are white to off-white, modified capsule-shaped, biconvex tablet, debossed with ’13’ and ’26’ on either side of functional scoreline on one side and plain on other side and are supplied as follows:

NDC 70710-1326-1: scored tablet, in bottles of 100 tablets with child-resistant closure.

Storage

Store at 20°C to 25°C (68°F to 77°F). [See USP controlled room temperature.]

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Risks from Concomitant Use with Opioids

Inform patients and caregivers that potentially fatal additive effects may occur if clobazam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Somnolence or Sedation

Advise patients or caregivers to check with their healthcare provider before clobazam is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol [see Warnings and Precautions (5.2, 5.3)].

If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that clobazam does not affect them adversely (e.g., impair judgment, thinking or motor skills).

Increasing or Decreasing the Clobazam Dose

Inform patients or caregivers to consult their healthcare provider before increasing the clobazam dose or abruptly discontinuing clobazam. Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

Hypersensitivity

Inform patients or caregivers that clobazam is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients [ see Warnings and Precautions (5.5)].

Interactions with Hormonal Contraceptives

Counsel women to also use non-hormonal methods of contraception when clobazam is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing clobazam to ensure contraceptive reliability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

Serious Dermatological Reactions

Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking clobazam, patients or caregivers should consult with healthcare providers immediately [see Warnings and Precautions (5.5)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and their families that AEDs, including clobazam, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Patients should report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.7)].

Pregnancy

Advise pregnant women and women of childbearing potential that the use of clobazam during pregnancy can cause fetal harm which may occur early in pregnancy before many women know they are pregnant. Instruct patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.

Advise patients that there is a pregnancy exposure registry that collects information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Nursing

Counsel patients that clobazam is excreted in breast milk. Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy and counsel nursing mothers to observe their infants for poor sucking and somnolence [see Use in Specific Populations (8.2)].

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev: 09/18

M E DICATION GUIDE

Clobazam (KLOE ba zam) Tablets , CIV

W h at is the most important information I should know about clobazam tablets?

  • Do not stop taking clobazam tablets without first talking to your healthcare provider. Stopping clobazam tablets suddenly can cause serious side effects.
  • Clobazam tablets are benzodiazepine medicine. Benzodiazepines can cause severe drowsiness, breathing problems (respiratory depression), coma, and death when taken with opioid medicines.
  • Clobazam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.
    • Do not drive, operate heavy machinery, or do other dangerous activities until you know how clobazam tablets affects you.
    • Clobazam tablets may cause problems with your coordination, especially when you are walking or picking things up.
  • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking clobazam tablets unt il you talk to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, clobazam tablets may make your sleepiness or dizziness much worse.
  • Clobazam tablets can cause withdrawal symptoms.
    • Do not stop taking clobazam tablets all of a sudden without first talking to a healthcare provider. Stopping clobazam tablets suddenly can cause seizures that will not stop (status epilepticus), hearing or seeing things that are not there (hallucinations), shaking, nervousness, and stomach and muscle cramps.
    • Talk to your healthcare provider about slowly stopping clobazam tablets to avoid withdrawal symptoms.
  • Clobazam tablets can be abused and cause dependence.
    • Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
  • Clobazam tablets are f ederal controlled substance (CIV) because it can be abused or lead to dependence. Keep clobazam tablets in a safe place to prevent misuse and abuse. Selling or giving away clobazam tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.
  • S erious skin reactions have been seen when clobazam tablets are taken with other medicines and may require stopping its use. Do not stop taking clobazam tablets without first talking to your healthcare provider.
    • A serious skin reaction can happen at any time during your treatment with clobazam tablets, but is more likely to happen within the first 8 weeks of treatment. These skin reactions may need to be treated right away.
    • Call your healthcare provider immediately if you have skin blisters, rash, sores in the mouth, hives or any other allergic reaction.
  • L ike other antiepileptic drugs, clobazam tablets m a y cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • new or worse anxiety
  • trouble sleeping (insomnia)
  • acting on dangerous impulses
  • attempts to commit suicide
  • feeling agitated or restless
  • new or worse irritability
  • an extreme increase in activity and talking (mania)
  • new or worse depression
  • panic attacks
  • acting aggressive, being angry, or violent
  • other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

W h at are clobazam tablets ?

Clobazam tablets are prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut syndrome in people 2 years of age or older.

It is not known if clobazam tablets are safe and effective in children less than 2 years old.

Do not take clobazam tablets if you:

  • are allergic to clobazam or any of the ingredients in clobazam tablets. See the end of this Medication Guide for a complete list of ingredients in clobazam tablets.

Before you take clobazam tablets, tell your healthcare provider about all your medical conditions, including if you:

  • have liver or kidney problems
  • have lung problems (respiratory disease)
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • use birth control medicine. Clobazam tablets may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use.
  • are pregnant or plan to become pregnant. Clobazam tablets may harm your unborn baby.
    • Tell your healthcare provider right away if you become pregnant while taking clobazam tablets. You and your healthcare provider will decide if you should take clobazam tablets while you are pregnant.
    • Babies born to mothers receiving benzodiazepine medications (including clobazam tablets) late in pregnancy may be at some risk of experiencing breathing problems, feeding problems, dangerously low body temperature, and withdrawal symptoms.
  • If you become pregnant while taking clobazam tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  • Clobazam can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take clobazam tablets. You and your healthcare provider should decide if you will take clobazam tablets or breastfeed. You should not do both.

T ell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking clobazam tablets with certain other medicines can cause side effects or affect how well clobazam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take clobazam tablets?

  • Take clobazam tablets exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how much clobazam tablets to take and when to take it.
  • Clobazam tablets can be taken whole, broken in half along the score, or crushed and mixed in applesauce.
  • Clobazam tablets can be taken with or without food.
  • Your healthcare provider may change your dose if needed. Do not change your dose of clobazam tablets without talking to your healthcare provider.
  • Do not stop taking clobazam tablets without first talking to your healthcare provider.
  • Stopping clobazam tablets suddenly can cause serious problems.
  • If you take too much clobazam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

W h at should I avoid while taking clobazam tablets?

  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how clobazam tablets affects you.
  • Do not drink alcohol or take other medicines that may make you sleepy or dizzy while taking clobazam tablets until you talk to your healthcare provider. When taken with alcohol or medicines that cause sleepiness or dizziness, clobazam tablets may make your sleepiness or dizziness much worse

W h at are the possible side effects of clobazam tablets?

Clobazam tablets m a y cause serious side effects, including: See “What is the most important information I should know about clobazam tablets?”

T h e most common side effects of clobazam tablets include:

  • sleepiness
  • cough
  • acting aggressive, being angry, or violent
  • tiredness
  • drooling
  • pain with urination
  • difficulty sleeping
  • problems with breathing
  • constipation
  • fever
  • slurred speech

These are not all the possible side effects of clobazam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store clobazam tablets?

  • Store clobazam tablets between 68°F to 77°F (20°C to 25°C).
  • Keep clobazam tablets in a dry place.
  • Keep clobazam tablets and all medicines out of the reach of children.

G eneral information about the safe and effective use of clobazam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use clobazam tablets for a condition for which it was not prescribed. Do not give clobazam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about clobazam tablets that is written for health professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

W h at are the ingredients in clobazam tablets?

A ctive ingredient: clobazam

Inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 03/18

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