Clobazam (Page 8 of 9)

Mutagenesis

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, 350, or 750 mg/kg/day, corresponding to 12, 84 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.

Study 1

Study 1 (N=238) was a randomized, double-blind, 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 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. Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1)

Image-02
(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-03
(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.

Study 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 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: White to off-white , oval tablets with functional score on one side with ‘L’ and ‘7’debossed either side of scoreline and plain on other side.

Clobazam tablets, 20 mg: White to off-white, oval tablets with functional score on one side with ‘L’ and ‘8’debossed either side of scoreline and plain on other side.

NDC 68180-157-06: 10 mg scored tablet, Bottles of 30,

NDC 68180-157-07: 10 mg scored tablet, Bottles of 60,

NDC 68180-157-09: 10 mg scored tablet, Bottles of 90,

NDC 68180-157-01: 10 mg scored tablet, Bottles of 100 and

NDC 68180-157-02: 10 mg scored tablet, Bottles of 500

NDC 68180-158-06: 20 mg scored tablet, Bottles of 30,

NDC 68180-158-07: 20 mg scored tablet, Bottles of 60,

NDC 68180-158-09: 20 mg scored tablet, Bottles of 90,

NDC 68180-158-01: 20 mg scored tablet, Bottles of 100 and

NDC 68180-158-02: 20 mg scored tablet, Bottles of 500

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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)].

Abuse, Misuse, and Addiction

Inform patients that the use of Clobazam, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure. Inform patients that the continued use of Clobazam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Clobazam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of Clobazam may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

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 (5.4, 5.5)].

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).

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 (5.6)].

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 (5.6)].

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 tablets 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 for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Nagpur 441 108

India.

Revised: May 2021 ID#: 267553

MEDICATION GUIDE

Clobazam (KLOE-ba-zam) Tablets, CIV

What is the most important information I should know about Clobazam Tablets?

  • Clobazam is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death. Get emergency help right away if any of the following happens:
    • shallow or slowed breathing
    • breathing stops (which may lead to the heart stopping)
    • excessive sleepiness (sedation)

Do not drive or operate heavy machinery until you know how taking clobazam with opioids affects you.

  • Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including clobazam, which can lead to overdose and serious side effects including coma and death.
    • Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including clobazam. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.
    • You can develop an addiction even if you take clobazam as prescribed by your healthcare provider.
    • Take clobazam exactly as your healthcare provider prescribed.
    • Do not share your clobazam with other people.
    • Keep clobazam in a safe place and away from children.
  • Physical dependence and withdrawal reactions. Clobazam can cause physical dependence and withdrawal reactions.
    • Do not suddenly stop taking clobazam. Stopping clobazam suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extremeincrease in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.
    • Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months , including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.
    • 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.
    • Do not take more clobazam than prescribed or take clobazam for longer than prescribed
  • Clobazam tablets can make you sleepy or dizzy and can slow your thinking and motor skills.
    • 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 drugs that may make you sleepy or dizzy while taking clobazam tablets without first talking 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.
  • Serious 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.
  • Like other antiepileptic drugs, clobazam tablets may 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 or irritability
  • trouble sleeping (insomnia)
  • acting on dangerous impulses
  • attempts to commit suicide
  • feeling agitated or restless
  • new or worse panic attacks
  • an extreme increase in activity and talking (mania)
  • new or worse depression
  • 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.

Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

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.

What are Clobazam Tablets?

  1. Clobazam tablets are a prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut syndrome in people 2 years of age or older.
  2. Clobazam tablets is a federally controlled substance (C-IV) because it contains clobazam that can be abused or lead to dependence. Keep clobazam tablets in a safeplace 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.

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.

Tell 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.

What should I avoid while taking clobazam tablets?

See “What is the most important information I should know about clobazam tablets?”

What are the possible side effects of clobazam tablets?

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

The 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. You may also report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

How should I store clobazam tablets?

  • Store clobazam tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Tablets

  • Keep clobazam tablets in a dry place.
  • Keep clobazam tablets and all medicines out of the reach of children.

General 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.

What are the ingredients in clobazam tablets?

Active ingredient: clobazam

Inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Nagpur — 441108

India

Revised: May 2021 ID#: 267561

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