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Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Store tablets and oral suspension at 20 °C to 25 °C (68 °F to 77 °F).

Keep container tightly closed in a dry and well-ventilated place.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required.

Precautions for safe handling: Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: General industrial hygiene practice.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained. Hypotension may be combated by the use of norepinephrine or metaraminol. Dialysis is of limited value. Flumazenil (Anexate) is a competitive benzodiazepine receptor antagonist that can be used as an antidote for benzodiazepine overdose. In particular, flumazenil is very effective at reversing the CNS depression associated with benzodiazepines but is less effective at reversing respiratory depression. Its use, however, is controversial as it has numerous contraindications. It is contraindicated in patients who are on long-term benzodiazepines, those who have ingested a substance that lowers the seizure threshold, or in patients who have tachycardia or a history of seizures. As a general rule, medical observation and supportive care are the mainstay of treatment of benzodiazepine overdose. Although benzodiazepines are absorbed by activated charcoal, gastric decontamination with activated charcoal is not beneficial in pure benzodiazepine overdose as the risk of adverse effects often outweigh any potential benefit from the procedure. It is recommended only if benzodiazepines have been taken in combination with other drugs that may benefit from decontamination. Gastric lavage (stomach pumping) or whole bowel irrigation are also not recommended.

The benzodiazepine antiepileptic drug clobazam can be added to existing AED treatment, usually without clinical toxicity. We report 3 patients in whom the addition of clobazam led within several weeks to clinically obvious phenytoin (PHT) intoxication in patients who had been taking maximum tolerable PHT doses. Symptoms and high PHT levels resolved with lowering the PHT dose. Clobazam and norclobazam levels were not elevated. This interaction is probably related to interference with hepatic degradation of PHT. Clinicians should be aware of possible PHT intoxication in patients starting clobazam.

The authors report preliminary findings on the effect of the new generation antiepileptic drug (AED) felbamate (FBM) on steady state plasma concentrations of clobazam (CLB), a benzodiazepine (frequently used as add-on therapy in patients with refractory epilepsy) and its active metabolite n-desmethyl-clobazam (N-CLB). The authors prospectively collected plasma samples from 66 children and adults with epilepsy receiving chronic CLB therapy. On the basis of concomitant AEDs, patients were divided into three subgroups otherwise comparable for age and weight-adjusted daily dose of CLB: group A (n = 22), receiving CLB monotherapy or CLB plus AEDs without inducing properties of cytochrome P450 (CYP) metabolism, namely valproic acid (VPA) or lamotrigine (LTG); group B (n = 28), receiving CLB plus AED inducer polytherapy (carbamazepine, phenobarbital, phenytoin), even associated with VPA (n = 9) or LTG (n = 12); group C (n = 16), receiving CLB plus FBM, associated with AED inducers, VPA or LTG. Level to weight-adjusted dose ratio (L/D) of CLB in groups B and C was twofold lower compared to group A (p < 0.001). L/D of N-CLB was twofold higher in group B and fivefold in group C compared to group A (p < 0.00 1). The metabolite-to-parent drug ratio shifted from a median value of 2.8 in group A to 13 in group B, and up to 29 in patients receiving polytherapy with FBM (p < 0.001). These data confirm previous reports of a significant increase in CLB clearance in patients receiving AED inducers, leading to an accumulation of its main metabolite. They also provide novel evidence of a further marked increase in N-CLB plasma concentrations in patients receiving FBM cotherapy. From a clinical point of view, this finding should be kept in mind in explaining possible toxicity in patients on complex AED polytherapy. Furthermore, knowledge of the in vivo interaction between CLB and FBM could help in identifying the CYP isoforms involved in the metabolism of both CLB and N-CLB.

Clobazam is a weak CYP3A4 inducer and may reduce the efficacy of some hormonal contraceptives that are metabolized by CYP3A4. To ensure contraceptive reliability, the manufacturer recommends that women receiving hormonal contraceptives also use nonhormonal forms of contraception during clobazam therapy and for 28 days following discontinuance of the drug.

The pharmacokinetic interaction between clobazam and cimetidine was studied in 9 healthy male volunteers in an open-labelled study. After a single oral dose of clobazam 30 mg, a wash-out period of 14 days was followed by daily doses of cimetidine 1 g for one week. Thereafter a single oral dose of clobazam 30 mg was again given. The plasma concentrations of clobazam and its main metabolite N-desmethyl-clobazam were measured by gas-chromatography. The area under the curve (AUC0-infinity) of plasma clobazam level was significantly larger after pretreatment with cimetidine and the elimination half life of clobazam was significantly longer. There were no statistically significant differences in Cmax and tmax for plasma clobazam. The plasma levels of N-desmethyl-clobazam did not show any significant change after the intake of cimetidine.

For more Interactions (Complete) data for Clobazam (11 total), please visit the HSDB record page.

Limited data are available on the hepatotoxicity of clobazam. In clinical trials, clobazam was not associated with an increased frequency of serum aminotransferase elevations as compared to placebo treatment, and there were no instances of clinically apparent liver injury. No individual case reports of clobazam hepatotoxicity have been published since its wide spread clinical availability. Liver injury from benzodiazepines is quite rare, but isolated instances of hepatotoxicity have been reported for clorazepate and clonazepam, two other benzodiazepines used predominantly in the therapy of epilepsy. Thus, clinically apparent liver injury due to clobazam must be rare, if it occurs at all.

The most common adverse drug reactions (noted during the trials compared to placebo) were sedation, somnolence, drowsiness, headache, nausea, pyrexia, lethargy, aggression, drooling, irritability, ataxia, constipation, dry mouth, blurred vision, depression, insomnia, and amnesia. Compared with other benzodiazepines (e.g., diazepam), the incidence of these side effects was much less with better tolerability. Tolerance to these side effects develops over time.

IDENTIFICATION AND USE: Clobazam is white to almost white, crystalline powder. Clobazam (DEA Code Number: 2751) is a Schedule IV controlled substance. It is used as anticonvulsant. HUMAN EXPOSURE AND TOXICITY: Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol. Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported rarely in both pediatric and adult patients treated with clobazam during postmarketing experience worldwide. Although such reactions may occur at any time during clobazam therapy, the risk is greater during the first 8 weeks of therapy or when clobazam is discontinued and then reinitiated. Physical and/or psychological dependence may occur in patients receiving clobazam. While the risk of dependence is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use of the drug (i.e., a few weeks) at recommended dosages. The risk of dependence also is increased in patients with a history of alcohol or substance abuse. As with all benzodiazepines, tolerance to the therapeutic effects of clobazam has been reported and may be a concern with long-term use of the drug. ANIMAL STUDIES: Signs exhibited during acute toxicity testing included somnolence, prostration, reduction in spontaneous motility, irregular breathing, ataxia, tremors, convulsions, loss of righting reflexes and reduction in body temperature. These were the most frequently observed signs in lethally poisoned animals. Clobazam was administered daily in the diet at doses of 0, 4, 20 and 100 mg/kg/day to groups of 60 male and 60 female rats for 104 weeks. Gross lesions identified at necropsy consisted of liver pallor and thyroid gland enlargement in males dosed at 100 mg/kg/day. The non-neoplastic histopathologic changes associated with treatment included an increased incidence of endometrial hyperplasia, cystic endometrial hyperplasia, and endometrial polyps and polypoid areas in females treated with 100 mg/kg/day. Thyroid changes included an increase in follicular cell adenomas in males (21.7% vs 5.7% in controls) treated with 100 mg/kg/day, and there was follicular carcinoma in one male (1.7%) of this group. One male rat in the 100 mg/kg/day group (1.7%) and one female rat in the 20 mg/kg/day (1.7%) group had squamous cell carcinomas in the thyroid gland. In the liver, changes included an increase in focal hyperplasia in females treated with 20 (11.7%) or 100 (6.7%) mg/kg/day. Nodular hyperplasias were increased in females treated with 100 mg/kg/day (3.3% vs 1.7% in controls). Hepatocellular carcinoma was found in one decedent female (1.7%) treated with 20 mg/kg/day. Clobazam was administered to Beagle dogs at doses of 0, 2.5, 5, 10, 20, 40 and 80 mg/kg for periods ranging from 6 to 12 months. Dose-dependent symptoms were noted and consisted of sedation, ataxia, mild tremors, somnolence, emesis, seizures and progressive rise in serum alkaline phosphatase. At the 80 mg/kg dose for 6 months a significant increase in the weight of the liver was observed in males and females. In the 12-month study using 0, 5, 10 and 40 mg/kg a dose-dependent increased accumulation of pigments in hepatocytes and Kupffer cells was observed in the 5 mg/kg group. In another 12-month study where 0, 2.5 and 5 mg/kg doses were used there were yellow granules in the epithelial cells of the proximal convoluted tubules in the 5 mg/kg group at one year. The studies have shown that convulsions were observed on the second and third day after abrupt discontinuation of the drug. In the one year study where 0, 5, 10 and 40 mg/kg of clobazam were used and in the 6-month study where 0, 5, 20 and 80 mg/kg were used, deaths occurred (9 and 2, respectively), but the exact cause could not be ascertained. However, the animals experienced convulsive seizures with foaming at the mouth during the treatment period. In rabbits, the rate of fetal resorption was higher in animals treated with 100 mg/kg than in the controls. In the group treated with 4 mg/kg, one unilateral exophthalmus, one exencephalus combined with ceolosomy and syndactyly of the front legs were observed, whilst in the 20 mg/kg group, one hydrocephalus with umbilical hernia was noted; these malformations were thought not to be drug related. 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.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of July 7, 2016: http://actor.epa.gov/dashboard/]

/SIGNS AND SYMPTOMS/ Overdose and intoxication with benzodiazepines, including Onfi, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.

/SIGNS AND SYMPTOMS/ Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported rarely in both pediatric and adult patients treated with clobazam during postmarketing experience worldwide. Although such reactions may occur at any time during clobazam therapy, the risk is greater during the first 8 weeks of therapy or when clobazam is discontinued and then reinitiated.

/SIGNS AND SYMPTOMS/ Physical and/or psychological dependence may occur in patients receiving clobazam. While the risk of dependence is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use of the drug (i.e., a few weeks) at recommended dosages. The risk of dependence also is increased in patients with a history of alcohol or substance abuse. As with all benzodiazepines, tolerance to the therapeutic effects of clobazam has been reported and may be a concern with long-term use of the drug.

/SIGNS AND SYMPTOMS/ To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration < or = 5 weeks) and in the open-label extension (OLE) trial OV-1004 (< or = 5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred > or = 1 day following and < or = 30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of < or = 40 mg/day, and 94 received clobazam dosages of > or = 120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of > or = 120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were < 30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of =40 mg/day, and those in the OLE trial received clobazam dosages of < or = 80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (=5 years).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Clobazam

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Signs exhibited during acute toxicity testing included somnolence, prostration, reduction in spontaneous motility, irregular breathing, ataxia, tremors, convulsions, loss of righting reflexes and reduction in body temperature. These were the most frequently observed signs in lethally poisoned animals.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Antiepileptic agents are known to cause adverse effects in human liver, including steatosis. Clobazam (CLB), a 1,5-benzodiazepine, is clinically used as an antiepileptic agent. In the previous study, 4-week treatment with CLB induced hepatomegaly in male rats. In the present study, the human risk of hepatomegaly was assessed and the causative mechanism in terms of cell proliferation and apoptosis, oxidative stress, and drug-metabolizing enzyme induction was elucidated by toxicological approach. Male SD rats were treated orally with 400 mg/kg CLB for 1, 3, 7, 14, or 28 days. The 28-day treatment was followed by 7 or 14 days of withdrawal. At the end of each treatment, the liver and plasma of each rat were examined. Liver weight increased from Day 3 of CLB treatment. This increase was mostly accompanied by hepatic centrilobular hypertrophy and proliferation of smooth endoplasmic reticulum (SER), and by an increase in microsomal proteins. Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 mRNA levels in the liver were upregulated as compared to the control group throughout the dosing period. On the other hand, the thiobarbituric acid reactive substance (TBARS) formulation, hepatocyte proliferation, and apoptosis, assumed to play roles in laying groundwork for effective induction of metabolizing enzymes, were increased only at the acute phase of treatment. These results suggested that CLB-induced hepatomegaly in male rats is mainly attributable to microsomal enzyme induction associated with Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 gene upregulation, but does not cause any toxicological concerns.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In order to elucidate the mechanisms by which long-term treatment with clobazam (CLB), 1,5-benzodiazepine, induces thyroid follicular cell tumors in male rats, male Sprague-Dawley (SD) rats were treated orally with 400 mg/kg of CLB for up to 4 weeks, and the contribution of feedback through elevated thyroid stimulating hormone (TSH) was investigated. Measurements taken after 1, 2, and 4 weeks of treatment revealed that thyroxine (T4)-UDP-glucuronosyltransferase (T4-UDPGT) activity was higher than that of untreated animals. This change was accompanied by increase in liver weights and centrilobular hepatocyte hypertrophy. In addition, plasma total triiodothyronine (T3) and T4 levels were lower than in the untreated rats when measured after 1 week of treatment. However, a high plasma TSH level was sustained throughout the 4-week treatment. Thyroid follicular cell hypertrophy began after 1 week of treatment, followed by increased thyroid weight after 2 weeks. Clearance of exogenous [125I] T4 from the blood of treated rats, determined after 4 weeks of treatment, was significantly faster than that in untreated rats, whereas iodine uptake and organification in the thyroid glands were not affected. These results suggest that CLB increases hepatic T4-UDPGT activity leading to acceleration of T4-clearance, which results in decreased plasma thyroidal hormones followed by compensatory increase of TSH biosynthesis and secretion. Chronic high levels of TSH would exert a continuous growth pressure on the thyroid, under which hypertrophic follicular cells can ultimately progress to frank neoplasms.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clobazam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Depressants: Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Clobazam (DEA Code Number: 2751) is included on this list.

Clobazam (DEA Code Number: 2751) is a Schedule IV controlled substance.

Schedule IV Controlled Substance: (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.

Anticonvulsants

MEDICATION

Use (kg; approx.) in Germany (2009): >50

For treatment and management of epilepsy and seizures associated with Lennox-Gastaut syndrome, a difficult-to-treat form of childhood epilepsy.

Belgium patent 707667; S. Rossi, United States of American patent 3984398 (1968, 1976 both to Roussel-UCLAF).

This drug was obtained by reaction of 2-nitrodiphenylamines with malonic acid, with a subsequently reductive ring closure.

Table: Clobazam Preparations [Table#8354]

Trade Names. Clarmyl (Roussel-Iberica, Spain), Frisin, Frisium, Karidium, Noiafren, Sentil (Hoechst), Urbadan, Urbanol (Roussel), Urbanyl (Diamant, France, Roussel).