Clorazepate Dipotassium

INDICATIONS AND USAGE Clorazepate dipotassium tablets are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. Clorazepate dipotassium tablets are indicated as adjunctive therapy in the management of partial seizures. The effectiveness of clorazepate dipotassium tablets in long-term management of anxiety, that is, more than 4 months, has not been assessed by systematic clinical studies. Long-term studies in epileptic patients, however, have shown continued therapeutic activity. The physician should reassess periodically the usefulness of the drug for the individual patient. Clorazepate dipotassium tablets are indicated for the symptomatic relief of acute alcohol withdrawal.

DOSAGE AND ADMINISTRATION For the Symptomatic Relief of Anxiety: Clorazepate dipotassium tablets are administered orally in divided doses. The usual daily dose is 30 mg. The dose should be adjusted gradually within the range of 15 to 60 mg daily in accordance with the response of the patient. In elderly or debilitated patients it is advisable to initiate treatment at a daily dose of 7.5 to 15 mg. Clorazepate dipotassium tablets may also be administered in a single dose daily at bedtime; the recommended initial dose is 15 mg. After the initial dose, the response of the patient may require adjustment of subsequent dosage. Lower doses may be indicated in the elderly patient. Drowsiness may occur at the initiation of treatment and with dosage increment. For the Symptomatic Relief of Acute Alcohol Withdrawal: The following dosage schedule is recommended: 1st 24 hours (Day 1) 30 mg initially; followed by 30 to 60 mg in divided doses 2nd 24 hours (Day 2) 45 to 90 mg in divided doses 3rd 24 hours (Day 3) 22.5 to 45 mg in divided doses Day 4 15 to 30 mg in divided doses Thereafter, gradually reduce the daily dose to 7.5 to 15 mg. Discontinue drug therapy as soon as patient’s condition is stable. The maximum recommended total daily dose is 90 mg. Avoid excessive reductions in the total amount of drug administered on successive days. As an Adjunct to Antiepileptic Drugs: In order to minimize drowsiness, the recommended initial dosages and dosage increments should not be exceeded. Adults: The maximum recommended initial dose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 90 mg/day. Children (9 to 12 years): The maximum recommended initial dose is 7.5 mg two times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 60 mg/day. Discontinuation or Dosage Reduction of Clorazepate Dipotassium Tablets: To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clorazepate dipotassium tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS and DRUG ABUSE AND DEPENDENCE ).

CONTRAINDICATIONS Clorazepate dipotassium tablets are contraindicated in patients with a known hypersensitivity to the drug and in those with acute narrow angle glaucoma.

ADVERSE REACTIONS The side effect most frequently reported was drowsiness. Less commonly reported (in descending order of occurrence) were: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache, and mental confusion. Other side effects included insomnia, transient skin rashes, fatigue, ataxia, genitourinary complaints, irritability, diplopia, depression, tremor, and slurred speech. There have been reports of abnormal liver and kidney function tests and of decrease in hematocrit. Decrease in systolic blood pressure has been observed. To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. If clorazepate dipotassium tablets is to be combined with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of the agents to be employed. Animal experience indicates that clorazepate dipotassium prolongs the sleeping time after hexobarbital or after ethyl alcohol, increases the inhibitory effects of chlorpromazine, but does not exhibit monoamine oxidase inhibition. Clinical studies have shown increased sedation with concurrent hypnotic medications. The actions of the benzodiazepines may be potentiated by barbiturates, narcotics, phenothiazines, monoamine oxidase inhibitors or other antidepressants. If clorazepate dipotassium tablets are used to treat anxiety associated with somatic disease states, careful attention must be paid to possible drug interaction with concomitant medication. In bioavailability studies with normal subjects, the concurrent administration of antacids at therapeutic levels did not significantly influence the bioavailability of clorazepate dipotassium tablets. Pregnancy: Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including clorazepate dipotassium tablets, during pregnancy. Healthcare providers are encouraged to register patients calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to clorazepate dipotassium tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to clorazepate dipotassium tablets during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data In ani …

DESCRIPTION Chemically, clorazepate dipotassium is a benzodiazepine. The empirical formula is C 16 H 11 ClK 2 N 2 O 4 ; the molecular weight is 408.92; 1 H -1, 4 Benzodiazepine-3-carboxylic acid, 7-chloro-2, 3-dihydro-2-oxo-5-phenyl-, potassium salt compound with potassium hydroxide (1:1) and the structural formula may be represented as follows: The compound occurs as a fine, white or light yellow, practically odorless powder. It is insoluble in the common organic solvents, but very soluble in water. Aqueous solutions are unstable, clear, light yellow, and alkaline. Each Clorazepate Dipotassium Tablet, USP 3.75 mg contains clorazepate equivalent to 2.9 mg. Each Clorazepate Dipotassium Tablet, USP 7.5 mg contains clorazepate equivalent to 5.8 mg. Each Clorazepate Dipotassium Tablet, USP 15 mg contains clorazepate equivalent to 11.6 mg. Inactive ingredients for Clorazepate Dipotassium Tablets, USP: Colloidal Silicon Dioxide, FD&C Blue No.2 Aluminum Lake (3.75 mg), FD&C Yellow No.6 Aluminum Lake (7.5 mg), Magnesium Oxide, Potassium Chloride, Potassium Carbonate, Microcrystalline Cellulose, Croscarmellose Sodium and Magnesium Stearate. structure

OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

HOW SUPPLIED 3.75 mg Tablets Clorazepate dipotassium tablets, USP are available as light blue colored, round, mottled uncoated tablets, debossed with "C" above the bisect, "19" below the bisect on one side and plain on other side. Each tablet contains 3.75 mg of clorazepate dipotassium. Bottles of 30 (NDC 60505-4754-3) Bottles of 100 (NDC 60505-4754-1) Bottles of 500 (NDC 60505-4754-5) Bottles of 1000 (NDC 60505-4754-7) 7.5 mg Tablets Clorazepate dipotassium tablets, USP are available as light peach colored, round, mottled uncoated tablets, debossed with "C" above the bisect, "20" below the bisect on one side and plain on other side. Each tablet contains 7.5 mg of clorazepate dipotassium. Bottles of 30 (NDC 60505-4755-3) Bottles of 100 (NDC 60505-4755-1) Bottles of 500 (NDC 60505-4755-5) Bottles of 1000 (NDC 60505-4755-7) 15 mg Tablets Clorazepate dipotassium tablets, USP are available as pink colored, round, mottled uncoated tablets, debossed with "C" above the bisect, "21" below the bisect on one side and plain on other side. Each tablet contains 15 mg of clorazepate dipotassium. Bottles of 30 (NDC 60505-4756-3) Bottles of 100 (NDC 60505-4756-1) Bottles of 500 (NDC 60505-4756-5) Bottles of 1000 (NDC 60505-4756-7) Recommended storage: Protect from moisture. Keep bottle tightly closed. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dispense in a USP tight, light-resistant container. APOTEX INC. Clorazepate Dipotassium Tablets, USP 3.75 mg, 7.5 mg and 15 mg Manufactured by: Manufactured for: CorePharma, LLC Apotex Corp. 215 Wood Avenue, Weston, Florida Middlesex, NJ 08846, USA USA 33326 Revised: May 2023 Rev: 4