Chemically, clorazepate dipotassium USP is a benzodiazepine. The empirical formula is C

The compound occurs as a fine, 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.

Clorazepate dipotassium tablets USP contain 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose, potassium carbonate anhydrous, potassium chloride, talc and the following coloring agents:

3.75 mg - FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake

7.5 mg - D&C Red No. 6 Barium Lake and D&C Yellow No. 10 Lake

15 mg - D&C Red No. 6 Barium Lake and FD&C Red No. 40 Lake

Pharmacologically, clorazepate dipotassium has the characteristics of the benzodiazepines. It has depressant effects on the central nervous system. The primary metabolite, nordiazepam, quickly appears in the blood stream. The serum half-life is about 2 days. The drug is metabolized in the liver and excreted primarily in the urine.

Studies in healthy men have shown that clorazepate dipotassium has depressant effects on the central nervous system. Prolonged administration of single daily doses as high as 120 mg was without toxic effects. Abrupt cessation of high doses was followed in some patients by nervousness, insomnia, irritability, diarrhea, muscle aches, or memory impairment.

Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug. Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about 40 to 50 hours. Plasma levels of nordiazepam increase proportionally with clorazepate dipotassium dose and show moderate accumulation with repeated administration. The protein binding of nordiazepam in plasma is high (97 to 98%).

Within 10 days after oral administration of a 15 mg (50 μCi) dose of

Nordiazepam is further metabolized by hydroxylation. The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

Clorazepate dipotassium is 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.

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

In those patients in which a degree of depression accompanies the anxiety, suicidal tendencies may be present and protective measures may be required. The least amount of drug that is feasible should be available to the patient.

Patients taking clorazepate dipotassium tablets for prolonged periods should have blood counts and liver function tests periodically. The usual precautions in treating patients with impaired renal or hepatic function should also be observed.

In elderly or debilitated patients, the initial dose should be small, and increments should be made gradually, in accordance with the response of the patient, to preclude ataxia or excessive sedation.

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.

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

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.

Studies in rats and monkeys have shown a substantial difference between doses producing tranquilizing, sedative and toxic effects. In rats, conditioned avoidance response was inhibited at an oral dose of 10 mg/kg; sedation was induced at 32 mg/kg; the LD

Twenty-four dogs were given clorazepate dipotassium orally in a 22-month toxicity study; doses up to 75 mg/kg were given. Drug-related changes occurred in the liver; weight was increased and cholestasis with minimal hepatocellular damage was found, but lobular architecture remained well preserved.

Eighteen rhesus monkeys were given oral doses of clorazepate dipotassium from 3 to 36 mg/kg daily for 52 weeks. All treated animals remained similar to control animals.

Although total leucocyte count remained within normal limits it tended to fall in the female animals on the highest doses.

Examination of all organs revealed no alterations attributable to clorazepate dipotassium. There was no damage to liver function or structure.

Clorazepate Dipotassium Tablets USP are available as tablets containing 15 mg of clorazepate dipotassium, USP.

The 15 mg tablets are round flat beveled edge, pale pink colored, slightly mottled tablet. One side is scored and engraved with "T" above the score and"47" below the score. Other side is plain.

Bottles of 6 (NDC 43063-893-06)

DISPENSE THE ACCOMPANYING

Clorazepate

Rx only