Clorazepate Dipotassium Tablets USP, 3.75 mg, 7.5 mg, & 15 mg

CIV

Rx only

Chemically, clorazepate dipotassium is a benzodiazepine. The empirical formula is C₁₆H₁₁ClK₂N₂O₄; the molecular weight is 408.92; 1H-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, 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 contain either 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium for oral administration. They also contain colloidal silicon dioxide, D&C red no. 6 – lake (7.5 and 15 mg), D&C yellow no. 10 – lake (7.5 mg only), FD&C Blue no. 2 – lake (3.75 mg only), FD&C red no. 40 – lake (3.75 and 15 mg), magnesium oxide heavy, magnesium stearate, microcrystalline cellulose, potassium carbonate anhydrous, potassium chloride and talc.

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 (97-98%).

Within 10 days after oral administration of a 15 mg (50µCi) dose of ¹⁴C-Clorazepate Dipotassium to two volunteers, 62-67% of the radioactivity was excreted in the urine and 15-19% was eliminated in the feces. Both subjects were still excreting measurable amounts of radioactivity in the urine (about l% of the ¹⁴C-dose) on day ten.

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.

Clorazepate dipotassium tablets are not recommended for use in depressive neuroses or in psychotic reactions.

Patients taking clorazepate dipotassium tablets should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery including motor vehicles.

Since clorazepate dipotassium has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS-depressant drugs, and cautioned that the effects of alcohol may be increased.

Because of the lack of sufficient clinical experience, clorazepate dipotassium tablets are not recommended for use in patients less than 9 years of age.

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.

If clorazepate dipotassium 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.

Overdosage is usually manifested by varying degrees of CNS depression ranging from slight sedation to coma. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

The treatment of overdosage should consist of the general measures employed in the management of overdosage of any CNS depressant. Gastric evacuation either by the induction of emesis, lavage, or both, should be performed immediately. General supportive care, including frequent monitoring of the vital signs and close observation of the patient is indicated. Hypotension though rarely reported, may occur with large overdoses. In such cases the use of agents such as Levophed^® Bitartrate (norepinephrine bitartrate injection, USP) or Aramine^® Injection metaraminol bitartrate injection, USP) should be considered.

While reports indicate that individuals have survived overdoses of clorazepate dipotassium as high as 450 to 675 mg, these doses are not necessarily an accurate indication of the amount of drug absorbed since the time interval between ingestion and the institution of treatment was not always known. Sedation in varying degrees was the most common physiological manifestation of clorazepate dipotassium overdosage. Deep coma when it occurred was usually associated with the ingestion of other drugs in addition to clorazepate dipotassium.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use

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 LD₅₀ was 1320 mg/kg. In monkeys aggressive behavior was reduced at an oral dose of 0.25 mg/kg; sedation (ataxia) was induced at 7.5 mg/kg; the LD₅₀ could not be determined because of the emetic effect of large doses, but the LD₅₀ exceeds 1600 mg/kg.

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.

3.75 mg round, flat tablets, pale violet colored, slightly mottled, scored and engraved on one side with "T45" and plain on the other side.

Bottles of 60      (NDC 21695-433-60)

7.5 mg round, flat tablets, orange colored, slightly mottled, scored and engraved on one side with "T46" and plain on the other side.

Bottles of 60      (NDC 21695-434-60)

Manufactured by:
Taro Pharmaceutical Industries Ltd.,
Haifa Bay, Israel 26110

Distributed by:
Taro Pharmaceuticals U.S.A., Inc.,
Hawthorne, NY 10532

www.taropharma.com

Revised: August, 2008
78548-0808-1

Repackaged by:

Rebel Distributors Corp

Thousand Oaks, CA 91320

Clorazepate Dipotassium 3.75mg