Clorazepate Dipotassium

Clorazepate Dipotassium

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Questions & Answers

Side Effects & Adverse Reactions

Use in Depressive Neuroses or Psychotic Reactions

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

Use in Children

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

Interference with Psychomotor Performance

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

Concomitant Use with CNS Depressants

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.

Physical and Psychological Dependence

Withdrawal symptoms (similar in character to those noted with barbiturates and alcohol) have occurred following abrupt discontinuance of clorazepate. Withdrawal symptoms associated with the abrupt discontinuation of benzodiazepines have included convulsions, delirium, tremor, abdominal and muscle cramps, vomiting, sweating, nervousness, insomnia, irritability, diarrhea, and memory impairment. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation of clorazepate should generally be avoided and a gradual dosage tapering schedule followed.

Caution should be observed in patients who are considered to have a psychological potential for drug dependence.

Evidence of drug dependence has been observed in dogs and rabbits which was characterized by convulsive seizures when the drug was abruptly withdrawn or the dose was reduced; the syndrome in dogs could be abolished by administration of clorazepate.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including clorazepate dipotassium, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo Patients with Events
Per 1,000 Patients
Drug Patients with Events
Per 1,000 Patients
Relative Risk:
Incidence of Events in Drug
Patients/Incidence in Placebo Patients
Risk Difference:
Additional Drug Patients with Events
Per 1,000 Patients
Epilepsy 1 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing clorazepate dipotassium or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Usage in Pregnancy

An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Clorazepate dipotassium, a benzodiazepine derivative, has not been studied adequately to determine whether it, too, may be associated with an increased risk of fetal abnormality. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.

To provide information regarding the effects of in utero exposure to clorazepate dipotassium, physicians are advised to recommend that pregnant patients taking clorazepate dipotassium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Usage During Lactation

Clorazepate dipotassium tablets should not be given to nursing mothers since it has been reported that nordiazepam is excreted in human breast milk.

Legal Issues

There is currently no legal information available for this drug.

FDA Safety Alerts

There are currently no FDA safety alerts available for this drug.

Manufacturer Warnings

There is currently no manufacturer warning information available for this drug.

FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

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.

History

There is currently no drug history available for this drug.

Other Information

Chemically, clorazepate dipotassium, USP is a benzodiazepine. The molecular 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:

Clorazepate Structural Formula

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 for oral administration, contain 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium, USP. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, magnesium oxide, magnesium stearate, microcrystalline cellulose, potassium carbonate, sodium chloride, sodium lauryl sulfate and the following coloring agents:

3.75 mg - FD&C Blue No. 2 Aluminum Lake

7.5 mg - FD&C Yellow No. 6 Aluminum Lake

Clorazepate Dipotassium Manufacturers


  • Pd-rx Pharmaceuticals, Inc.
    Clorazepate Dipotassium Tablet [Pd-rx Pharmaceuticals, Inc.]
  • Rebel Distributors Corp
    Clorazepate Dipotassium Tablet [Rebel Distributors Corp]
  • Physicians Total Care, Inc.
    Clorazepate Dipotassium Tablet [Physicians Total Care, Inc.]
  • Contract Pharmacy Services-pa
    Clorazepate Dipotassium Tablet [Contract Pharmacy Services-pa]
  • Remedyrepack Inc.
    Clorazepate Dipotassium (Clorazepate Dipotassium) Tablet [Remedyrepack Inc. ]
  • Taro Pharmaceuticals U.s.a., Inc.
    Clorazepate Dipotassium Tablet [Taro Pharmaceuticals U.s.a., Inc.]
  • Pd-rx Pharmaceuticals, Inc.
    Clorazepate Dipotassium Tablet [Pd-rx Pharmaceuticals, Inc.]
  • Pd-rx Pharmaceuticals, Inc.
    Clorazepate Dipotassium Tablet [Pd-rx Pharmaceuticals, Inc.]
  • Mylan Pharmaceuticals Inc.
    Clorazepate Dipotassium Tablet [Mylan Pharmaceuticals Inc.]
  • Ranbaxy Pharmaceuticals Inc.
    Clorazepate Dipotassium Tablet [Ranbaxy Pharmaceuticals Inc.]
  • Bryant Ranch Prepack
    Clorazepate Dipotassium Tablet [Bryant Ranch Prepack]
  • Bryant Ranch Prepack
    Clorazepate Dipotassium Tablet [Bryant Ranch Prepack]
  • Bryant Ranch Prepack
    Clorazepate Dipotassium Tablet [Bryant Ranch Prepack]
  • Pd-rx Pharmaceuticals, Inc.
    Clorazepate Dipotassium Tablet [Pd-rx Pharmaceuticals, Inc.]
  • A-s Medication Solutions Llc
    Clorazepate Dipotassium Tablet [A-s Medication Solutions Llc]
  • American Health Packaging
    Clorazepate Dipotassium Tablet [American Health Packaging]

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