Special Warning : אזהרת שימוש

WARNINGS
Risks from Concomitant Use with Opioids
Concomitant use of benzodiazepines, including clorazepate dipotassium, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe clorazepate dipotassium concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of clorazepate dipotassium than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking clorazepate dipotassium, prescribe a lower initial dose of the opioid and titrate based upon clinical response.
Advise both patients and caregivers about the risks of respiratory depression and sedation when clorazepate dipotassium are used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see DRUG INTERACTIONS).

Use in Depressive Neuroses or Psychotic Reactions
Clorazepate dipotassium are not recommended for use in depressive neuroses or in psychotic reactions.

Use in Children
This medication is reserved for use in adults and children over 6 years of age.
Interference with Psychomotor Performance
Patients taking clorazepate dipotassium 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 (5-100 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    Drug Patients     Relative Risk:     Risk Difference: with Events         with              Incidence of       Additional Per 1000 Patients   Events            Events in Drug     Drug
Per 1000          Patients           Patients with
Patients          /Incidence         Events
in Placebo         Per 1000
Patients           Patients
Epilepsy                1.0                3.4                3.5                2.4 Psychiatric             5.7                8.5                1.5                2.9 Other                   1.0                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.

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

PRECAUTIONS
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 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.

Information for Patients
To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is essential that they consult with their physician before either increasing the dose or abruptly discontinuing this drug.
Patients, their caregivers, and families should be counseled that AEDs, including clorazepate dipotassium, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clorazepate dipotassium and should counsel them in its appropriate use.

Pediatric Use
See WARNINGS.

Geriatric Use
Clinical studies of clorazepate dipotassium were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Elderly or debilitated patients may be especially sensitive to the effects of all benzodiazepines, including clorazepate dipotassium. In general, elderly or debilitated patients should be started on lower doses of clorazepate dipotassium and observed closely, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy. Dose adjustments should also be made slowly, and with more caution in this patient population (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Effects on Driving