Diazepam (Page 2 of 4)

Labor and Delivery

Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants).

Nursing Mothers

Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving diazepam.

PRECAUTIONS

General

If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed — particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants (see Drug Interactions).

The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.

Psychiatric and paradoxical reactions are known to occur when using benzodiazepines (see ADVERSE REACTIONS). Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly.

A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see DRUG ABUSE AND DEPENDENCE).

In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated).

Some loss of response to the effects of benzodiazepines may develop after repeated use of diazepam for a prolonged time.

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 advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Drug Interactions

Centrally Acting Agents

If diazepam is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

Alcohol

Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.

Antacids

Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20 to 25 minutes greater in the presence of antacids. However, this difference was not statistically significant.

Compounds Which Inhibit Certain Hepatic Enzymes

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole.

Phenytoin

There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD = 1 mg/kg/day] on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Category D (see WARNINGS, Pregnancy).

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

Geriatric Use

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Insufficiency

Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis. In such patients, a 2 to 5 fold increase in mean half-life has been reported. Delayed elimination has also been reported for the active metabolite desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic encephalopathy. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Hepatic Insufficiency).

ADVERSE REACTIONS

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported:

Central Nervous System: confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo

Gastrointestinal System: constipation, nausea, gastrointestinal disturbances

Special Senses: blurred vision, diplopia, dizziness

Cardiovascular System: hypotension

Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly.

Urogenital System: incontinence, changes in libido, urinary retention

Skin and Appendages: skin reactions

Laboratories: elevated transaminases and alkaline phosphatase

Other: changes in salivation, including dry mouth, hypersalivation

Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.

Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance.

Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy.

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