Pharmacokinetics

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including Valium, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs 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 Valium 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 Valium than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Valium, 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 Valium is 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 PRECAUTIONS: Drug Interactions).

Abuse, Misuse, and Addiction

The use of benzodiazepines, including Valium, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse).

Before prescribing Valium and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Valium, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Valium along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Valium or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Valium).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Neonatal Sedation and Withdrawal Syndrome

Use of Valium late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy). Monitor neonates exposed to Valium during pregnancy or labor for signs of sedation and monitor neonates exposed to Valium during pregnancy for signs of withdrawal; manage these neonates accordingly.

General

If Valium 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 Valium for a prolonged time.

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Drug Interactions

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/m 2basis) 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/m 2basis) 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/m 2basis).

Pregnancy

Nursing Mothers

Diazepam is present in breastmilk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed infants, advise patient that breastfeeding is not recommended during treatment with Valium.

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 have 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).

Postmarketing Experience:

Injury, Poisoning and Procedural Complications:There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcohol), and in the elderly.

Controlled Substance

Valium contains diazepam, a Schedule IV controlled substance.

Abuse

Valium is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Tolerance

Tolerance to Valium may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of Valium may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Discontinuation or Dosage Reduction of Valium

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Valium or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactionsand DRUG ABUSE AND DEPENDENCE: Dependence).

Storage

Store at room temperature 59° to 86°F (15° to 30°C). Dispense in tight, light-resistant containers as defined in USP/NF.