Valium

• RISKS FROM CONCOMITANT USE WITH OPIOIDS;
• ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.
• Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS ).
• The use of benzodiazepines, including VALIUM, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.
• Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes.
• Before prescribing VALIUM and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (see WARNINGS ) .
• The continued use of benzodiazepines, including VALIUM, may lead to clinically significant physical dependence.
• The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose.
• Abrupt discontinuation or rapid dosage reduction of VALIUM after continued use may precipitate acute withdrawal reactions, which can be life-threatening.
• To reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALIUM or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS ) .

• Valium is contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age.
• Valium is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome.
• It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma.

• 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:
• 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:
• 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.
• Acute Withdrawal Reactions The continued use of benzodiazepines, including Valium, may lead to clinically significant physical dependence.
• Abrupt discontinuation or rapid dosage reduction of Valium after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE:
• Dependence ).
• Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE:
• Dependence ).
• Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.
• Since Valium has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during Valium therapy.
• As with other agents that have anticonvulsant activity, when Valium is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication.
• Abrupt withdrawal of Valium in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.
• Pregnancy An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested.
• There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy.
• There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy.
• In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period.
• Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m 2 basis).
• Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis.
• Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce long-term changes in cellular immune responses, brain neurochemistry, and behavior.
• In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.
• The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.
• If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• Patients should also 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.
• Labor and Delivery Special care must be taken when Valium 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 Valium.
• 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
• 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 Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.
• 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 2 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/m 2 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/m 2 basis).
• Pregnancy 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
• 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 ).
• 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
• Some loss of response to the effects of benzodiazepines may develop after repeated use of Valium for a prolonged time.

Category D (see WARNINGS: Pregnancy ).

• Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.
• Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors.
• When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
• Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.
• Centrally Acting Agents If Valium 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 Valium, 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 - 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.

• Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma.
• In mild cases, symptoms include drowsiness, confusion, and lethargy.
• In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (very rarely).
• Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored.
• Management of Overdosage Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure.
• Vomiting should be induced (within 1 hour) if the patient is conscious.
• Gastric lavage should be undertaken with the airway protected if the patient is unconscious.
• Intravenous fluids should be administered.
• If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption.
• Special attention should be paid to respiratory and cardiac function in intensive care.
• General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained.
• Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures.
• Dialysis is of limited value.
• As with the management of intentional overdosage with any drug, it should be considered that multiple agents may have been ingested.
• 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.
• Caution should be observed in the use of flumazenil in epileptic patients treated with benzodiazepines.
• The complete flumazenil package insert, including CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS , should be consulted prior to use.
• Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE ).

• 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 Physical Dependence Valium may produce physical dependence from continued therapy.
• Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
• Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.
• Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses), those who have had longer durations of use (see WARNINGS:
• Dependence and Withdrawal Reactions ).
• To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Valium or reduce the dosage (see DOSAGE and ADMINISTRATION:
• Discontinuation or Dosage Reduction of Valium and WARNINGS:
• Dependence and Withdrawal Reactions ).
• Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor.
• More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.
• Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal.
• Protracted withdrawal symptoms may last weeks to more than 12 months.
• As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.
• 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.
• Valium contains diazepam, a Schedule IV controlled substance.