Valium - Waylis Therapeutics LLC | Patheon, Inc.

Table 1 provides the recommended oral dosage of VALIUM by indication for adults less than 65 years of age.

Pediatric Patients 6 Months of Age and Older

The recommended starting dosage in pediatric patients 6 months of age and older is 1 mg to 2.5 mg orally, three or four times daily. Increase the dosage gradually as needed and tolerated [see Use in Specific Populations (8.4)].

Geriatric or Debilitated Patients

The recommended starting dosage in geriatric patients 65 years of age and older or debilitated patients is 2 mg to 2.5 mg orally, once or twice daily. Increase the dosage gradually as needed and tolerated [see Use in Specific Populations (8.5, 8.8)].

Patients with Hepatic Impairment

In patients with mild or moderate hepatic impairment, reduce the recommended dosage by half compared to those with normal hepatic function [see Dosage and Administration (2.1)]. VALIUM is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

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 and Precautions (5.3), Drug Abuse and Dependence (9.3)].

Concomitant use of benzodiazepines, including VALIUM, and opioids may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions (7.1)]. 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.

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 (9.2)].

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.

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 (2.3)].

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 (9.3)].

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 (9.3)].

Benzodiazepines, including VALIUM, may produce central nervous system (CNS) depression. Caution patients receiving VALIUM against engaging in hazardous occupations or activities requiring complete mental alertness (e.g., operating machinery or driving a motor vehicle). Alcohol should be avoided and medications that produce CNS depression should be used with caution during treatment with VALIUM [Drug Interactions (7.2)].

Antiepileptic drugs (AEDs), including VALIUM, 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 2 shows absolute and relative risk by indication for all evaluated AEDs.

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 VALIUM or any other AED must balance the risk of suicidal thoughts or behaviors 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.

Benzodiazepines, including VALIUM, may worsen preexisting depression [see Warnings and Precautions (5.5)]. Monitor patients for worsening of preexisting depression. Appropriate precautions (e.g., limiting the total prescription size) should be considered.

Paradoxical reactions, such as aggression, agitation, anger, irritability, psychoses, hallucinations, anxiety, nightmares, and increased muscle spasticity have been reported during benzodiazepine use [see Adverse Reactions (6)]. These reactions are more likely to occur in pediatric and geriatric patients. Gradually discontinue VALIUM if paradoxical reactions occur [see Dosage and Administration (2.3)].

Use of benzodiazepines, including VALIUM, either alone or in combination with other CNS depressants, may lead to potentially fatal respiratory depression [see Warnings and Precautions (5.4)]. In patients with impaired respiratory function treated with benzodiazepines, respiratory depression and apnea have been reported.

Use VALIUM with caution in patients with impaired respiratory function related to a concurrent disease process [see Use in Specific Populations (8.7)]. If signs and symptoms of respiratory depression or apnea occur in any patient, consider discontinuing VALIUM.

Benzodiazepines, including VALIUM, can increase intraocular pressure in patients with glaucoma. VALIUM may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALIUM is contraindicated in patients with acute narrow-angle glaucoma.

Maternal 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. Monitor neonates exposed to diazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to diazepam during pregnancy for signs of withdrawal; manage these neonates accordingly [see Use in Specific Populations (8.1)].

Limit dosage and duration of concomitant use of VALIUM and opioids and monitor patients closely for respiratory depression and sedation.

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 gamma-aminobutyric acid (GABAA) 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 [see Warnings and Precautions (5.1)].

Avoid consumption of alcohol and use caution during concomitant use of other medications that produce CNS depression with VALIUM.

VALIUM produces additive CNS depressant effects, which can include potentially fatal respiratory depression, when used concomitantly with other medications that produce CNS depression, or with consumption of alcohol [see Warnings and Precautions (5.4, 5.8)].

Table 3 describes drug interactions where concomitant use of another drug affects VALIUM.

Pregnancy Exposure Registries

There are pregnancy exposure registries that monitor pregnancy outcomes in women exposed to psychiatric medications and antiepileptic drugs (AEDs), including VALIUM, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the appropriate registry below:

• The National Pregnancy Registry for Psychiatric Medications by calling 1-866-961-2388 or visiting online at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications.
• The North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at www.aedpregnancyregistry.org.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.10) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not support a clear association with benzodiazepines and major birth defects (see Data). There are risks to the mother and fetus associated with untreated epilepsy during pregnancy (see Clinical Considerations).

In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Data).

The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryofetal Risk

Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Females with epilepsy should not discontinue diazepam abruptly due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.3)].

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to VALIUM during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to VALIUM during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.10)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, recent case-control and cohort studies of benzodiazepine use during pregnancy were adjusted for confounding exposures to alcohol, tobacco and other medications; these studies did not support an association with benzodiazepines and major birth defects.

Animal Data

Diazepam has been shown to cause malformations when administered orally to pregnant mice and hamsters during the period of organogenesis at doses of 100 mg/kg/day or greater, approximately 12 and 20 times the maximum recommended human dose (MRHD) based on mg/m² body surface area, respectively. Cleft palate and encephalopathy were the most common and consistently reported malformations produced at maternally toxic doses of diazepam. 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 published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic inhibition to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at clinically relevant plasma concentrations. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans.

Risk Summary

Diazepam and its active metabolite, N-methyldiazepam, are present in breastmilk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk (see Clinical Considerations ). There are no data on the effects of diazepam and/or its active metabolite on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VALIUM and any potential adverse effects on the breastfed infant from VALIUM or from the underlying maternal condition.

Clinical Considerations

Infants exposed to VALIUM through breastmilk should be monitored for sedation, poor feeding, and poor weight gain.

VALIUM is indicated for use in pediatric patients for the:

• Treatment of anxiety disorders
• Short-term treatment of anxiety symptoms
• Treatment of tremor, acute agitation, hallucinosis, and impending delirium tremens or delirium tremens in acute alcohol withdrawal
• Adjunctive treatment of skeletal muscle spasm due to:
  • reflex spasm to local pathology
  • spasticity caused by upper motor neuron disorders
  • athetosis
  • stiff-person syndrome
• Adjunctive treatment of seizure disorders

Paradoxical reactions are more likely to occur in pediatric patients than in adult patients [see Warnings and Precautions (5.7)].

VALIUM is not recommended for use in pediatric patients less than 6 months of age.

Prolonged central nervous system depression has been observed in neonates treated with diazepam.

Extensive accumulation of diazepam and its major metabolite, des-methyldiazepam, has been noted following chronic administration of diazepam in healthy geriatric male subjects [see Clinical Pharmacology (12.3)]. Metabolites of VALIUM are substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function than in patients with normal renal function.

Because geriatric patients are more likely to have decreased renal function, care should be taken in dosage selection. A lower starting dosage is recommended, and the dosage should be increased gradually as needed and tolerated, to reduce the risk of adverse reactions [see Dosage and Administration (2.2)].

Paradoxical reactions are more likely to occur in geriatric patients compared to younger adult patients [see Warning and Precautions (5.7)

Patients with hepatic impairment are more sensitive to adverse reactions associated with VALIUM, including increased susceptibility to sedation and delirium [Clinical Pharmacology (12.3)].

The recommended dosage of VALIUM in patients with mild or moderate hepatic impairment is half the recommended dosage as those with normal hepatic function [see Dosage and Administration (2.2)]. Valium is not recommended in patients with severe hepatic impairment.

In patients with impaired respiratory function, respiratory depression and apnea have been reported with use of benzodiazepines. Use VALIUM with caution in patients with impaired respiratory function related to a concurrent disease process. If signs and symptoms of respiratory depression or apnea occur, consider discontinuing VALIUM [Warnings and Precautions (5.8)].

Debilitated patients are at an increased risk of adverse reactions to VALIUM. A lower starting dosage is recommended, and the dosage should be increased gradually as needed and tolerated, to reduce the risks of adverse reactions [see Dosage and Administration (2.2)].

VALIUM contains diazepam, a Schedule IV controlled substance.

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 and Precautions (5.2)].

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).

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) and those who have had longer durations of use [see Warnings and Precautions (5.3)].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALIUM or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

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.

The mechanism of action of diazepam for the listed indications [see Indications and Usage (1)] is thought to involve potentiation of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter, resulting from binding at the benzodiazepine site of the GABA_A receptor.

The effects of diazepam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Diazepam-induced psychomotor impairment in women on contraceptives may be higher during the 7-day menstrual pause when off the hormone preparation than when taking the contraceptive. There is some limited evidence that benzodiazepines can increase the incidence of break-through bleeding in women with hormonal contraceptives.

Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 to 1.5 hours with a range of 0.25 to 2.5 hours.

Following daily dosing, diazepam levels reach a steady state within approximately 5 days and desmethyl diazepam levels reach a steady state within approximately 10 days. Average steady-state levels of diazepam after once daily administration are approximately twice as high as the peak levels of the drug after the first dose.

Effect of Food

Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food, mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in C_max of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.

Distribution

Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). The volume of distribution at steady-state is 0.8 to 1.0 L/kg. Diazepam and its metabolites cross the blood-brain and placental barriers. The decline in the plasma concentration-time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.

Both protein binding and volume of distribution of desmethyl-diazepam are similar to those of diazepam.

Elimination

Metabolism

Oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Diazepam is mainly metabolized to pharmacologically active metabolites such as desmethyl-diazepam, a pathway accounting for 50 to 60% of total diazepam clearance; 3-hydroxylation (27% of total diazepam clearance) is slow, leading to only low plasma levels of the oxidation products temazepam and oxazepam. Temazepam and oxazepam are further conjugated to glucuronides. After multiple doses of diazepam, plasma concentration ratios of desmethyl-diazepam to diazepam were 1.1 ± 0.2, temazepam to diazepam 0.11 ± 0.05, and oxazepam to diazepam 0.09 ± 0.03.

Diazepam has an initial rapid and extensive distribution phase being followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours.

Excretion

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged.

Specific Populations

Geriatric Patients

Age decreases the capacity of the liver for N-demethylation and 3-hydroxylation of diazepam. Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. Consequently, geriatric patients may have lower peak concentrations, and on multiple dosing higher trough concentrations. It will also take longer to reach steady-state [see Dosage and Administration (2.2), Use in Specific Populations (8.5)]. Conflicting information has been published on changes of plasma protein binding in geriatric patients.

Pediatric Patients

In pediatric patients 3 to 8 years of age the mean half-life of diazepam has been reported to be 18 hours [see Dosage and Administration (2.2)].

Patients with Renal Impairment

In chronic renal failure, elimination of diazepam, as indicated by clearance of unbound drug, was similar to that in healthy volunteers; thus steady-state concentrations of unbound diazepam at any given daily dose on the average should not be different between patients with renal impairment and healthy individuals.

Patients with Hepatic Impairment

In mild and moderate cirrhosis, average half-life is increased. The average increase has been variously reported from 2-fold to 5-fold, with individual half-lives over 500 hours reported. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours (range 66 to 104 hours), with chronic active hepatitis to 60 hours (range 26 to76 hours), and with acute viral hepatitis to 74 hours (range 49 to129). In chronic active hepatitis, clearance is decreased by almost half [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].

Drug Interaction Studies

The metabolism of diazepam and its main metabolite, desmethyl-diazepam depends on the cytochrome P450 isozymes CYP3A4 and CYP2C19. Modulators of these enzymes may lead to changes in diazepam disposition and effects. Inhibitors of CYP3A4 and CYP2C19 decrease metabolic rate and may lead to higher concentrations of diazepam and the desmethyl metabolite. Inducers of CYP3A4 and CYP2C19 may lead to lower concentrations of diazepam and the desmethly metabolite [see Drug Interactions (7.3)].

Effect of Other Drugs on the Pharmacokinetics of Diazepam

Enzyme Inhibitors

Grapefruit juice contains strong inhibitors of CYP3A4. Diazepam exposure was increased and time to reach maximum concentration was delayed when diazepam was given with grapefruit juice instead of water [see Drug Interactions (7.3)].

Antimycotic azole derivatives inhibit CYP3A4 and CYP2C19 pathways and lead to increased exposure to diazepam and prolonged elimination half-life of diazepam [see Drug Interactions (7.3)].

The serotonin reuptake inhibitor fluvoxamine is also an inhibitor of both of diazepam's degradation pathways and increased not only exposure to diazepam and prolonged its elimination half-life but also increased exposure and time to reach steady-state of the desmethyl metabolite. Fluoxetine showed a more moderate effect on diazepam AUC [see Drug Interactions (7.3)].

Combined hormonal contraceptives appear to reduce the clearance and prolong elimination half-life of diazepam.

Proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, pantoprazole may increase the diazepam AUC.

The histamine H₂-receptor antagonist cimetidine, an inhibitor of multiple CYP isozymes, including CYP3A4 and CYP2C19, reduces the clearance of diazepam and of desmethyl-diazepam and results in higher exposure and a prolonged elimination half-life of diazepam and its main metabolite [see Drug Interactions (7.3)]. No such pharmacokinetic interaction was seen with the H₂-receptor antagonists ranitidine and famotidine.

Disulfiram inhibits the metabolism of diazepam and likely the further metabolism of diazepam's active metabolites.

Antituberculosis therapy may change the disposition of diazepam. In the presence of isoniazid, diazepam mean exposure (AUC) and half-life were increased.

The calcium channel blocker diltiazem, a substrate for the same CYP isozymes as diazepam and an inhibitor of CYP3A4, increased AUC and prolonged half-life of diazepam [see Drug Interactions (7.3)].

The primary metabolite of idelalisib is a strong CYP3A4 inhibitor and increases the serum concentrations of diazepam [see Drug Interactions (7.3)].

The psychostimulants modafinil and armodafinil induce CYP3A4 and inhibit CYP2C19; they may prolong the elimination of diazepam [see Drug Interactions (7.3)].

Enzyme Inducers

Rifampicin and carbamazepine, potent inducers of CYP3A4, may lead to a reduction in exposure of diazepam [see Drug Interactions (7.3)].

Antacids

Antacids may lower the diazepam peak but have no effect on the extent of absorption of diazepam. Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The time to reach peak concentrations are 20-25 min longer for diazepam in presence of antacids.

Effect of Diazepam on the Pharmacokinetics of Other Drugs

Diazepam has not been found to induce or inhibit metabolizing enzymes.

Diazepam is a substrate for CYP2C19 and CYP3A4; therefore, VALIUM may interfere with the metabolism and increase the exposure of drugs which are sensitive substrates for CYP2C19 and CYP3A4.13

Carcinogenesis

An increased incidence of liver tumors was observed in male mice and rats that were administered diazepam in the diet for 80 and 104 weeks, respectively at a dose of 75 mg/kg/day, approximately 9 and 18 times the maximum recommended human dose (MRHD) based on mg/m² body surface area, respectively.

Mutagenesis

The data currently available are inadequate to determine the mutagenic potential of diazepam.

Impairment of Fertility

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 24 times the MRHD based on mg/m² body surface area) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted up to a dose of 80 mg/kg/day (approximately 19 times the MRHD based on mg/m² body surface area).

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers as defined in USP/NF.