sician should periodically reassess the usefulness of the drug for the individual patient.

diazepam, 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 diazepam 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 diazepam tablets, 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 diazepam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). use of diazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of diazepam tablets 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 diazepam tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see dosage and administration: discontinuation or dosage reduction of diazepam tablets ). 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 diazepam, may lead to clinically significant physical dependence. abrupt discontinuation or rapid dosage reduction of diazepam tablets 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 ). diazepam is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. since diazepam has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other cns-depressant drugs during diazepam therapy. as with other agents that have anticonvulsant activity, when diazepam 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 diazepam 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 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 tablets.

apy with lowest dose and increase as required. not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated discontinuation or dosage reduction of diazepam tablets to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam tablets 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 reactions and drug abuse and dependence: dependence ).

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. 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. to report suspected adverse events, contact fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

stribution diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). in young healthy males, the volume of distribution at steady-state is 0.8 to 1 l/kg. 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. metabolism diazepam is n-demethylated by cyp3a4 and 2c19 to the active metabolite n-desmethyldiazepam, and is hydroxylated by cyp3a4 to the active metabolite temazepam. n-desmethyldiazepam and temazepam are both further metabolized to oxazepam. temazepam and oxazepam are largely eliminated by glucuronidation. elimination the initial distribution phase is 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. 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. pharmacokinetics in special populations children in children 3 to 8 years old the mean half-life of diazepam has been reported to be 18 hours. newborns in full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 to 34 weeks gestational age and 8 to 81 days post-partum. in both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. longer half-lives in infants may be due to incomplete maturation of metabolic pathways. geriatric 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, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. it will also take longer to reach steady-state. conflicting information has been published on changes of plasma protein binding in the elderly. reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simply aging. hepatic insufficiency 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 to 76 hours), and with acute viral hepatitis to 74 hours (range 49 to 129). in chronic active hepatitis, clearance is decreased by almost half.