mines, 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. 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).

reassess the usefulness of the drug for the individual patient.

ribe 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, 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 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 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 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 ). 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 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. neonatal sedation and withdrawal syndrome use of diazepam 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 diazepam during pregnancy or labor for signs of sedation and monitor neonates exposed to diazepam during pregnancy for signs of withdrawal; manage these infants accordingly.

rapy 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 to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam 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 ). proper use of diazepam oral solution (concentrate) diazepam oral solution (concentrate) is a concentrated oral solution as compared to standard oral liquid medications. it is recommended that diazepam oral solution (concentrate) be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings. use only with a calibrated dropper. draw into the dropper the amount prescribed for a single dose. then squeeze the dropper contents into a liquid or semi-solid food. stir the liquid or food gently for a few seconds. the diazepam oral solution (concentrate) formulation blends quickly and completely. the entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. do not store for future use.

eactions 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.

mines, 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. 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).

ommended 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. the background risk of major birth defects and miscarriage for the indicated population is 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 fetal/neonatal adverse reactions benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. monitor neonates exposed to diazepam during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems monitor neonates exposed to diazepam during pregnancy for signs of withdrawal. manage these neonates accordingly (see warnings : neonatal sedation and withdrawal syndrome ). labor or 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). 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, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. animal data diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 20 times the maximum recommended adult dose [0.4 mg/kg/day] or greater on a mg/m2 basis). cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis. 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 plasma concentrations relevant for seizure control in humans. 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.

ed with food. distribution: 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 1.0 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 hours). in chronic active hepatitis, clearance is decreased by almost half.

addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see warnings : abuse, misuse, and addiction and drug abuse and dependence ). withdrawal reactions inform patients that the continued use of diazepam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of diazepam may precipitate acute withdrawal reactions, which can be life-threatening. inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. instruct patients that discontinuation or dosage reduction of diazepam may require a slow taper (see warnings : dependence and withdrawal reactions and drug abuse and dependence ). 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. pregnancy advise pregnant females that use of diazepam 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 newborns (see warnings : neonatal sedation and withdrawal syndrome and precautions : pregnancy ). instruct patients to inform their healthcare provider if they are pregnant. advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to diazepam during pregnancy (see precautions , pregnancy ). nursing advise patients that breastfeeding is not recommended during treatment with diazepam (see precautions : nursing mothers ).