`
`
`
`
` VALIUM®
`
`brand of
`
` diazepam
` TABLETS
`
`
`Rx Only
`DESCRIPTION
`
`Valium (diazepam) is a benzodiazepine derivative. The chemical name of
`diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin­
`2-one. It is a colorless to light yellow crystalline compound, insoluble in
`
` water. The empirical formula is C16H13ClN2O and the molecular weight is
`284.75. The structural formula is as follows:
`
`
`Valium is available for oral administration as tablets containing 2 mg, 5 mg or
`
` 10 mg diazepam. In addition to the active ingredient diazepam, each tablet
`contains the following inactive ingredients: anhydrous lactose, corn starch,
`pregelatinized starch and calcium stearate with the following dyes: 5-mg
`tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; 10-mg tablets
`contain FD&C Blue No. 1. Valium 2-mg tablets contain no dye.
`
`CLINICAL PHARMACOLOGY
`Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-
`relaxant, anticonvulsant and amnestic effects. Most of these effects are
`thought to result from a facilitation of the action of gamma aminobutyric acid
`(GABA), an inhibitory neurotransmitter in the central nervous system.
`
`Pharmacokinetics
`Absorption
`After oral administration >90% of diazepam is absorbed and the average time
`to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to
`2.5 hours. Absorption is delayed and decreased when administered with a
`moderate fat meal. In the presence of food mean lag times are approximately
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`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 Cmax 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%). 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 - 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
`- 34 weeks gestational age and 8 - 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.
`
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`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 - 104 hours), with
`chronic active hepatitis to 60 hours (range 26 - 76 hours), and with acute viral
`hepatitis to 74 hours (range 49 - 129). In chronic active hepatitis, clearance is
`decreased by almost half.
`
`INDICATIONS
`Valium is indicated for the management of anxiety disorders or for the short-
`term relief of the symptoms of anxiety. Anxiety or tension associated with the
`stress of everyday life usually does not require treatment with an anxiolytic.
`In acute alcohol withdrawal, Valium may be useful in the symptomatic relief
`of acute agitation, tremor, impending or acute delirium tremens and
`hallucinosis.
`
`Valium is a useful adjunct for the relief of skeletal muscle spasm due to reflex
`spasm to local pathology (such as inflammation of the muscles or joints, or
`secondary to trauma), spasticity caused by upper motor neuron disorders (such
`as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome.
`Oral Valium may be used adjunctively in convulsive disorders, although it has
`not proved useful as the sole therapy.
`
`The effectiveness of Valium in long-term use, that is, more than 4 months, has
`not been assessed by systematic clinical studies. The physician should
`periodically reassess the usefulness of the drug for the individual patient.
`
`CONTRAINDICATIONS
`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
`severe hepatic
`myasthenia gravis,
`severe
`respiratory
`insufficiency,
`
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`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.
`
`WARNINGS
`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/m2 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
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`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
`
`recommended in patients receiving Valium.
`
`is
`
`therefore not
`
`PRECAUTIONS
`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,
`
`(see Drug
`barbiturates, MAO
`inhibitors and other antidepressants
`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
`(see DRUG ABUSE AND
`history of alcohol or drug abuse
`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).
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`Some loss of response to the effects of benzodiazepines may develop after
`
` repeated use of Valium for a prolonged time.
`
`Information for Patients
`To assure the safe and effective use of benzodiazepines, patients should be
`
` informed that, since benzodiazepines may produce psychological and physical
`dependence, it is advisable that they consult with their physician before either
`increasing the dose or abruptly discontinuing this drug. The risk of
`
` dependence increases with duration of treatment; it is also greater in patients
`with a history of alcohol or drug abuse.
`Patients should be advised against the simultaneous ingestion of alcohol and
`other CNS-depressant drugs during Valium therapy. As is true of most CNS-
`
` acting drugs, patients receiving Valium should be cautioned against engaging
` in hazardous occupations requiring complete mental alertness, such as
`
`operating machinery or driving a motor vehicle.
`
`Drug Interactions
`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
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`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/m2
`
`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/m2 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/m2 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 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).
` its major metabolite,
`and
`Extensive
`accumulation of diazepam
`
`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 has been reported in patients with cirrhosis. In such
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`patients, a 2- to 5- fold increase in mean half-life has been reported. Delayed
`
`reported
`active metabolite
`elimination has
`also been
`for
`the
`desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic
`
`encephalopathy. Increases in half-life have also been reported in hepatic
`in both acute and chronic hepatitis (see CLINICAL
`fibrosis and
`PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic
`Insufficiency).
`
`ADVERSE REACTIONS
`Side effects most commonly reported were drowsiness, fatigue, muscle
`weakness, and ataxia. The following have also been reported:
`Central Nervous System: confusion, depression, dysarthria, headache, slurred
`speech, tremor, vertigo
`Gastrointestinal System: constipation, nausea, gastrointestinal disturbances
`
`Special Senses: blurred vision, diplopia, dizziness
`Cardiovascular System: hypotension
`Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute
`hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage,
`hallucinations, psychoses, delusions, increased muscle spasticity, insomnia,
`sleep disturbances, and nightmares. Inappropriate behavior and other adverse
`
`behavioral effects have been reported when using benzodiazepines. Should
`
`
`these occur, use of the drug should be discontinued. They are more likely to
`occur in children and in the elderly.
`Urogenital System: incontinence, changes in libido, urinary retention
`Skin and Appendages: skin 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 Valium 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.
`
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`DRUG ABUSE AND DEPENDENCE
`Diazepam is subject to Schedule IV control under the Controlled Substances
`
` Act of 1970. Abuse and dependence of benzodiazepines have been reported.
`
` Addiction-prone individuals (such as drug addicts or alcoholics) should be
`under careful surveillance when receiving diazepam or other psychotropic
`agents because of the predisposition of such patients to habituation and
`
` dependence. Once physical dependence to benzodiazepines has developed,
`termination of treatment will be accompanied by withdrawal symptoms. The
`risk is more pronounced in patients on long-term therapy.
` Withdrawal symptoms, similar in character to those noted with barbiturates
`
`and alcohol have occurred following abrupt discontinuance of diazepam.
`These withdrawal symptoms may consist of tremor, abdominal and muscle
`cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension,
`restlessness, confusion and irritability. In severe cases, the following
`symptoms may occur: derealization, depersonalization, hyperacusis,
`numbness and tingling of the extremities, hypersensitivity to light, noise and
`physical contact, hallucinations or epileptic seizures. The more severe
`withdrawal symptoms have usually been limited to those patients who had
`
`received excessive doses over an extended period of time. Generally milder
`withdrawal symptoms (e.g., dysphoria and insomnia) have been reported
`following abrupt discontinuance of benzodiazepines taken continuously at
`therapeutic levels for several months. Consequently, after extended therapy,
`abrupt discontinuation should generally be avoided and a gradual dosage
`tapering schedule followed.
`
`Chronic use (even at therapeutic doses) may lead to the development of
`physical dependence: discontinuation of the therapy may result in withdrawal
`or rebound phenomena.
`Rebound Anxiety: A transient syndrome whereby the symptoms that led to
`treatment with Valium recur in an enhanced form. This may occur upon
`
`discontinuation of treatment. It may be accompanied by other reactions
`including mood changes, anxiety, and restlessness.
`Since the risk of withdrawal phenomena and rebound phenomena is greater
`after abrupt discontinuation of treatment, it is recommended that the dosage be
`decreased gradually.
`
`OVERDOSAGE
`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.
`
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`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
`including CONTRAINDICATIONS,
`flumazenil
`package
`insert,
`WARNINGS, and PRECAUTIONS, should be consulted prior to use.
`Withdrawal symptoms of the barbiturate type have occurred after the
`(see DRUG ABUSE AND
`discontinuation
`of
`benzodiazepines
`DEPENDENCE).
`
`DOSAGE AND ADMINISTRATION
`Dosage should be individualized for maximum beneficial effect. While the
`usual daily dosages given below will meet the needs of most patients, there
`
`will be some who may require higher doses. In such cases dosage should be
`increased cautiously to avoid adverse effects.
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` USUAL DAILY DOSE:
` ADULTS:
`
`
`Management of Anxiety Disorders and Relief Depending upon severity of symptoms—2 mg
`
` of Symptoms of Anxiety.
`to 10 mg, 2 to 4 times daily
`Symptomatic Relief
`in Acute Alcohol 10 mg, 3 or 4 times during the first 24 hours,
`Withdrawal.
`reducing to 5 mg, 3 or 4 times daily as needed
`
`Adjunctively for Relief of Skeletal Muscle 2 mg to 10 mg, 3 or 4 times daily
`Spasm.
`
`Adjunctively in Convulsive Disorders.
`2 mg to 10 mg, 2 to 4 times daily
`
`Geriatric Patients, or in the presence of 2 mg to 2.5 mg, 1 or 2 times daily initially;
`
`debilitating disease.
`increase gradually as needed and tolerated
`
`PEDIATRIC PATIENTS:
`
`
`Because of varied responses to CNS-acting 1 mg to 2.5 mg, 3 or 4 times daily initially;
`
`drugs, initiate therapy with lowest dose and
`increase gradually as needed and tolerated
`
`increase as required. Not for use in pediatric
`
`
`patients under 6 months.
`
`
`HOW SUPPLIED
`For oral administration, Valium is supplied as round, flat-faced scored tablets
`with V-shaped perforation and beveled edges. Valium is available as follows:
`2 mg, white - bottles of 100 (NDC 0140-0004-01); 5 mg, yellow - bottles of
`
`100 (NDC 0140-0005-01) and 500 (NDC 0140-0005-14); 10 mg, blue -
`bottles of 100 (NDC 0140-0006-01) and 500 (NDC 0140-0006-14).
`
`Engraved on tablets:
`2 mg—2 VALIUM® (front)
`ROCHE (twice on scored side)
`
`5 mg—5 VALIUM® (front)
`ROCHE (twice on scored side)
`
`10 mg—10 VALIUM® (front)
`ROCHE (twice on scored side)
`
`
`
`
`
`
`
`STORAGE
`
`Store at room temperature 59º to 86ºF (15º to 30ºC). Dispense in tight, light-
`resistant containers as defined in USP/NF.
`
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`Distributed by:
`
`
`
`
`for Roche Products Inc.
`27899464
`Revised: January 2008
`Printed in USA
`Copyright © 1987-2008 by Roche Products Inc. All rights reserved.
`
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