VALIUM (diazepam) is an anxiolytic-sedative drug useful in the symptomatic relief of anxiety and tension states. It has also adjunctive value in the relief of certain neurospastic conditions.

: Diazepam is rapidly and completely absorbed from the gastrointestinal tract, peak plasma concentrations appearing 30-90 minutes after oral ingestion.

: Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). The volume of distribution at steady state is 0.8-1.0 L/kg. In humans, comparable blood levels of VALIUM were obtained in maternal and cord blood indicating placental transfer of the drug.

: 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. Oxazepam and temazepam are further conjugated to glucuronic acid.

: The acute half-life is six to eight hours with a slower decline thereafter (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 in their conjugated forms. The clearance of diazepam is 20-30 mL/min.

: The elimination half-life may be prolonged in the newborn, in the elderly and in patients with liver disease. In renal failure the half-life of diazepam is unchanged.

INDICATIONS

Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress. VALIUM (diazepam) is useful in the symptomatic management of mild to moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear or aggressiveness, such as may occur in: psychoneurosis, anxiety reactions due to stress conditions and anxiety states with somatic expression. In acute alcoholic withdrawal, VALIUM may be useful in the symptomatic relief of acute agitation, tremor and impending acute delirium tremens. VALIUM is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology, such as inflammation of the muscle and joints or secondary to trauma; spasticity caused by upper motor neuron disorders, such as cerebral palsy and paraplegia; athetosis and the rare "stiff man syndrome".

Geriatrics (> 65 years of age)

Evidence from clinical studies and experience indicates that elderly patients are especially susceptible to dose-related adverse events. For a brief description see PRECAUTIONS, Use in Elderly and DOSAGE AND ADMINISTRATION, Elderly.

Pediatrics (< 18 years of age)

VALIUM is contraindicated in children under 6 months (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION, Children).

CONTRAINDICATIONS

WARNINGS

Benzodiazepines are not recommended for the primary treatment of psychotic illness. Benzodiazepines should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.

The concomitant use of VALIUM with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of VALIUM possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see DRUG INTERACTIONS). Patients should be advised against the concurrent use of alcohol and other CNS depressant drugs.

VALIUM should be used with extreme caution in patients with a history of alcohol or drug abuse. VALIUM (diazepam) should be avoided in patients with dependence on CNS depressants including alcohol. An exception to the latter is the management of acute withdrawal reactions. Benzodiazepines have produced habituation, dependence and withdrawal symptoms similar to those noted with barbiturates and alcohol. The risk of dependence increases with dose and duration, and is greater in patients with a medical history of alcohol and drug abuse (see PRECAUTIONS-Dependence Liability, Withdrawal).

Since diazepam has a central nervous system depressant effect, patients should be warned against driving, operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and physical coordination. Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or operate machinery. This effect is increased if the patient has had alcohol. Driving, operating machinery and other hazardous activities should be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient's physician and should be based on the patient's response to treatment and the dosage involved. They also should be warned against the concomitant use of alcohol and other CNS depressant drugs.

Respiratory depression may occur following administration of VALIUM. This effect may be aggravated by pre-existing airway obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this can be avoided by careful adjustment of the dose to individual requirements. VALIUM should be used with caution in patients with chronic respiratory diseases and a lower dose is recommended due to the risk of respiratory depression.

PRECAUTIONS

General: Lactose is a non-medicinal ingredient in VALIUM. Therefore, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine. Patients receiving VALIUM should be advised to proceed cautiously wherever mental alertness and physical coordination are required (see WARNINGS Driving and Hazardous Activities).

: Some loss of response to the effects of benzodiazepines may develop after repeated use of VALIUM (diazepam) for prolonged time.

: Use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence (see ADVERSE REACTIONS). This risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.

: Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. Withdrawal symptoms may develop after a lengthy period of use at therapeutic doses. The possibility that such effects may also occur following short-term use, especially at high doses, or if the daily dose is reduced rapidly or abruptly discontinued should be considered. Symptoms of withdrawal may consist of 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. Since these symptoms are similar to those for which the patient is being treated, it may appear that he/she has suffered a relapse upon discontinuation of the drug.

: Rebound anxiety is a transient syndrome whereby the symptoms that led to treatment with VALIUM recur in an enhanced form. This may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness.

Since the risks of withdrawal symptoms and rebound anxiety are greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose.

Amnesia: It should be borne in mind that benzodiazepines may induce anterograde amnesia. Anterograde amnesia may occur using therapeutic dosages of benzodiazepines, the risk increasing at higher dosages. Effects of anterograde amnesia may be associated with inappropriate behaviour.

Mental and Emotional Disorders: It should be recognized that suicidal tendencies may be present in patients with emotional disorders and that protective measures and appropriate treatment may be necessary and should be instituted without delay. As with other benzodiazepines, diazepam should not be used in individuals with physiological anxiety or normal stresses of daily living, but only in the presence of disabling manifestations of an appropriate pathological anxiety disorder. These drugs are not effective in patients with characterological and personality disorders or those with obsessive-compulsive disorders. Diazepam is also not recommended for management of depressive or psychotic disorders. Benzodiazepines should not be used to treat anxiety associated with depression, as suicide may be precipitated in these patients.

Psychiatric and >paradoxical= reactions: Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines, and are more likely to occur in children and the elderly. Should this occur, the use of the drug should be discontinued. Since excitement and other paradoxical reactions can result from the use of anxiolytic sedatives in psychotic patients, diazepam should not be used in ambulatory patients suspected of having psychotic tendencies.

: The safety of diazepam for use in pregnancy has not been established. An increased risk of congenital malformation (e.g., congenital malformations of the heart, cleft lip and/or palate) associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested. VALIUM should not be used during pregnancy except if absolutely necessary.

Continuous administration of benzodiazepines during pregnancy may give rise to hypotension, reduced respiratory function and hypothermia in the newborn child. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence. Withdrawal symptoms in newborn infants have occasionally been reported with this class of drug. Special care must be taken when VALIUM is used during labour 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 neonate. 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). If the drug is prescribed to a woman of childbearing potential, she should be warned to consult her physician regarding discontinuation of the drug if she plans to become or suspects that she is pregnant.

Use by Nursing Mothers: Diazepam passes into breast milk. Breast-feeding is therefore not recommended in patients receiving VALIUM.

Use in pediatric patients: Not recommended for use in children under six months. (See Contraindications)

: Elderly and debilitated patients or those with organic brain disorders have been found to be prone to central nervous system depression following even low doses. For these patients it is recommended that the dosage be limited to the smallest, effective amount with incremental increases made gradually depending on the response, to preclude development of ataxia, over sedation or other possible adverse effects (See DOSAGE AND ADMINISTRATION).

: Careful consideration should be given if VALIUM is to be used in patients with epilepsy as the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the doses of standard anticonvulsant medication. An abrupt withdrawal of VALIUM in such cases may also be associated with the temporary increase in the frequency and/or severity of seizures.

Impaired Hepatic or Renal Function: In patients with impaired hepatic or renal function, it is recommended to initiate therapy, if necessary, at a very low dose and to increase the dosage only to the extent that such an increase is compatible with the degree of residual function of these organs. If VALIUM is administered for protracted periods, such patients should be monitored closely and have periodic blood counts and liver function tests.

Pharmacokinetic Drug-Drug Interaction (DDI)

The oxidative metabolism of diazepam, leading to the formation of the active metabolites N-desmethyldiazepam, 3-hydroxydiazepam (temazepam) and oxazepam, is mediated by CYP2C19 and CYP3A cytochrome P450 isoenzymes. As shown by in vitro study, the hydroxylation reaction is carried out mainly by CYP3A isoform whereas the demethylation is mediated by both CYP3A and CYP2C19. Results from in vivo studies in human volunteers have confirmed the in vitro observations. In consequence substrates, which are modulators of CYP3A and or of CYP2C19, may potentially alter the pharmacokinetics of diazepam. Drugs like ritonavir, cimetidine, ketoconazole, itraconazole, clarithromycin, verapamil, erythromycin, diltiazem, fluvoxamine, fluoxetine, and omeprazole which are CYP3A or CYP2C19 inhibitors may lead to increased and prolonged sedation. There have also been reports that the metabolic elimination of phenytoin is affected by diazepam. Cisapride may lead to a temporary increase in the sedative effects of orally administered benzodiazepines due to faster absorption.

Pharmacodynamic Drug-Drug Interaction (DDI)

Enhanced effects on sedation, respiration, and hemodynamics may occur when VALIUM is co-administered with any centrally acting depressants including alcohol, antipsychotics (phenothiazine, thioxanthene and butyrophenone classes), anxiolytics/sedatives, hypnotics, antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants), anticonvulsants, muscle relaxants, narcotic analgesics, anesthetics and sedative antihistamines. Therefore, if diazepam is to be combined with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agent involved because of the possible additive or potentiation of drug effects. In the case of narcotic analgesics enhancement of euphoria may also occur, leading to an increase in psychological dependence. Patients receiving VALIUM should be advised to avoid alcohol and other central nervous system depressants (see WARNINGS, Concomitant use of alcohol / CNS depressants, and OVERDOSAGE sections).

Drug-Food Interactions

Grapefruit juice decreases the activity of CYP3A4, which is implicated in the metabolism of diazepam, and may contribute to increased plasma levels of the drug.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most common adverse reactions reported for VALIUM (diazepam) are fatigue, drowsiness, muscle weakness and ataxia; they are usually dose-related. These adverse events occur predominantly at the start of therapy and usually disappear with prolonged administration. The more serious adverse reactions occasionally reported are leucopenia, jaundice and hypersensitivity. Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are recommended during long term therapy. Allergic reactions and a very few cases of anaphylaxis have been reported to occur with benzodiazepines. An increased risk for falls and fractures has been reported in elderly benzodiazepine users. Anterograde amnesia may occur using therapeutic dosages of benzodiazepines, the risk increasing at higher dosages. Effects of anterograde amnesia may be associated with inappropriate behaviour.

Psychiatric and >paradoxical= reactions: Release of hostility and other paradoxical effects such as irritability, excitability, restlessness, agitation, aggression, delusion, anger, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur with the use of benzodiazepines. Should this occur, the drug should be discontinued. These effects are more likely to occur in children and in the elderly (See PRECAUTIONS-Psychiatric and paradoxical reactions). Minor changes in EEG patterns have been observed in patients on VALIUM therapy. These changes consist of low to moderate voltage fast activity, 20 to 30 cycles per second and are of no known significance. 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 (See WARNINGS-General; PRECAUTIONS-Dependence Liability). Abuse of benzodiazepines has been reported (See WARNINGS-General).

Post-Market Adverse Drug Reactions

Other adverse events, listed by body systems, include the following:

Cardiovascular System:

Hypotension, circulatory depression, irregular heart rate, cardiac failure including cardiac arrest.

Digestive System:

Dry mouth, nausea, gastrointestinal disturbances, constipation and hypersalivation, jaundice.

Metabolic and Nutritional Disorders:

increased transaminases, increased blood alkaline phosphatase

Nervous System:

Ataxia, tremor, vertigo, dizziness, headache, slurred speech, dysarthria, confusion, emotional poverty, alertness decreased, depression, libido increased or decreased, euphoria, hypoactivity and memory impairment.

Respiratory SystemSkin and Appendages: Special Senses:

: Respiratory depression including respiratory failure

Skin rash, generalized exfoliative dermatitis.

Diplopia, vision blurred

Urogenital System:

Incontinence, urinary retention.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

The main symptoms of benzodiazepine overdosage are drowsiness, over sedation, dysarthria, nystagmus, and ataxia. When the effects of the drug overdosage begin to wear off, the patient exhibits some jitteriness and overstimulation. Overdose of VALIUM is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. There are minimum effects on respiration, pulse and blood pressure unless the overdosage is extreme. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

In managing overdosage, consider the possibility of multiple drug involvement. Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure. Induction of vomiting is not generally recommended. If CNS depression is severe consider the use of flumazenil (ANEXATE(r)), a benzodiazepine receptor antagonist. The following should be kept in mind when flumazenil is used in the treatment of benzodiazepine overdosage: Flumazenil should only be administered under closely monitored conditions. In view of the short half life (about 1 hour) and duration of action of flumazenil, and the possible need for repeat doses, the patient should be closely monitored until all possible central benzodiazepine effects (e.g., resedation) have subsided. Particular caution is necessary when using flumazenil in cases of multiple drug overdosage, since the toxic effects (cardiac arrhythmias and/or convulsions) of other psychotropic drugs, especially cyclic antidepressants, may increase as the effects of benzodiazepines subside. Flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose.

The benzodiazepine receptor antagonist flumazenil (ANEXATE(r)) is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Refer to the prescribing information for flumazenil (ANEXATE(r)), for further information on the correct use of this drug. For up-to-date information on the management of a suspected drug overdose, the physician should consider contacting a regional Poison Control Centre.

DOSAGE AND ADMINISTRATION

Dosage for VALIUM (diazepam) should be individualized for maximal 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. Lower doses are recommended for elderly and debilitated patients, and patients with debilitating diseases. In the first few days of administration a cumulative effect of drug may occur, and therefore, the dosage should be increased only after stabilization is apparent. The tablet can be divided into equal halves to facilitate dosing.

The duration of treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment evaluated, especially if the patient is symptom free. It should not exceed 2 - 3 months, including the tapering-off period. Extension beyond this period should not take place without re-evaluation of the situation. It may be useful to inform the patient when treatment is started that it will be of limited duration and explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient be aware of the possibility of rebound phenomena, thereby minimizing anxiety over such symptoms, should they occur during withdrawal. There is evidence that, in the case of short-acting benzodiazepines, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. When long-acting benzodiazepines such as diazepam are being used, it is important to warn against changing to a short-acting benzodiazepine as withdrawal symptoms may develop.

Symptomatic relief of anxiety and tension in psychoneurosis and anxiety reactions Depending upon severity of symptoms - 2 mg to 10 mg, two to four times daily. Symptomatic relief in acute alcohol withdrawal 10 mg, three or four times during the first 24 hours, reducing to 5 mg, three or four times daily as needed. Adjunctively for relief of skeletal muscle spasm. 2 mg to 10 mg, three to four times daily. Elderly and debilitated patients, or in the presence of debilitating disease. 2 mg, one or two times daily initially, increase gradually as needed and tolerated (See PRECAUTIONS-Use in Elderly, Impaired Hepatic or Renal Function)

Because of varied responses, initiate therapy with lowest dose and increase as required. Not for use in children under six months. (See Contraindications) 1 mg to 2.5 mg, three or four times daily initially; increase gradually as needed and tolerated.

PHARMACEUTICAL INFORMATION

VALIUM contains as active substance diazepam (7-chloro-1, dihydro-l-methyl-5-phenyl-2H-1, 4-benzodiazepine-2-one), a benzodiazepine derivative. It is a colorless, crystalline compound, insoluble in water and has a molecular weight of 284.74.

VALIUM is available for oral administration as tablets containing 5 mg of diazepam. Non-medicinal ingredients are corn starch, iron oxide yellow, lactose and magnesium stearate. For warning related to lactose, see PRECAUTIONS-General.

AVAILABILITY OF DOSAGE FORMS

PHARMACOLOGY

In laboratory animals, diazepam was shown to possess sedative, muscle relaxant and anticonvulsant properties. Diazepam has a taming effect in fighting mice and vicious monkeys and a calming effect on the irritability of rats with septal lesions. Diazepam causes sedation in cats at a dose which depresses the EEG activity of the cortex, hippocampus, amygdala and septum. Diazepam is active as a muscle relaxant in the inclined screen test in mice, in blocking decerebrate rigidity in cats and in blocking the spinal reflex in cats anaesthetized with chloralose. Diazepam has demonstrated anticonvulsant activity in antistrychnine, anti-metrazol, anti-maximal electroshock and, to a lesser degree, anti-minimal electroshock tests in mice. Diazepam has shown minimal or no effect in anti-Parkinsonism activity in monkeys, anti-emetic activity in dogs, cardiovascular effects in dogs and endocrine effects in rats and rabbits.

TOXICOLOGY

In a forty-two week chronic toxicity study in rats diazepam was administered in doses up to and including 240 mg/kg/day; no abnormalities were observed on normal growth, food consumption, blood counts, gross and microscopic findings. Reproduction studies in rats have been performed with diazepam in oral doses of 1, 10, 80, and 100 mg/kg/day. At the lower dose levels the survival of offspring was within normal limits. Further studies in rats at oral doses up to and including 80 mg/kg/day did not confirm a teratological effect on the offspring. At the 100 mg/kg dose level there was a decrease in the number of pregnancies and surviving offspring and several neonates showed skeletal or other defects. The carcinogenic potential of oral diazepam has been studied in several rodent species. An increase in the incidence of hepatocellular tumours occurred in male mice. No significant increase in the incidence of tumours was observed in female mice, rats, hamsters or gerbils. A number of studies have provided weak evidence of a mutagenic potential at high concentrations which are, however, far above therapeutic doses in humans. Diazepam was found to be teratogenic in mice at dose levels of 45-50 mg/kg, 100 mg/kg, and 140 mg/kg/day as well as in hamsters at 280 mg/kg. In contrast, this drug was shown to be non teratogenic at 80 and 300 mg/kg/day in rats and at 20 and 50 mg/kg/day in rabbits.

ACTIONS AND CLINICAL PHARMACOLOGY