Diazepam

Indications and Usage Section INDICATIONS AND USAGE Diazepam Tablets are 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, Diazepam Tablets may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. Diazepam Tablets are 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 diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of Diazepam Tablets 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.

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. ADULTS: USUAL DAILY DOSE: Management of Anxiety Disorders and Relief of Symptoms of Anxiety. Depending upon severity of symptoms – 2 mg to 10 mg, 2 to 4 times daily Symptomatic Relief in Acute Alcohol Withdrawal. 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed. Adjunctively for Relief of Skeletal Muscle Spasm. 2 mg to 10 mg, 3 or 4 times daily Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily Geriatric Patients, or in the presence of debilitating disease. 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated. PEDIATRIC PATIENTS: Because of varied responses to CNS-acting drugs, initiate therapy 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 ).

CONTRAINDICATIONS Diazepam Tablets are 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. Diazepam Tablets are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. They may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but are contraindicated in acute narrow-angle glaucoma.

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 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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Drug Interactions Opioids 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 GABA A 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. Centrally Acting Agents If diazepam tablets are 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 diazepam tablets, 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 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.

DESCRIPTION Diazepam is a benzodiazepine derivative. The chemical name of diazepam is 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2 H -1,4-benzodiazepin-2-one. It is a colorless to light yellow crystalline compound, insoluble in water. The molecular formula is C 16 H 13 ClN 2 O and the molecular weight is 284.74. The structural formula is as follows: Diazepam is available for oral administration as tablets containing 2 mg, 5 mg or 10 mg diazepam, USP. In addition to the active ingredient diazepam, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn) and sodium lauryl sulfate. The 5 mg tablets also contain FD&C Yellow No. 6 Aluminum Lake. The 10 mg tablets also contain D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake. Diazepam Structural Formula

OVERDOSAGE SECTION 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. 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 flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, should be consulted prior to use. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).

HOW SUPPLIED Diazepam Tablets USP, 2 mg are available as white, round, flat face, beveled edge tablets, debossed “3925” and bisected on one side and “TEVA” on the other side, containing 2 mg of diazepam, USP. NDC 76420-783-02 Bottles of 2 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-03 Bottles of 3 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-05 Bottles of 5 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-10 Bottles of 10 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-20 Bottles of 20 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-30 Bottles of 30 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-60 Bottles of 60 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-90 Bottles of 90 tablets (repackaged from NDC 0172-3925-XX) NDC 76420-783-01 Bottles of 100 tablets (relabeled from NDC 0172-3925-60) NDC 76420-783-55 Bottles of 500 tablets (relabeled from NDC 0172-3925-70) Diazepam Tablets USP, 5 mg are available as yellow, round, flat face, beveled edge tablets, debossed “3926” and bisected on one side and “TEVA” on the other side, containing 5 mg of diazepam, USP. NDC 76420-533-02 Bottles of 2 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-03 Bottles of 3 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-05 Bottles of 5 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-10 Bottles of 10 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-20 Bottles of 20 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-30 Bottles of 30 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-60 Bottles of 60 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-90 Bottles of 90 tablets (repackaged from NDC 0172-3926-XX) NDC 76420-533-01 Bottles of 100 tablets (relabeled from NDC 0172-3926-60) NDC 76420-533-55 Bottles of 500 tablets (relabeled from NDC 0172-3926-70) NDC 76420-533-00 Bottles of 1000 tablets (relabeled from NDC 0172-3926-80) Diazepam Tablets USP, 10 mg are available as light blue, round, flat face, beveled edge tablets, debossed “3927” and bisected on one side and “TEVA” on the other side, containing 10 mg of diazepam, USP. NDC 76420-784-02 Bottles of 2 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-03 Bottles of 3 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-05 Bottles of 5 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-10 Bottles of 10 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-20 Bottles of 20 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-30 Bottles of 30 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-60 Bottles of 60 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-90 Bottles of 90 tablets (repackaged from NDC 0172-3927-XX) NDC 76420-784-01 Bottles of 100 tablets (relabeled from NDC 0172-3927-60) NDC 76420-784-55 Bottles of 500 tablets (relabeled from NDC 0172-3927-70) NDC 76420-784-00 Bottles of 1000 tablets (relabeled from NDC 0172-3927-80) Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Keep this and all medications out of the reach of children. Relabeled and Repackaged by: Enovachem PHARMACEUTICALS Torrance, CA 90501