DIAZEPAM- diazepam_tablet

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. After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 to 1. 5 hours with a range of 0. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 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 C max 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. 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. 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. 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. In children 3 to 8 years old the mean half-life of diazepam has been reported to be 18 hours. 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. 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. 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.
Pharmacokinetics
After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 to 1. 5 hours with a range of 0. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 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 C max 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. 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. 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. 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.

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 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 diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of diazepam 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 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 en dash 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. 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. 5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated. 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 DRUG ABUSE AND DEPENDENCE: Dependence.

Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: Gastrointestinal System: Special Senses: Cardiovascular System: Psychiatric and Paradoxical Reactions: Urogenital System: Skin and Appendages: Laboratories: Other: 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. Injury, Poisoning and Procedural Complications: To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www. gov/medwatch for voluntary reporting of adverse reactions.

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.

Pharmacokinetics in Special Populations
In children 3 to 8 years old the mean half-life of diazepam has been reported to be 18 hours. 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. 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. 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.
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
Pregnancy
Advise pregnant females that use of diazepam tablets 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
Nursing
Advise patients that breastfeeding is not recommended during treatment with diazepam tablets (see PRECAUTIONS: Nursing Mothers
Pregnancy
Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome Clinical Considerations (see Data) 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 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 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
Nursing Mothers
Diazepam is present in breastmilk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed infants, advise patient that breastfeeding is not recommended during treatment with diazepam tablets.
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). Extensive accumulation of diazepam and its major metabolite, 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 have been reported in patients with cirrhosis. In such patients, a 2- to 5-fold increase in mean half-life has been reported. Delayed elimination has also been reported for the active metabolite desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic encephalopathy. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic Insufficiency

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 If diazepam 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 diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. 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 to 25 minutes greater in the presence of antacids. However, this difference was not statistically significant. 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. There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.

WARNINGS
Concomitant use of benzodiazepines, including diazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe diazepam tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of diazepam tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking 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 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. , 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. , 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. 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. , 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. 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.
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 2 2
OVERDOSAGE
Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

REMEDYREPACK INC.

DIAZEPAM- diazepam_tablet Product manual source documgent