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. Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects.
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.
Abrupt withdrawal of diazepam in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures. As with other agents which 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.
Updated October 10, 2016.
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.
1. Diazepam Tablets USP 10 mg also contain FD&C Blue No.
Diazepam 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, magnesium stearate and microcrystalline cellulose.
Oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.
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. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. 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.
Diazepam is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.
Psychiatric and paradoxical reactions are known to occur when using benzodiazepines (see ADVERSE REACTIONS ). These reactions are more likely to occur in children and the elderly. Should this occur, use of the drug should be discontinued.
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. 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. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered.
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.
Diazepam Tablets USP are contraindicated in patients with a known hypersensitivity to this drug and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Diazepam is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic 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.
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).
Safety and effectiveness in pediatric patients below the age of 6 months have not been established.
Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximay eight times the maximum recommended human dose or greater on a mg/m 2 basis). Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis. 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.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see DRUG ABUSE AND DEPENDENCE ).
If diazepam 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, barbiturates, MAO inhibitors and other antidepressants (see Drug Interactions ).
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). 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.
Children In children 3 - 8 years old the mean half-life of diazepam has been reported to be 18 hours.
Centrally Acting Agents 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.
The decline in the plasma concentration-time profile after oral administration is biphasic. Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximay one tenth of those in maternal plasma (days 3 to 9 post-partum). The initial distribution phase has a half-life of approximay 1 hour, although it may range up to >3 hours. In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. Distribution Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%).
Reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simply aging. Consequently, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. Geriatric Elimination half-life increases by approximay 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. Conflicting information has been published on changes of plasma protein binding in the elderly. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. It will also take longer to reach steady-state.
These withdrawal symptoms may consist of tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. 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. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. 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. Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuance of diazepam.
Alcohol Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.
Phenytoin There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
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. There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. 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.
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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.
No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximay 13 times the MRHD on a mg/m 2 basis). In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximay 6 and 12 times, respectively, the maximum recommended human dose on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. 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 (approximay 16 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. The data currently available are inadequate to determine the mutagenic potential of diazepam.
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.
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. 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. 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.
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.
The risk is more pronounced in patients on long-term therapy. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. 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. Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970.
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. Absorption is delayed and decreased when administered with a moderate fat meal. This results in an average decrease in C max of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food. 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. In the presence of food mean lag times are approximay 45 minutes as compared with 15 minutes when fasting.
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 ). In such patients, a 2- to 5- fold increase in mean half-life has been reported. Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis.
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). At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression.
Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.
In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.
Diazepam Tablets USP 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.
Temazepam and oxazepam are largely eliminated by glucuronidation. 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.
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. 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.
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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Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving diazepam.
Category D ( see WARNINGS: Pregnancy ).
As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle. Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy.
There is also an increase in volume of distribution, and average clearance decreases by almost half. The average increase has been variously reported from 2-fold to 5-fold, with individual half-lives over 500 hours reported. 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). Hepatic Insufficiency In mild and moderate cirrhosis, average half-life is increased. In chronic active hepatitis, clearance is decreased by almost half.
However, there is no effect on the extent of absorption. However, this difference was not statistically significant. Antacids Diazepam peak concentrations are 30% lower when antacids are administered concurrently. 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.
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.
Some loss of response to the effects of benzodiazepines may develop after repeated use of diazepam for a prolonged time.
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. 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.
Diazepam Tablets USP 5 mg also contain D&C Yellow No. 10.
The chemical name of diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. The empirical formula is C 16 H 13 ClN 2 O and the molecular weight is 284.75. The structural formula is as follows:. Diazepam is a benzodiazepine derivative. It is a colorless to light yellow crystalline compound, insoluble in water.
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).
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.
Pharmacokinetics in Special Populations.Diazepam