Zetran

Uses

Zetran is used for the management of anxiety disorders or for the shortterm 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, Zetran may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

Zetran 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 Zetran may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of Zetran 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.

Zetran is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Refractory Epilepsy, Intermittent distinct from a patient’s usual seizure pattern, stereotypic episode Epileptic seizure, Refractory seizure disorders, Skeletal muscle spasm, Sedation, Perioperative management therapy

How Zetran works

Zetran is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties .

Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA) . GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability .

Dosage

Zetran dosage

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:

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

Side Effects

Drowsiness and light headedness the next day; confusion and ataxia (specially in the elderly); amnesia may occur; dependence; paradoxical increase in aggression; occasionally headache, vertigo, hypotension, gastrointestinal disturbances, visual disturbances, dysarthria, tremor, changes in libido, incontinence, urinary retention, blood disorders and jaundice reported.

Toxicity

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation . In most cases only observation of vital functions is required .

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support) .

Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease . Severe effects in overdose also include rhabdomyolysis and hypothermia . Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored .

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 become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug .

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) .

Zetran passes into breast milk . Breastfeeding is therefore not recommended in patients receiving diazepam .

Safety and effectiveness in pediatric patients below the age of 6 months have not been established .

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 .

Decreases in clearance and protein binding, and increases in volume of distribution and half-life has 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 .

Precaution

Zetran is not recommended for use in patients with depressive disorders or psychosis. Patients should be advised against the concurrent use of alcohol and other CNS depressant drugs. Patients with known or presumed dependence from alcohol or drugs should not take benzodiazepines.

Since Zetran has a CNS depressant effect, patients should be warned against driving, operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and physical coordination.

Interaction

Zetran may potentiate or interact with the effects of other CNS acting drugs such as alcohol, narcotics, hypnotics, sedative antihistamines, antipsychotics, anxiolytics/ sedatives, anesthetics, antidepressants and anticonvulsants. Besides these diazepam may interact with phenytoin, cimetidine, levodopa, lithium.

Food Interaction

• Avoid alcohol.
• Take on an empty stomach. Food may decrease absorption and time to therapeutic effect.

[Moderate] GENERALLY AVOID: Acute alcohol ingestion may potentiate the CNS depression and other CNS effects of many benzodiazepines.

Tolerance may develop with chronic ethanol use.

The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition.

Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme.

However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits intestinal rather than hepatic CYP450 3A4.

Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy.

Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4.

Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

Orange juice is not expected to interact with these drugs.

Zetran Drug Interaction

Major: acetaminophen / hydrocodone, acetaminophen / hydrocodoneModerate: duloxetine, duloxetine, pregabalin, pregabalinUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, polyethylene glycol 3350, polyethylene glycol 3350, acetaminophen, acetaminophen, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Zetran Disease Interaction

Major: acute alcohol intoxication, closed-angle glaucoma, drug dependence, renal/liver disease, respiratory depression, seizures, prolonged hypotension, myasthenia gravis, renal/liver diseaseModerate: depression, obesity, paradoxical reactions

Volume of Distribution

In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg .

Elimination Route

After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >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 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 .

Half Life

Zetran has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principal active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration . The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease .

Clearance

The clearance of diazepam is 20 to 30 mL/min in young adults .

Elimination Route

Zetran and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates .

Pregnancy & Breastfeeding use

Category D: The use of Zetran during the first trimester of pregnancy should almost always be avoided as it bears a risk of congenital malformation.

Zetran has been detected in breast milk. If possible the use of diazepam should be avoided during lactation.

Contraindication

Patients with known hypersensitivity to benzodiazepines, & myasthenia gravis are contraindicated to diazepam.

Acute Overdose

Symptoms: Somnolence, ataxia, confusion, dysarthria, little or no resp depression, hypotension, muscular weakness, deep coma, severe depression, diminished reflexes.

Management: Symptomatic and supportive treatment. Empty stomach by vomiting or gastric lavage. Activated charcoal may help reduce absorption. Flumazenil may be used for the complete or partial reversal of the sedative effects but there is a risk of seizure esp in long-term benzodiazepine users and in cyclic antidepressant overdose.

Storage Condition

Store between 15-30°C. Protect from light. Inj: Avoid freezing.

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