Anxiol

Diazepam.

Each mL contains: Diazepam 5 mg.

Pharmacology: Diazepam is a long-acting benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnestic properties. Its actions are mediated by enhancement of the activity of gamma-aminobutyric acid (GABA).
Pharmacokinetics: Absorption may be erratic following intramuscular administration of Diazepam and lower peak plasma concentrations may be obtained compared with those following oral administration. Diazepam is highly lipid soluble and crosses the blood-brain barrier, it acts promptly on the brain, and its initial effects decrease rapidly as it is redistributed into fat depots and tissues.
Diazepam 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 to 5 days of its principal active metabolite, desmethyldiazepam. Diazepam and desmethyldiazepam accumulate on repeated administration and the relative proportion of desmethyldiazepam in the body increases on long-term administration. No simple correlation has been found between plasma concentrations of diazepam or its metabolites and their therapeutic effect.
Diazepam is extensively metabolized in the liver. It is excreted in the urine, mainly in the form of free or conjugated metabolites.
Diazepam is 98 to 99% bound to plasma proteins.
The plasma elimination half-life of diazepam and/or its metabolites is prolonged in neonates, in the elderly, and in patients with liver disease. In addition to crossing the blood-brain barrier, diazepam and its metabolites also cross the placental barrier and are distributed into breast milk.

Diazepam is used in the short-term treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant (particularly in the management of status epilepticus and febrile convulsions), in the control of muscle spasm, and in the management of withdrawal symptoms.

Diazepam administered parenterally with the risk of dependence very much influencing the dose and duration of treatment. Doses should be the lowest that can control symptoms and courses of treatment should be short, not normally exceeding 4 weeks, with diazepam being withdrawn gradually. Elderly and debilitated patients should be given not more than one-half the usual adult dose. Dosage reduction may also be required in patients with liver or kidney dysfunction.
Diazepam is also given by deep intramuscular or slow intravenous injection. Although absorption following intramuscular injection may be erratic and provides lower blood concentrations than those following oral administration. Intravenous injection should be carried out slowly into a large vein of the antecubital fossa at a recommended rate of no more than 1 mL of a 0.5% solution (5 mg) per minute. It is advisable to keep the patient in the supine position and under medical supervision for at least an hour after administration. Diazepam may be administered by continuous intravenous infusion; because of the risk of precipitation of diazepam, solutions should be freshly prepared. Facilities for resuscitation should always be available when diazepam is given intravenously.
Diazepam may be given for severe anxiety by intramuscular or intravenous injection when a dose of up to 10 mg may be given, repeatedly if necessary after 4 hours.
Diazepam given for premedication before general anesthesia by intravenous injection the dose is usually 100 to 200 mcg per kg body-weight. Diazepam may also be given for sedation during minor surgical and medical procedures; doses of 10 to 20 mg, given by intravenous injection over 2 to 4 minutes are recommended.
Diazepam is used in a variety of seizures. It is given intravenously to adults in a dose of 10 to 20 mg given at a rate of 5 mg per minute and repeated if necessary after 30 to 60 minutes. Other schedules involve administering smaller amounts more frequently or giving diazepam, intramuscularly, though again absorption may be slow. Once the seizures have been controlled, a slow intravenous infusion providing up to 3 mg per kg over 24 hours has been administered to protect against recurrence. Doses by intravenous or intramuscular injection in children are within the range of 200 to 300 mcg per kg; alternatively 1 mg may be given for each year of age.
Diazepam may be given to alleviate muscles spasm. If given by intramuscular or slow intravenous injection the dose is 10 mg repeated if necessary after 4 hours. Larger doses are used in tetanus in adults and children with 100 to 300 mcg per kg body-weight being given every 1 to 4 hours by intravenous injection. Alternatively 3 to 10 mg per kg may be given over 24 hours by continuous intravenous infusion.
Symptoms of the alcohol withdrawal syndrome may be controlled by diazepam. It is given by injection if the symptoms are severe and if delirium tremens has developed; 10 to 20 mg by intramuscular or intravenous injection may be adequate, although some patients may require higher doses.
Or as prescribed by a physician.

Symptoms of Overdosage: Impairment of consciousness is fairly rapid in poisoning by benzodiazepines. Deep coma or other manifestations of severe depression of brainstem vital functions are rare; more common is a sleep-like state from which the patient can be temporarily roused by appropriate stimuli. There is usually little or no respiratory depression, and cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension. Since tolerance to benzodiazepines develop rapidly, consciousness is often regained while concentrations of drug in the blood are higher than those which induced coma. Anxiety and insomnia can occur during recovery from acute overdosage, while a full-blown withdrawal syndrome, possibly with major convulsions, can occur in patients who have previously been chronic users.
Treatment for Overdosage: The treatment of benzodiazepine overdosage is generally symptomatic and supportive. The specific benzodiazepine antagonist is flumazenil; if used, expert advice is essential since serious adverse effects may occur in patients dependent on benzodiazepines. It should be used with extreme caution, if at all, in multiple drug overdoses or for the differential diagnosis of unclear cases of overdose.

Diazepam should be avoided in patients with pre-existing CNS depression or coma, respiratory depression, acute pulmonary insufficiency, or sleep apnoea.
Many manufacturers of diazepam and other benzodiazepines advise against their use in patients with glaucoma, but the rationale for this contraindication is unclear.

Diazepam solution for injection contains benzyl alcohol as preservative. Prolonged use of high-dose intravenous infusions of diazepam can result in benzyl alcohol poisoning.

Diazepam should be used with care in those with chronic pulmonary insufficiency, in the elderly or debilitated patients who may be more prone to adverse effects. Caution is required in patients with muscle weakness, or impaired liver or kidney function; its use should be avoided in severe hepatic impairment. The sedative effects of diazepam are most marked during the first few days of administration; affected patients should not drive or operate machinery. Monitoring of cardiorespiratory function is generally recommended when benzodiazepines are used for deep sedation.
Diazepam is not appropriate for the treatment of chronic psychosis or for phobic or obsessional states. Diazepam-induced disinhibition may precipitate suicide or aggressive behavior and it should not be used alone to treat depression or anxiety as associated with depression; it should also be used with care in patients with personality disorders Caution is required in patients with organic brain changes particularly arteriosclerosis. In cases of bereavement, psychological adjustment may be inhibited by diazepam.
Dependence characterized by a withdrawal syndrome may develop after regular use of diazepam, even in therapeutic doses for short periods; because of its dependence liability, diazepam should be used with caution in patients with a history of alcohol or drug addiction.
Since hypotension and apnoea may occur when diazepam is given intravenously it has been recommended that this route should only be used when facilities for reversing respiratory depression with mechanical ventilation are available. Patients should remain supine and under medical supervision for at least one hour after intravenous injection. Intravenous infusion is best undertaken in specialist centers with intensive care facilities where close and constant supervision can be undertaken.
Dependence: The development of dependence is common after regular use of diazepam and other benzodiazepines, even in therapeutic doses for short periods. Dependence is particularly likely in patients with a history of alcohol or drug abuse and in patients with marked personality disorders. Benzodiazepines should not therefore be discontinued abruptly after regular use for even a few weeks, but should be withdrawn by gradual reduction of the dose; the time needed for withdrawal can vary from about 4 weeks to a year or more. High doses of diazepam and other benzodiazepines, injected intravenously, have been abused for their euphoriant effects.

Use of diazepam in the first trimester of pregnancy has occasionally been associated with congenital malformations in the infant but no clear relationship has been established. Administration of diazepam in late pregnancy has been associated with intoxication of the neonate.

Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of diazepam use. They generally decrease on continued administration and are a consequence of CNS depression. Less frequent effects include vertigo, headache, confusion, depression, slurred speech or dysarthria, changes in libido, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. Some patients may experience a paradoxical excitation which may lead to hostility, aggression, and disinhibition. Jaundice, blood disorders, and hypersensitivity reactions have been reported rarely. Respiratory depression and hypotension occasionally occur with high dosage and parenteral administration.
Pain and thrombophlebitis may occur with some intravenous formulations of diazepam; raised liver enzyme values have occurred.
Use of diazepam in the first trimester of pregnancy has occasionally been associated with congenital malformations in the infant but no clear relationship has been established. Administration of diazepam in late pregnancy has been associated with intoxication of the neonate.

Enhanced sedation or respiratory and cardiovascular depression may occur if diazepam is given with other drugs that have CNS depressant properties; these include alcohol, antidepressants, antihistamines, antipsychotics, general anesthetics, other hypnotics or sedatives, and opioid analgesics. The sedative effect of diazepam may also be enhanced by Cisapride. Adverse effects may also be produced by concomitant administration with drugs which interfere with the metabolism of diazepam. Drugs which have been reported to alter the pharmacokinetics of diazepam are the following: Analgesics: Diazepam used with opioid analgesics in anesthetic or analgesic regimens is expected to produce additive sedative effect.
Antibacterials: Rifampicin has decreased the half life of diazepam.
Anticoagulants: Plasma binding of diazepam and desmethyldiazepam was reduced, and free concentrations increased, immediately following heparin intravenously.
Antidepressants: Plasma concentrations of diazepam are affected by fluvoxamine. It has been suggested that patients taking fluvoxamine who require benzodiazepine should preferentially receive one such as lorazepam which has a different metabolic pathway.
Fluoxetine can increase the plasma concentrations of diazepam but the plasma concentrations of desmethyldiazepam are reduced and it is considered that the overall effect is likely to be mirror.
Antiepileptics: Carbamazepine, Phenobarbital and Phenytoin are all inducers of hepatic drug-metabolising enzymes. Therefore in patients receiving long-term therapy with these drugs the metabolism of benzodiazepines may be enhanced.
Sodium valproate has been reported to displace diazepam from plasma-protein binding sites.
Antivirals: The non-nucleoside reverse transcriptase inhibitors delavirdine and efavirenz, and HIV-protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir may inhibit the hepatic microsomal systems involved in the metabolism of some benzodiazepines. Prolonged administration of protease inhibitors may also induce these metabolic systems; interactions may therefore be complex and difficult to predict. Concomitant administration requires monitoring with dosage adjustments for the benzodiazepine or else should be avoided. Diazepam should not be used concomitantly with HIV-protease inhibitors.
Beta blockers: A clear pattern of interaction between benzodiazepines and beta blocker has not emerged. Propranolol and metoprolol may inhibit the metabolism of diazepam.
Clozapine: There have been reports of cardiorespiratory collapse in patients taking clozapine and benzodiazepines. Hypersalivation associated with clozapine and benzodiazepines may be exacerbated when these drugs are used together.
Digoxin: Raised serum-digoxin concentrations have been reported in patients also taking diazepam. The clearance of digoxin was reduced clearance.
Disulfiram: Chronic treatment with disulfiram can inhibit the metabolism of diazepam leading to a prolonged half-life and reduced clearance.
Gastrointestinal drugs: Cimetidine can inhibit the hepatic metabolism of diazepam. The clearance of diazepam has generally been decreased and the half-life prolonged. Some studies have also demonstrated impaired metabolic clearance of desmethyldiazepam.
Continuous omeprazole administration affects the pharmacokinetics of a single intravenous dose of diazepam. Omeprazole decreases the clearance and prolongs the elimination half-life of diazepam; in addition both the formation and elimination of desmethyldiazepam appear to be decreased. The effects may be greater in rapid than in slow metabolisers of omeprazole and vary between ethnic groups.
Levodopa: Reversible deterioration of parkinsonism has been reported in patients receiving levodopa who were given benzodiazepines such as diazepam.
Neuromuscular blockers: There are conflicting reports of the effect of diazepam on neuromuscular blockers; potentiation or antagonism of neuromuscular block, and a lack of interaction have all been reported.
Oral contraceptives: Some studies with diazepam have supported suggestions that oral contraceptives may inhibit the biotransformation of benzodiazepines metabolized by oxidation.
Penicillamine: Phlebitis associated with intravenous diazepam resolved with local heat but recurred on two separate occasions after oral penicillamine.
Smooth muscle relaxants: Intracavernosal papaverine produced prolonged erection in 2 patients who had been given intravenous diazepam as an anxiolytic before the papaverine.
Tobacco smoking: Drowsiness as a side effect of diazepam is less frequent in smokers than non-smokers.
Xanthines: Reports of aminophylline give intravenously reversing the sedation from intravenous diazepam. Xanthine-containing beverages may be expected to decrease the incidence of benzodiazepine-induced drowsiness because of their CNS-stimulating effects and their ability to induce hepatic drug-metabolising enzymes.

Store at temperatures not exceeding 30°C and protect from light.

Anxiolytics

N05BA01 - diazepam ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.

DD, Rx