Each tablet contains:

active ingredient: phenazepam – 1.0 mg;

excipients: microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic, povidone, aerosil 200, talc purified, magnesium stearate.

7-Bromo-1,3-dihydro-5-(2-chlorophenyl)- 2H-1,4-benzodiazepin-2-one; 51753-57-2.

Anxiolytic; N05BA.

Phenazepam is a benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnestic properties. Its action is mediated by enhancement of the activity of gamma-aminobutyric acid (GABA). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA’s functions within the CNS include involvement in sleep induction and in the control of neuronal excitability, epilepsy, anxiety, memory, and hypnosis. Two subtypes of GABA receptors have been identified: A and B. Benzodiazepines interact with GABAA receptors to produce their sedative, hypnotic, anxiolytic, anticonvulsant, and antinociceptive effects. The GABAA receptors within the CNS are composed of different subunits, 4 of which have been described: a, b, g and d. These subunits combine to form macromolecular complexes, which include a chloride ion channel and regions to which GABA receptor and benzodiazepines bind, as well as binding sites for other substances. The different types of subunit comprising the GABAA receptor determine its activity. The presence of a g subunit confers benzodiazepine sensitivity and it is the type of a subunit(s) present that determines whether the benzodiazepines activity is mainly anxiolytic or mainly sedative. Two types of benzodiazepine receptor are suggested: type I, found throughout the brain and in large concentrations in the cerebellum and type II found mainly in the cerebral cortex, spinal cord, and hippocampus. It is the benzodiazepine type I receptors that are thought to be responsible for the anxiolytic actions of benzodiazepines. The possibility of different types of GABA receptor associated with different functions remains to be fully exploited with the development of a benzodiazepine specially selected for its anxiolytic effect and lacking sedative and muscle relaxant activity.

Phenazepam is readily and completely absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 1 to 2 hours of oral administration. Phenazepam is extensively metabolized in the liver. It is excreted in the urine. The plasma elimination half-life (T1/2) is about 6-10 hours. The plasma elimination half-life of Phenazepam is prolonged in neonates, in the elderly, and in patients with liver and/or kidney disease. Phenazepam crosses the placental barrier and is distributed into breast milk.

Phenazepam 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. Phenazepam is administered orally 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 Phenazepam 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. Phenazepam may be given for severe anxiety in oral doses of 0.25 to 0.5 mg 2-3 times daily to a maximum of 10 mg daily (for adults). Benzodiazepines have a limited role in insomnia and Phenazepam is used for the short-term management of insomnia associated with anxiety in a dose of 0. 25 – 2.5 mg be mouth at bedtime. Phenazepam is used in a variety of seizures.It is given by mouth as an adjunct in some types of epilepsy; for this purpose, 2 to 10 mg may be given daily in divided doses. Symptoms of the alcohol withdrawal syndrome may be controlled by Phenazepam given by mouth in a dose of 2.5 to 5 mg daily.

Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of Phenazepam 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, 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. Raised liver enzyme values have occurred. Overdosage can produce CNS depression and coma or paradoxical excitation. However, fatalities are rare when taken alone. Use of Phenazepam 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 Phenazepam in late pregnancy has been associated with intoxication of the neonate.

The treatment of benzodiazepine overdosage is generally symptomatic and supportive. Activated charcoal may be given to those patients who have taken more than 1 mg per kg body-weight of Phenazepam and who present within 1 hour. Gastric lavage is generally not advocated in overdoses of benzodiazepines alone. The specific benzodiazepine antagonist, flumazenil, is rarely required; 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.

The development of dependence is common after regular use of Phenazepam, 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 withdrawal by gradual reduction of the dose; the time needed for withdrawal can vary fro about 4 weeks to a year or more. The extent to which tolerance occurs has been debated but appears to involve psychomotor performance more often than anxiolytic effects. Drug-seeking behavior is uncommon with therapeutic doses of benzodiazepines. High doses of Phenazepam, injected intravenously, have been abused for their euphoriant effects. Benzodiazepine withdrawal syndrome: Development of dependence to benzodiazepines cannot be predicted but risk factors include high dosage, regular continuous use, the use of benzodiazepines with short half-life, use in patients with dependent personality characteristics or a history of drug or alcohol dependence, and the development of tolerance. The mechanism of benzodiazepine dependence is unclear. One possible mechanism is a relative deficiency of functional gamma-aminobutyric acid (GABA) activity resulting from down-regulation of GABA receptors. Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitation, mild systolic hyeprtension, tachycardia, and orthostatic hypotension. Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines. With increased awareness of the problems of benzodiazepine dependence, emphasis has been placed on prevention by proper use and careful patient selection. Benzodiazepines should be reserved for the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress and is occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness. Benzodiazepines can be withdrawn in steps of about one-eight of the daily dose every fortnight (range one-tenth to one-quarter). The daily dosage of Phenazepam can then be reduced in steps of 0.25 to 0.5 mg at fortnight intervals. If troublesome abstinence effects occur the dose should be held level for a longer period before further reduction; increased dosage should be avoided if possible. It is better to reduce too slowly than too quickly. Time required for withdrawal can vary from about 4 weeks to a year or longer. Adjuvant therapy should generally be avoided although a bet blocker may be given for prominent sympathetic over activity and an antidepressant for clinical depression. Antipsychotic drugs may aggravate symptoms.

Phenazepam should be avoided in patients with pre-existing CNS depression or coma, respiratory depression, acute pulmonary insufficiency, or sleep apnoea, and used with care in those with chronic pulmonary insufficiency. Phenazepam should be given with care to 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 Phenazepam are most marked during the first few days of administration; affected patients should not drive or operate machinery. Monitoring of cardio-respiratory function is generally recommended when benzodiazepines are used for deep sedation. Phenazepam is not appropriate for the treatment of chronic psychosis or for phobic or obsessional states. Phenazepam-induced disinhibition may precipitate suicide or aggressive behaviour and it should not, therefore, be used alone to treat depression or anxiety 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 Phenazepam. Phenazepam should be avoiding in patients with glaucoma. Phenazepam is ontraindicated in patients with a known hypersensitivity to this drug, because of lack of sufficient clinical experience. Dependence characterized by a withdrawal syndrome may develop after regular use of Phenazepam, even in therapeutic doses for short periods; because of its dependence liability, Phenazepam should be used with caution in patients with a history of alcohol or drug addiction.

Phenazepam crosses the placenta.

Phenazepam is distributed into breast milk. Chronic use of benzodiazepines by nursing mothers has been reported to cause lethargy and weight loss in the infants. Since neonates metabolize benzodiazepines more slowly than adults and accumulation of the benzodiazepine and/or its metabolites may occur, use by nursing mothers may cause sedation, feeding difficulties, and/or weight loss in the infant.

Phenazepam is contraindicated in children under 6 months of age.

Old age may alter the distribution, elimination, and clearance of benzodiazepines. Metabolic clearance of benzodiazepines metabolized principally by oxidation appears to be reduced but not clearance of those biotransformed by glucuronide conjugation or nitroreduction. Prolonged half-life in the elderly may be a result of such a decrease in clearance or of an increase in the volume of distribution. The clinical consequence of these changes depends on factors such as dosage schedule and extent of first-pass extraction by the liver. Irrespective of pharmacokinetic changes, the elderly may exhibit increased sensitivity to acute doses of benzodiazepines. Impairment of memory, cognitive function, and psychomotor performance and behaviour disinhibition may be more common than with younger patients. Long-term use commonly exacerbates underlying dementia in elderly patients. Nonetheless, if administration of a benzodiazepine is considered necessary in elderly patients, a short-acting drug is to be preferred. It should also be remembered that the elderly are at risk of sleep-related breathing disorders, such as sleep apnoea and the use of hypnotics such as benzodiazepines should be avoided in these patients.

Enhanced sedation or respiratory and cardiovascular depression may occur if Phenazepam is given with other drugs that have CNS-depressant properties; these include alcohol, antidepressants, antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives, and opioid analgesics. The sedative effect of benzodiazepines may also be enhanced by cisapride. Adverse effects may also be produced by concomitant administration with drugs, which interfere with the metabolism of benzodiazepines.

White, scored cylindrical form tablets.

1 blister packet with 24 tablets in the cardboard box.

3 years. Do not use after the expiration date.

To be dispensed with prescription.

Store at a room temperature (15-25⁰C), in a dry place, out of the reach of children. Protect from light.