Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: RANBAXY PHARMACEUTICALS (PTY) LTD, 14 Lautre Road, Stormill, Ext.1, Roodepoort, 1724, South Africa
BETAPAM is contraindicated in patients with:
BETAPAM is not recommended for the primary treatment of psychotic illness.
BETAPAM should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.
Dependence on other CNS depressants including alcohol, except in the acute withdrawal reactions. (See section 4.4).
The concomitant use of BETAPAM with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of BETAPAM possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression. (See section 4.5).
BETAPAM should be used with extreme caution in patients with a history of alcohol or drug abuse, see Medicine abuse and dependence below.
BETAPAM should be avoided in patients with dependence on CNS depressants including alcohol. (see section 4.3).
An exception to the latter is the management of acute withdrawal reactions.
A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression, (see section 4.3). Lower doses should also be used for elderly and debilitated patients.
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using BETAPAM. Should this occur, the use of BETAPAM should be discontinued. They are more likely to occur in children and in the elderly.
It should be borne in mind that BETAPAM may induce anterograde amnesia. Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.
Some loss of response to the effects of BETAPAM may develop after repeated use for a prolonged period of time.
Since the safety and effectiveness in paediatric patients below the age of 6 months have not been established, BETAPAM should be used in this age group with extreme caution and only when other therapeutic alternatives are not available.
There is a potential for abuse and the development of physical and psychological dependence, especially with prolonged use and high doses. The risk of dependence is greater in patients with a medical history of alcohol and/or drug abuse. BETAPAM should be used with extreme caution in these patients.
Once physical dependence had developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headache, muscle pain, convulsions, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Withdrawal symptoms may occur after long periods of ordinary therapeutic doses.
BETAPAM may increase the frequency and severity of attacks of grand mal epilepsy, during treatment or abrupt withdrawal.
A transient syndrome, whereby the symptoms that led to treatment with BETAPAM, recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness.
Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be gradually decreased.
The duration of treatment should be as short as possible. (see section 4.2). The overall duration of treatment, generally, should not be more than 8 to 12 weeks, including the tapering-off process. Caution should be observed in patients suffering from anxiety accompanied by an underlying depressive disorder.
The action of other central nervous system depression substances such as narcotics, barbiturates and monoamine oxidase inhibitors may be enhanced. (see section 4.3).
Withdrawal should be gradual in patients receiving high doses for prolonged periods of time. Patients should be cautioned regarding the additive effect of alcohol.
BETAPAM should be given with caution to the elderly, and to patients with hepatic or renal dysfunction, obstructive airways disease and arteriosclerosis.
BETAPAM should be given with caution to infants, who may not be able to metabolise diazepam. (see section 4.6).
BETAPAM contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
BETAPAM contains Tartrazine which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of Tartrazine sensitivity in the general population is currently thought to be low it is frequently seen in patients who also have aspirin sensitivity.
Enhanced effects of sedation, respiration, and haemodynamics may occur when BETAPAM is coadministered with other centrally acting depressants such as antipsychotics, anxiolytics or sedatives, antidepressants, hypnotics, anticonvulsants, narcotic analgesics, anaesthetics and sedative antihistamines, or alcohol.
Concomitant use of barbiturates, alcohol or other central nervous system depressants increases cardiorespiratory depression with increased risk of apnoea.
Alcohol should be avoided in patients receiving BETAPAM. (See section 4.4 and 4.9).
The oxidative metabolism of diazepam, leading to the formation of N-desmethyldiazepam, of 3 hydroxydiazepam (tenazepam) and of oxazepam, is mediated by CYP2C19 and CYP3A cytochrome P450 isoenzymes.
As shown by in vitro study, the hydroxylation reaction is carried out mainly by CYP3A isoform whereas the N-desmethylation is mediated by both CYP3A and CYP2C19.
Results from in vivo studies in human volunteers have confirmed the in vitro observations.
In consequence substrates, which are modulators of CYP3A and or of CYP2C19, may potentially alter the pharmacokinetics of diazepam. Medicines like cimetidine, ketoconazole, fluvoxamine, fluoxetine and omeprazole which are CYP3A or CYP2C19 inhibitors may lead to increased and prolonged sedation. There have also been reports that the metabolic elimination of phenytoin is affected by diazepam.
Cisapride may lead to a temporary increase in the sedative effects of orally administered benzodiazepines due to faster absorption.
The safety of diazepam for use in pregnancy has not been established. An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested. Continuous administration of benzodiazepines during pregnancy may give rise to the so-called floppy-infant syndrome, manifested by hypotension, reduced respiratory function and hypothermia in the newborn child. Withdrawal symptoms in newborn infants have been reported with BETAPAM. Special care must be taken when BETAPAM is used during labour and delivery, as high single doses may produce irregularities in the foetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory depression in the neonate. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the medicine is not yet fully developed (especially in premature infants).
Since diazepam passes into breast milk, BETAPAM should not be administered to breast feeding mothers.
Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or operate machinery. Patients should be advised, particularly at the initiation of therapy, against taking charge of vehicles or machinery or performing potentially hazardous tasks where loss of concentration could lead to accidents.
| System Organ Class | Frequency | Adverse Reaction |
|---|---|---|
| Psychiatric disorders | Less frequent | Drowsiness, confusion, numbed emotions, depression, reduced alertness, increase or decrease in libido. Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. If these occur, BETAPAM should be discontinued. There is potential for abuse. Withdrawal symptoms (including convulsions) have occurred following abrupt cessation, especially in patients who have received large doses for prolonged periods. Physical and psychic dependence, (see section 4.4). |
| Nervous system disorders | Less frequent | Fatigue, headache, ataxia, dizziness, hypersalivation, slurred speech, dysarthria, tremor, numbed emotions, anterograde amnesia - (see section 4.4), reduced alertness, dry mouth, vertigo. BETAPAM may increase the frequency and severity of attacks of grand mal epilepsy, during treatment or abrupt withdrawal. |
| Eye disorders | Less frequent | Diplopia, blurred vision |
| Ear and labyrinth disorders | Less frequent | Vertigo |
| Cardiac disorders | Less frequent | Cardiac failure including cardiac arrest, variations in pulse rate |
| Vascular disorders | Less frequent | Hypotension, variations in pulse rate, circulatory depression |
| Respiratory, thoracic and mediastinal disorders | Less frequent | Circulatory depression |
| Gastrointestinal disorders | Less frequent | Constipation, nausea |
| Hepato-biliary disorders | Less frequent | Elevated transaminases and alkaline phosphatase, jaundice |
| Skin and subcutaneous tissue disorders | Less frequent | Skin reactions |
| Renal and urinary disorders | Less frequent | Incontinence, urinary retention |
| General disorders and administration site conditions | Frequent | Fatigue, drowsiness and muscle weakness; they are usually dose-related. Drowsiness is more common in elderly and debilitated patients and in those receiving high doses. |
| Investigations | Less frequent | Elevated transaminases and alkaline phosphatase. |
| Injury and poisoning | Less frequent | There have been reports of falls and fractures in benzodiazepine users, including BETAPAM. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly. |
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/index/8
Not applicable.
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