Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.
A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
The duration of treatment should be as short as possible (see section 4.2 Posology and method of administration) and should not exceed 4-6 weeks, including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.
It may be useful to inform the patient when treatment’s started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.
When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Patients taking prazepam for prolonged periods should have blood counts and liver function tests periodically.
Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also section 4.8).
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued.
They are more likely to occur in children and the elderly.
Benzodiazepines should not be given to children without the careful assessment of the need to do so; the duration of treatment must be kept to a minimum.
Elderly patients should be given a reduced dose (see section 4.2). A lower dose is also recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. Due to myorelaxant effect, elderly patients are of risk of falls and consequently hip fracture – caution is advised.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Limit dosages and durations to the minimum required.
Concomitant intake with alcohol: The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.
Combination with CNS depressants: Benzodiazepines, including prazepam, produce additive CNS depressant effects, including respiratory depression, when co-administered with other CNS depressants such as opioids, antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines (see section 4.4).
In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychological dependence.
Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines that are metabolised only by conjugation.
CYP3A4 inhibitors may reduce the metabolism of prazepam and increase the potential for toxicity.
Oral contraceptives can increase the effects of prazepam because oral contraceptives inhibit oxidative metabolism, thereby increasing serum concentrations of concomitantly administered benzodiazepines that undergo oxidation. Patients receiving oral contraceptive therapy should be observed for evidence of increased effects of prazepam. Caution is therefore recommended when oral contraceptives are co-administered with prazepam.
Benzodiazepines should be combined cautiously with clozapine because they could cause additive CNS depressant effects. Severe confusion, hypotension and respiratory depression have occurred rarely in those patients receiving clozapine concurrently or following benzodiazepine therapy. In patients receiving concomitant clozapine, the starting doses of the benzodiazepine should be approximately one-half of the usual dose until experience with the patient has been gained.
There is no evidence regarding prazepam’s safety in human pregnancy, nor is there evidence from animal work that it is free from hazard. Animal studies with benzodiazepines have shown minor effects on the foetus while a few studies have reported late behavioural disturbances in offspring exposed in utero.
No adequate well-controlled, studies with prazepam have been performed in pregnant women. The data concerning teratogenicity associated with benzodiazepine exposure in humans are inconsistent. There are indications from some early studies that in utero exposure may be associated with congenital malformations. Later studies have provided no clear evidence of the association of benzodiazepine use and the development of these defects. In cases where an association with benzodiazepines was found, the exposure occurred mainly during the first trimester. Chronic administration during the last trimester may be associated with intrauterine growth retardation. Use during the last trimester up to delivery is associated with neonatal complications including respiratory distress syndrome, floppy infant syndrome (hypotonia, lethargy and sucking difficulties), and withdrawal syndrome (tremors, irritability, hypertonicity, diarrhea/vomiting and vigorous sucking). If benzodiazepines are used during pregnancy, or if the patient becomes pregnant while taking benzodiazepines, the patient should be apprised of the potential hazard to the fetus.
Studies with animals have shown reproductive toxicity (see section 5.3).
Prazepam is not recommended during pregnancy and in women of childbearing potential not using contraception.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
In view of their molecular size, prazepam and its metabolites are probably excreted in human milk, therefore Centrax should not be given to nursing mothers.
Studies in rats have shown a decrease in fertility and mating at high doses (see section 5.3).
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see section 4.5).
The following side effects have been observed and reported. These findings are characteristic of benzodiazepine drugs with the following frequencies
| System Organ Class | Very Common ≥1/10 | Common ≥1/100 to <1/10 | Uncommon ≥1/1,000 to <1/100 | Rare ≥1/10,000 to <1/1,000 | Very Rare <1/10,000 | Frequency not known (cannot be estimated from the available data) |
|---|---|---|---|---|---|---|
| Psychiatric disorders | Confusion, Vivid dreams | Numbed emotions, Reduced alertness | ||||
| Nervous system disorders | Drowsiness* | Ataxia, Dizziness, Headache, Hyperactivity (Stimulations/Excitability), Light headedness, Slurred speech, Tremor | Syncope | |||
| Eye disorders | Blurred/Double vision | |||||
| Cardiac disorders | Palpitations | |||||
| Gastrointestinal disorders | Dry mouth, Gastrointestinal disturbances | |||||
| Skin and subcutaneous tissue disorders | Sweating, Skin rash | Itch | Skin reactions | |||
| Musculoskeletal and connective tissue disorders | Joint pains | Muscle weakness | ||||
| Renal and urinary disorders | Genitourinary complaints | |||||
| General disorders and administration site conditions | Fatigue, Weakness | Swelling of feet | ||||
| Investigations | Decreased | |||||
| Reproductive system disorders | Changes in libido |
* Drowsiness during the day
Other side effects include the following:
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).
Pre-existing depression may be unmasked during benzodiazepine use.
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepine or benzodiazepine-like agents. They may be quite severe with this product. They aremore likely to occur in children and the elderly.
Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4 Special warnings and precautions for use). Psychic dependence mayoccur. Abuse of benzodiazepines has been reported.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
