Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: sanofi-aventis south africa (pty) ltd., 2 Bond Street, Midrand,1685, South Africa
Anterograde amnesia may occur even if benzodiazepines are used in normal dose range, but especially at higher dose levels. In case of loss or bereavement psychological adjustment may be inhibited by benzodiazepines.
Clobazam, as contained in URBANOL, can cause muscle weakness. Therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia special observation is required, and a dose reduction may be necessary. URBANOL is contraindicated in patients with myasthenia gravis or sleep apnoea syndrome (see section 4.3).
Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed and aggressive behaviour towards self and others may be precipitated. Extreme caution should therefore be used in prescribing benzodiazepines, including URBANOL, in patients with personality disorders.
Benzodiazepines, including URBANOL, may lead to physical and psychological dependence. The risk of dependence increases with the dose and duration of treatment. However, this risk is present even with daily intake of URBANOL over periods of only a few weeks and applies not only to possible abuse with particularly high doses but also to the therapeutic dose range. The risk of dependence is increased in patients with a history of alcohol or drug abuse. Therefore, the duration of treatment should be as short as possible (see section 4.2). The therapeutic benefit must be balanced against the risk of dependence during prolonged use. Rebound phenomena are characterised by a recurrence in enhanced form of the symptoms which originally led to URBANOL treatment.
This 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 be decreased gradually.
Once physical dependence has developed, abrupt termination of URBANOL treatment will lead to withdrawal symptoms. These may include headaches, sleep disturbances, extreme anxiety, tension, restlessness, confusion, excitability and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hallucinations and symptomatic psychoses (e.g. withdrawal delirium), numbness and tingling sensations in the extremities, muscle pain, tremor, sweating, nausea, hyperacusis, hypersensitivity to light, noise and physical contact, as well as epileptic seizures.
A withdrawal syndrome may also occur when abruptly changing over from a benzodiazepine with a long duration of action (for example URBANOL) to one with a short duration of action.
Clobazam is not recommended during the first trimester of pregnancy and in women of childbearing potential not using contraception (see sections 4.3 and 4.6).
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam, as contained in URBANOL, in both children and adults during the post-marketing experience SJS/TEN could be associated with a fatal outcome. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment. URBANOL should be immediately discontinued when SJS/TEN is suspected. If signs or symptoms suggest SJS/TEN, use of URBANOL should not be resumed and alternative therapy should be considered (see section 4.8).
URBANOL is contraindicated in patients with severe respiratory insufficiency (see section 4.3).
In patients with impairment of renal or hepatic function, responsiveness to clobazam, as contained in URBANOL, and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long-term treatment renal and hepatic function must be checked regularly.
In the elderly, due to the increased sensitivity to adverse reactions such as drowsiness, dizziness and muscle weakness, there is an increased risk of fall that may result in serious injury. A dose reduction is recommended.
In the treatment of epilepsy with benzodiazepines – including clobazam, as contained in URBANOL – consideration must be given to the possibility of a decrease in anti-convulsant efficacy (development of tolerance) during the course of treatment.
In patients who are CYP2C19 poor metabolisers, levels of the active metabolite Ndesmethylclobazam are expected to be increased as compared to extensive metabolisers. As this may lead to increased side effects, dosage adjustment of URBANOL may be necessary (e.g. low starting dose with careful dose titration – see section 5.2).
It is recommended that patients abstain from drinking alcohol during treatment with URBANOL, as there is an increased risk of sedation and other adverse effects (see section 4.5).
Concomitant use of opioids and benzodiazepines, including clobazam, as contained in URBANOL, may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of opioids and URBANOL for use in patients for whom alternative treatment options are inadequate. If a decision is made to prescribe URBANOL concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation (see section 4.5).
URBANOL is not recommended for the primary treatment of psychotic illness. In patients with depression or anxiety associated with depression, URBANOL must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepines (such as URBANOL) alone, can precipitate suicide in such patients.
Before treatment of anxiety states associated with emotional instability it must first be determined whether the patient suffers from a depressive disorder requiring adjunctive or different treatment.
In patients with schizophrenic or other psychotic illnesses, use of benzodiazepines is recommended only for adjunctive treatment, i.e. not for primary treatment.
Patients receiving barbiturates, antihistamines, narcotics or other central nervous system depressants: There is an additive risk of central nervous system depression when these medicines are taken together with URBANOL. Large doses may produce syncope.
The duration of treatment should be as short as possible (see section 4.2) but should not exceed 8–12 weeks in case of anxiety, including the 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 is 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 product is being discontinued.
Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% (see section 5.2) and therefore lead to increased clobazam effects (see section 4.4).
Especially when URBANOL is administered in higher doses, a mutually potentiating effect is to be expected if other CNS depressant medicines (such as antipsychotics, anxiolytics, certain antidepressant medicines, anticonvulsant medicines, sedative antihistamines, anaesthetics, hypnotics or narcotic analgesics, or other sedatives) are taken at the same time. Special caution is also necessary when URBANOL is administered in cases of intoxication with such substances or with lithium.
If URBANOL is administered simultaneously with anticonvulsants, the dosage must be adjusted under regular medical supervision (EEG monitoring), as there may be interactions with the patient’s anticonvulsant medication.
In patients receiving concomitant treatment with valproic acid, there may be a slight to moderate rise in plasma valproic acid concentration. Phenytoin plasma levels may rise if patients receive concomitant treatment with URBANOL.
Where possible, it is recommended that blood levels of concomitantly administered valproic acid or phenytoin be monitored.
Carbamazepine and phenytoin may increase the metabolic conversion of clobazam to the active metabolite N-desmethylclobazam.
Stiripentol increases plasma levels of clobazam and its active metabolite, N-desmethylclobazam, through inhibition of CYP3A and CYP2C19. Monitoring of blood levels is recommended, prior to initiation of stiripentol and then once new steady-state concentration has been reached, i.e. after approximately 2 weeks.
If URBANOL is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.
The effects of muscle relaxants and nitrous oxide may be enhanced.
Strong and moderate inhibitors of CYP2C19 may result in increased exposure to Ndesmethylclobazam (N-CLB), the active metabolite of clobazam. Dosage adjustment of URBANOL may be necessary when co-administered with strong (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C19 inhibitors (see section 5.2).
Clobazam is a weak CYP2D6 inhibitor (see section 5.2). Dose adjustment of medicines metabolised by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol) may be necessary.
URBANOL should be used judiciously during pregnancy and preferably avoided. Administration of URBANOL before or during childbirth can result in the occurrence of respiratory depression (including respiratory distress and apnoea), which may be associated with other disorders such as signs of sedation, hypothermia, hypotonia, feeding difficulties in the new-born and an increase in fetal heart rate (signs and symptoms of the so-called “floppy infant syndrome”). Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk of developing a withdrawal syndrome in the postnatal period. Appropriate monitoring of the new-born in the postnatal period is recommended.
Generally, URBANOL must not be used in the first trimester of pregnancy (see section 4.3). In the later stages of pregnancy, it must only be used if there are compelling indications.
URBANOL must not be used in breastfeeding women, since it passes into breast milk (see section 5.2).
Some adverse effects (e.g., sedation, muscle weakness) may impair the patient’s ability to concentrate and react, and therefore constitute a risk in situations where these abilities are of special importance (e.g., climbing dangerous heights, operating a vehicle or machinery).
The following CIOMS frequency rating is used, when applicable: 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); not known (cannot be estimated from the available data).
Not known: blood dyscrasias have been reported
Common: decreased appetite
Common: irritability, aggressiveness, restlessness, depression (pre-existing depression may be unmasked), drug tolerance (especially during prolonged use) (see section 4.4), acute agitation
Uncommon: abnormal behaviour, confusional state, anxiety, delusion, nightmare, loss of libido (particularly with high doses or in long-term treatment, and is reversible)
Not known: dependence (especially during prolonged use) (see section 4.4), initial insomnia, anger, fits of rage, nightmares, hallucination, psychotic disorder, poor sleep quality, difficulty in falling asleep or sleeping through suicidal ideation or tendencies. In the event of such reactions, treatment with URBANOL must be discontinued
Pre-existing depression may be unmasked during benzodiazepine use.
Tolerance and dependence may develop, especially during prolonged use (see section 4.4).
Very common: tiredness and sleepiness (somnolence), especially at the beginning of treatment and when higher doses are used
Common: sedation, dizziness, disturbance in attention, slowed or indistinct speech (disorders of articulation), (particularly with high doses or in long-term treatment, and is reversible), headache, tremor, ataxia or a fine tremor of the fingers may occur
Uncommon: numbed emotions, emotional poverty, anterograde amnesia may occur even if benzodiazepines are used in the normal dose range, but especially at higher dose levels, amnesia effects may be associated with inappropriate behaviour, memory impairment
Not known: slowed reaction time, drowsiness*, disorientation and confusion, muscle weakness, lethargy, cognitive disorder, impairment of consciousness (sometimes combined with respiratory disorders, may occur in very rare cases, particularly in elderly patients; these effects sometimes persist for a considerable length of time), nystagmus (particularly with high doses or in long-term treatment), unsteadiness of gait and other motor functions (such reactions occur particularly with high doses or in long-term treatment, and are reversible).
* drowsiness is more common in elderly and debilitated patients and in patients receiving high doses.
Uncommon: visual disorders (diplopia). Such reactions occur particularly with high doses or in long-term treatment and are reversible.
Not known: URBANOL may cause respiratory depression, especially if administered in high doses. Therefore, particularly in patients with pre-existing compromised respiratory function (e.g. in patients with bronchial asthma) or brain damage, respiratory insufficiency may occur or deteriorate.
Common: dry mouth, constipation, decreased appetite, nausea/vomiting
Unknown: hepatic dysfunction has been reported
Uncommon: cutaneous reactions, such as rash may develop in very rare cases
Not known: photosensitivity reactions, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis (including some cases with fatal outcome)
Not known: muscle spasms, muscle weakness
Very common: fatigue, especially at the beginning of treatment and when higher doses are used
Not known: slow response to stimuli, hypothermia
Uncommon: weight gain (particularly with high doses or in longterm treatment, and is reversible)
Uncommon: fall
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to:
Not applicable.
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