Frisium® 10: composition and pharmaceutical form
One tablet contains 10 mg of clobazam. It can be taken whole or crushed and mixed with apple purée, and it can also be split into equal 5 mg doses — which matters, because treatment regimens start from small doses.
Clobazam may be given with or without food. The medicine contains lactose, so it should not be used in rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
How Frisium® 10 works
Clobazam is an anxiolytic and anticonvulsant from the benzodiazepine group. That dual action explains the dual list of indications: the medicine is used both in anxiety states and as an addition to anticonvulsant therapy, but the doses in the two cases differ several-fold.
In the body clobazam is converted into the active metabolite N-desmethylclobazam, and that route explains most of the medicine's particularities. In patients who metabolise drugs slowly through the CYP2C19 isoenzyme the concentration of the active metabolite is higher than in fast metabolisers, and the dose may need adjusting; carbamazepine and phenytoin, by contrast, increase the conversion of clobazam into that metabolite. It is also worth remembering that in the treatment of epilepsy with benzodiazepines the anticonvulsant effect may weaken — tolerance may develop.
Indications
The first group of indications is acute and chronic anxiety states expressed as heightened anxiety, tension, inner restlessness, agitation, irritability, sleep disturbances of emotional origin, and also psychovegetative and psychosomatic disturbances, for example of the circulatory or digestive system.
Before prescribing, the doctor rules out conditions that call for different treatment.
- in psychovegetative and psychosomatic disturbances, causes of organic origin are ruled out;
- before treating anxiety states accompanied by mood disturbances, it is first established whether depressive disorders are present that require additional or different treatment;
- the second group of indications is the use of the medicine as an add-on in epilepsy where previous anticonvulsant treatment has not given satisfactory results.
Method of use and dosage
Doses in anxiety and in epilepsy differ fundamentally: in the first case the daily dose is capped at 30 mg, in the second it reaches about 80 mg. One rule holds throughout — start with a small dose and raise it gradually.
| Situation | Regimen |
| Anxiety states, adults | usually 20 mg a day to start and, if needed, up to 30 mg; exceeding 30 mg a day is not recommended |
| Anxiety states, older people | a low starting dose with gradual increases under close observation; a maintenance dose of 10–15 mg a day is most often enough |
| Epilepsy, adults | an addition to one or more anticonvulsants: start at 5–15 mg a day and raise gradually to a maximum of about 80 mg a day |
| Epilepsy, children from 6 years | start at 5 mg a day; a maintenance dose of 0.3–1 mg per kilogram of body weight is usually enough, with increases under close control |
| Children under 6 years | there are no dosing recommendations because no suitable formulation exists; from 6 months to 6 years the medicine is not used, other than for treating seizures on absolute indications |
Treatment of anxiety is kept as short as possible and no longer than 8–12 weeks including the tapering period, with the patient reassessed no later than after 4 weeks and regularly thereafter. In renal and hepatic impairment the effect of the medicine is stronger and susceptibility to adverse reactions greater: here too low starting doses and gradual increases under close control are needed. If the daily dose is divided, the larger part is taken in the evening, and doses of up to 30 mg may be taken as a single evening dose. Prolonged continuous use is avoided, because it leads to dependence. If clobazam has been taken for a long time, dosing must not be stopped abruptly: the dose is reduced gradually under medical supervision, otherwise seizures and other withdrawal symptoms are possible — and that rule holds even when the medicine is withdrawn for lack of effect.
Contraindications
Hypersensitivity to clobazam or to any excipient. Myasthenia gravis, because of the risk of worsening muscle weakness. Severe respiratory failure and sleep apnoea syndrome, because of the risk of deterioration. Severe hepatic impairment, because of the risk of encephalopathy. Breastfeeding.
A separate restriction concerns children: benzodiazepines must not be given to children without a careful assessment of the need for such treatment, and between the ages of 6 months and 6 years the medicine is not used at all, except in particular cases of treating seizures on absolute indications.
Special warnings and precautions
The use of benzodiazepines, including clobazam, may lead to physical and psychological dependence. The risk grows with the dose and the length of treatment, but it exists even when the patient takes clobazam daily for only a few weeks, and not only at very high doses but at therapeutic ones too. In those prone to dependence on alcohol or medicines the risk is higher, so with prolonged use the benefit is weighed against the risk of dependence.
- on abrupt discontinuation, rebound — the return of intensified original symptoms such as anxiety or seizures — and a withdrawal syndrome are possible: headache, sleep disturbance, heightened anxiety, disorientation and agitation, loss of the sense of reality, depersonalisation, hallucinations, symptomatic psychoses, muscle pain, tremor, sweating, seizures; the same syndrome may follow an abrupt switch from a long-acting benzodiazepine to a short-acting one;
- after marketing, severe skin reactions were reported — Stevens-Johnson syndrome and toxic epidermal necrolysis — in both children and adults, with a possible fatal outcome; their signs are watched for particularly closely during the first 8 weeks, dosing is stopped immediately on suspicion, and if the symptoms point to them the medicine is never used again;
Clobazam can depress the respiratory centre, especially at high doses, so in respiratory failure breathing is monitored and the dose reduced, while with muscle weakness in the history or spinal or cerebellar ataxia special observation and a lower dose are needed. Alcohol should be avoided during treatment because of the risk of excessive sedation, and with benzodiazepines even at the recommended dose anterograde amnesia may occur. In older people, being more prone to drowsiness, dizziness and muscle weakness, the risk of falls with serious injury is higher, so the dose is reduced. In personality disorders the medicine is used with caution because of the risk of suicidal behaviour, and with long treatment renal and hepatic function is monitored. Sedation, amnesia and loss of muscle strength affect driving.
Interaction with other medicines
The main line of interactions is the summing of central nervous system depression. Especially at high doses of clobazam it is intensified alongside antipsychotics, anxiolytics, antidepressants, anticonvulsants, sedating antihistamines, anaesthetics, hypnotics and opioid analgesics. Particular caution is needed in patients who have suffered poisoning with those medicines or with lithium. Alcohol taken at the same time may raise the bioavailability of clobazam by 50% and thereby strengthen its action. With opioid analgesics euphoria may be enhanced and psychological dependence increased, and clobazam potentiates the action of muscle relaxants and of nitrous oxide.
- in epilepsy the dose is adjusted under medical supervision with EEG monitoring: valproic acid and phenytoin may rise in plasma alongside clobazam, and both are monitored where possible;
- carbamazepine and phenytoin increase the conversion of clobazam into its active metabolite, while stiripentol, by inhibiting CYP3A4 and CYP2C19, raises the concentrations of both clobazam and its metabolite: the clobazam concentration is checked before stiripentol is started and again once steady state is reached, after about 2 weeks;
- potent and moderate CYP2C19 inhibitors increase exposure to the active metabolite, so when combined with fluconazole, fluvoxamine, ticlopidine or omeprazole the clobazam dose may need adjusting; clobazam itself is a weak CYP2D6 inhibitor, and the dose of dextromethorphan, pimozide, paroxetine or nebivolol sometimes has to be changed;
The practical conclusion is simple: with clobazam it is not the rare combinations that matter but the most ordinary ones — alcohol, hypnotics, painkillers, antiepileptics: those are what change both the effect and the safety.
Pregnancy and breastfeeding
Animal studies show a harmful effect of clobazam on reproduction, and safety data in pregnant women are scarce. Cases of disturbances have been recorded in fetuses and newborns of mothers with epilepsy who were taking antiepileptic medicines alongside clobazam, and the influence of those factors cannot be excluded. Clobazam crosses the placenta.
The medicine is not recommended in the first trimester or in women of childbearing age not using contraception; in pregnancy it is used only where the potential benefit to the mother outweighs the risk to the fetus, and at the lowest effective dose. Use before or during delivery may cause respiratory depression in the newborn, up to respiratory failure and apnoea, together with sedation, hypothermia, reduced muscle tone and feeding difficulties — the signs of the so-called floppy infant syndrome. Prolonged use in late pregnancy may lead to physical dependence in the infant and a withdrawal syndrome after birth, so the newborn is monitored. During breastfeeding the medicine is not used: clobazam passes into breast milk.
Adverse reactions
Very common were drowsiness — especially at the start of treatment, at high doses and with prolonged use — and general fatigue. Common were a sedative effect, dizziness, impaired concentration, slurred speech, headache, tremor, ataxia, reduced appetite, dry mouth, nausea and constipation, and on the mental side irritability, aggression, restlessness, agitation, depression and tolerance to the medicine with long treatment.
- uncommon: atypical behaviour, confusion, delusions, nightmares, reduced libido, amnesia, double vision, rash, weight gain, falls;
- frequency not known, mental: dependence especially with long treatment, difficulty falling asleep, fits of anger, hallucinations, psychotic reactions, suicidal tendencies;
- frequency not known, other: cognitive disturbance, disturbance of consciousness — particularly in older people and sometimes with respiratory disturbance — nystagmus, gait disturbance, respiratory depression, muscle weakness, hypothermia, photosensitivity, urticaria, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Many of the events on this list are flagged the same way in the product information: they occur mainly at high doses or with long treatment and are transient — slurred speech, double vision, nystagmus, gait disturbance, reduced libido, weight gain. Respiratory disturbance, by contrast, is most dangerous where respiratory function is already impaired: in asthma or with brain damage.
Overdose
Overdose and poisoning with benzodiazepines, including clobazam, can cause central nervous system depression with dizziness, disorientation and drowsiness, which may worsen into ataxia, respiratory depression, a fall in blood pressure and, rarely, coma. The manifestations are stronger and at times life-threatening if other agents depressing the nervous system, including alcohol, were used at the same time; their influence is taken into account in treatment.
Gastric lavage, intravenous fluids and supportive treatment are used, with monitoring of consciousness, breathing, pulse and blood pressure; equipment must be available in case of airway obstruction and respiratory failure. Low blood pressure is restored by fluid replacement and, if necessary, sympathomimetics. Forced diuresis and haemodialysis are ineffective for removing clobazam, and because of limited experience it is hard to judge the effectiveness of physostigmine and flumazenil.
How to get a prescription for Frisium® 10 online
The medicine is prescription-only, and what shapes the conversation with the doctor above all is which of the two indications it is being prescribed for: an anxiety state or epilepsy. Both the dose and the maximum length of the course follow from that: in anxiety the treatment is kept within 8–12 weeks with tapering, while in epilepsy the medicine remains an addition to the main therapy.
It is worth reporting in advance myasthenia, severe respiratory failure and sleep apnoea, liver and kidney disease, ataxia and muscle weakness in the history, personality disorders and depression, past dependence on alcohol or medicines, pregnancy and breastfeeding, and — because of the lactose in the composition — galactose intolerance. The medicines being taken are listed separately: antiepileptics, hypnotics and sedatives, opioid analgesics, fluconazole, fluvoxamine, omeprazole. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
