Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

Epilepsy: Treatment must always be planned on an individual basis. In many patients it will be possible to use 'Mysoline' alone, but in some, 'Mysoline' will need to be combined with other anticonvulsants or with supporting therapy.

'Mysoline' is usually given twice daily. Begin with 125 mg once daily late in the evening. Every 3 days increase the daily dosage by 125 mg until the patient is receiving 500 mg daily. Thereafter, every 3 days increase the daily dosage by 250 mg in adults or 125 mg in children under 9 years - until control is obtained or the maximum tolerated dosage is being given. This may be as much as 1.5 g a day in adults; 1 g a day in children.

Average daily maintenance doses:

The total daily dose is usually best divided and given in two equal amounts, one in the morning and the other in the evening. In certain patients, it may be considered advisable to give a larger dose when the seizures are more frequent. For instance: 1) if the attacks are nocturnal then all or most of the day's dose may be given in the evening; 2) if the attacks are associated with some particular event such as menstruation, a slight increase in the appropriate dose is often beneficial.

Elderly patients: It is advisable to monitor elderly patients with reduced renal function who are receiving primidone.

Patients on other anticonvulsants: Where a patient's attacks are not sufficiently well controlled with other anticonvulsants, or disturbing side effects have arisen, 'Mysoline' may be used to augment or replace existing treatment. First add 'Mysoline' to the current anticonvulsant treatment by the method of gradual introduction described previously. When a worthwhile effect has been achieved and the amount of 'Mysoline' being given has been built up to at least half the estimated requirement, withdrawal of the previous treatment can then be attempted. This should be done gradually over a period of 2 weeks, during which time it may be necessary to increase the 'Mysoline' dosage to maintain control.

Withdrawal of previous treatment should not be too rapid or status epilepticus may occur. Where phenobarbitone formed the major part of the previous treatment, however, both its withdrawal and 'Mysoline' substitution should be made earlier, so as to prevent excessive drowsiness from interfering with accurate assessment of the optimum dosage of 'Mysoline'.

Essential tremor: Initially a dose of 50 mg daily should be introduced using 'Mysoline' Suspension. The daily dose should be increased gradually over a 2 to 3 week period until remission of symptoms or the highest dose tolerated up to a maximum of 750 mg daily.

Patients with essential tremor who have not previously been exposed to anticonvulsants, or other drugs known to induce increased hepatic enzyme activity, may experience acute symptoms of tolerance to 'Mysoline', frequently characterised by vertigo, unsteadiness and nausea. It is, therefore, essential to start such patients at a low dosage (initially 50 mg daily) increasing very slowly up to the maximum tolerated dose or that which produces remission of tremor (up to 750mg daily).

Child Dosage

Contra Indications

Patients who exhibit hypersensitivity or an allergic reaction to primidone, to a constituent of the formulation or to phenobarbitone, should not receive the drug. Primidone should not be administered to patients with acute intermittent porphyria.

Special Precautions

'Mysoline' should be given with caution and may be required in reduced dosage in children, the elderly, debilitated patients or those with impaired renal, hepatic or respiratory function.

Primidone is a potent CNS depressant and is partially metabolised to phenobarbitone. After prolonged administration there is a potential for tolerance, dependence and a withdrawal reaction on abrupt cessation of treatment.

Exceptionally, as with phenytoin and phenobarbitone, megaloblastic anaemia may develop requiring discontinuation of primidone. This condition may respond to treatment with folic acid and/or vitamin B12. There have been isolated reports of other blood dyscrasias.

Mysoline has the potential to harm the foetus, see section 4.6 before considering use during pregnancy.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for primidone.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Interactions

Both primidone and its major metabolite phenobarbitone are metabolized by, and also induce, liver enzyme activity, principally the CYP 450 3A4 enzyme system..

Agents which inhibit the CYP 450 3A4 enzyme system, such as chloramphenicol, felbamate, nelfinavir*, metronidazole and sodium valproate may result in increased plasma levels of concomitantly administered primidone and its metabolite phenobarbitone.

In addition, St. John's Wort* induces the CYP450 enzyme system and may result in a reduction of plasma levels of concomitantly administered primidone and of its major metabolite phenobarbitone.

Theophylline protein binding may affect phenobarbitone binding, affecting free phenobarbitone levels.

Mysoline therapy may also lead to altered pharmacokinetics in concomitantly administered drugs, whose metabolism may be increased and lead to lowered plasma levels and/or a shorter half-life. These drugs include androgens*, beta-antagonists, carbamazepine, cyclosporin, cloazepine, chloramphenicol, corticosteroids/glucocorticosteroids, cyclophosphamide, dicoumarins, digitoxin*, doxycycline, ethosuxamide, etoposide, felbamate, granisetron, lamotrigine, losartan, methadone*, metronidazole, mainserin, montelukast*, nelfinavir*, nimodipine, oral-contraceptives, oxcarbazepine, phenytoin, quinidine, rocuronium, sodium valproate, tiagabine, theophyllines, topiramate, tricyclic antidepressants, vecuronium, warfarin and zonisamide.

Mysoline inhibits the glucoronidation of paracetamol* and may increase the hepatotoxicity of paracetamol.

The CNS depressant effect of Mysoline is additive to those of other CNS depressants such as alcohol, opiates and barbiturates.

The above interactions are potentially clinically significant.

* No formal interaction studies have been performed. The inclusion of the drug is based on reports of their influence or dependence upon enzyme systems influenced by, or of relevance to the metabolic pathways of primidone or its major metabolite, phenobarbitone.

Adverse Reactions

If adverse effects do appear, the most common side effects are drowsiness and listlessness but these generally occur only in the beginning of treatment.

Visual disturbances, nausea, headache, dizziness, vomiting, nystagmus and ataxia have been reported but are usually transient even when pronounced. On occasions an idiosyncratic reaction may occur which involves these symptoms in an acute and severe form necessitating withdrawal of treatment.

Vitamin D supplementation may be needed during long-term Mysoline therapy, since vitamin D catabolism may be increased.

Exceptionally, as with phenytoin and phenobarbitone, megaloblastic anaemia may develop requiring discontinuation of primidone. This condition may respond to treatment with folic acid and/or Vitamin B12.

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