PRIMIDONE Tablets Ref.[7908] Active ingredients: Primidone

Primidone 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.

Primidone 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.

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.

Primidone 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, clozapine, chloramphenicol, corticosteroids/glucocorticosteroids, cyclophosphamide, dicoumarins, digitoxin*, doxycycline, ethosuxamide, etoposide, felbamate, granisetron, lamotrigine, losartan, methadone*, metronidazole, mianserin, montelukast*, nelfinavir*, nimodipine, oral-contraceptives, oxcarbazepine, phenytoin, quinidine, rocuronium, sodium valproate, tiagabine, theophyllines, topiramate, tricyclic antidepressants, vecuronium, warfarin and zonisamide.

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

The CNS depressant effect of primidone 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.

Pregnancy

Primidone is suspected to have caused serious birth defects when administered during pregnancy. In infants born of epileptic mothers treated with primidone, there have been reports of congenital abnormalities including congenital heart disease, cleft palate and conditions associated with maternal folate deficiency, including spina bifida, microencephaly and anencephaly. Primidone should not be used during pregnancy unless clearly necessary to manage epilepsy in the mother where withdrawal of therapy may cause risks or where alternative anti-epileptic managements are unsuitable.

Withdrawal symptoms may occur in the newly born whose mothers have received primidone during late pregnancy.

Long-term anticonvulsant therapy can be associated with decreased serum folate levels. As folic acid requirements are also increased during pregnancy, regular screening of patients at risk is advised, and treatment with folic acid and Vitamin B12, although controversial, should be considered.

Anticonvulsant therapy in pregnancy has occasionally been associated with coagulation disorders in the neonates. For this reason pregnant patients should be given Vitamin K1 through the last month of pregnancy up to the time of delivery. In the absence of such pretreatment, 10 mg Vitamin K1 may be given to the mother at the time of delivery and 1 mg should be given immediately to the neonate at risk.

Lactation

During breast feeding the baby should be monitored for sedation.

As with most other anticonvulsants, patients who drive vehicles or operate machinery should be made aware of the possibility of impaired reaction time.

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

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Primidone. The mechanism by which Primidone affects bone metabolism has not been identified.

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. Common (>1/100), less common (1/100-1/1000), rare (<1/1000).

General

Common: Drowsiness

Less common: Headache, dizziness

Central and peripheral nervous system

Common: Listlessness, ataxia, visual disturbances, nystagmus

Rare: Personality changes, which may include psychotic reactions.

Gastrointestinal

Common: Nausea

Less common: Vomiting

Dermatological

Less common: Allergic reactions particularly affecting the skin can include maculopapular, morbilliform or scarlatiniform rashes.

Haematological

Rare: Megaloblastic anaemia, blood dyscrasias

Hepatic

Rare: Elevations in hepatic enzymes, including gamma-glutamyl transferase (gamma GT) and alkaline phosphatase.

Musculoskeletal

Rare: Arthralgia, osteomalacia.

As with phenobarbitone, Dupuytren’s contracture has been reported.

Dermatological

Rare: Severe reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and lupus erythematosus.

Vitamin D supplementation may be needed during long-term Primidone 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.

Not applicable.