INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo MYSOLINE® Tablets

SCHEDULING STATUS
S3

PROPRIETARY NAME
(and dosage form)

MYSOLINE® Tablets

COMPOSITION
Each MYSOLINE tablet contains 250 mg
primidone.

PHARMACOLOGICAL CLASSIFICATION
A 2.5 Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION
Pharmacodynamic properties
The activity of primidone is due to the anticonvulsant properties of three active moieties; namely primidone itself and its two major metabolites, phenobarbitone and phenylethylmalonamide. The relative contribution of these three moieties to the clinical anticonvulsant effect has not been firmly established. Although the precise mode of action of primidone is unknown, effects on the neuronal membrane particularly with respect to alteration of ionic fluxes are likely to play a fundamental role.
Pharmacokinetics
Primidone is usually absorbed rapidly from the gastro-intestinal tract with wide individual variation. Peak plasma levels are attained approximately 3 hours after ingestion. Primidone is well distributed in all organs and tissues; it crosses the blood-brain and placental barriers and is excreted in breast milk. Primidone has a plasma half-life of 7 to 14 hours which is considerably shorter than those of its principal metabolites. Primidone and phenylethylmalonamide are bound to plasma proteins to only a small extent, whereas approximately half of phenobarbitone is bound. Approximately 40% of the drug is excreted unchanged in urine.

INDICATIONS
MYSOLINE is indicated for treatment of epilepsy for:
Generalised tonic-clonic seizures
Partial seizures with or without secondary generalisation (temporal lobe seizures; focal seizures)
It is also effective in the control of myoclonic jerks and akinetic attacks.

CONTRA-INDICATIONS
Patients who exhibit hypersensitivity or allergic reactions to primidone should not receive the medicine. MYSOLINE should not be administered to patients with acute intermittent porphyria.
Concomitant use of MYSOLINE and phenobarbitone is contra-indicated, except when transferring treatment from one to the other (see Special precautions).
Patients with severe hepatic, renal or respiratory impaired function.
Pregnancy and lactation (see PREGNANCY AND LACTATION).

WARNINGS
MYSOLINE has the potential to harm the foetus (refer to PREGNANCY AND LACTATION section).

INTERACTIONS
Both MYSOLINE and its major metabolite, phenobarbitone, induce liver enzyme activity, principally the CYP 450 3A4 enzyme system. This may lead to alteration in the pharmacokinetics of concomitantly administered medicines. Other medicines whose metabolism may be increased and lead to lowered plasma levels and/or shorter half-life by concomitant MYSOLINE therapy include: Androgens, beta-antagonists, carbamazepine, cyclosporin, clozapine, chloramphenicol*, corticosteroids/ glucocorticoids, cyclosphosphamide, dicoumarins, digoxin, 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.
Breakthrough bleeding and failure of contraceptive therapy have been noted in patients taking anticonvulsant medicines and oral contraceptive steroids.
The following agents also inhibit the CYP 450 3A4 enzyme system and may result in increased plasma levels of concomitantly administered MYSOLINE and its metabolite phenobarbitone: Chloramphenicol*, felbamate*, nelfinavir*, metronidazole* and sodium valproate*.
St John’s Wort induces the enzyme system and may result in a reduction of plasma levels of concomitantly administered MYSOLINE and of its metabolite phenobarbitone.
MYSOLINE inhibits the glucuronidation of paracetamol and may increase the hepatotoxicity of paracetamol.
Theophylline* protein binding may affect phenobarbitone binding, the major metabolite of MYSOLINE, affecting free phenobarbitone levels.
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.
* Indicates that the interaction affects both the concomitant agent and MYSOLINE.

PREGNANCY AND LACTATION
Pregnancy
There have been reports of congenital abnormalities, including congenital heart disease, cleft palate and conditions associated with maternal folate deficiency, in infants born of epileptic mothers treated with primidone. MYSOLINE is not recommended during pregnancy (see WARNINGS).
Withdrawal symptoms may occur in the newly born whose mothers have received MYSOLINE during late pregnancy.
Long-term MYSOLINE 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 should be considered.
Anticonvulsant therapy in pregnancy has occasionally been associated with coagulation disorders in the neonate. 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 pre-treatment, 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.
Lactation
Breastfeeding is not recommended.

DOSAGE AND DIRECTIONS FOR USE
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.
When MYSOLINE is used with or to replace existing anticonvulsant therapy, the dosage should be increased gradually while that of the other medication is maintained or decreased gradually in order to maintain seizure control. This should be done over a period of two weeks.
MYSOLINE is usually given twice daily. Begin with half a tablet once daily late in the evening. Every three days increase the daily dosage by half a tablet until the patient is receiving 2 tablets daily. Thereafter, every three days increase the daily dosage by one tablet in adults or half a tablet in children under 9 years - until control is obtained or the maximum tolerated dosage is being given. This may be as much as 6 tablets a day in adults; 4 tablets a day in children.
Average daily maintenance doses:
  Tablets mg
Children up to 2 years 1 to 2 250 to 500
Children 2 to 5 years 2 to 3 500 to 750
Children 6 to 9 years 3 to 4 750 to 1 000
Adults and children over 9 years 3 to 6 750 to 1 500
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 at the appropriate time is often beneficial.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
If side-effects do appear, the most common side-effects are drowsiness and listlessness but these generally occur only in the beginning of treatment.
Common: >1/100, <1/10
Uncommon: >1/1000, <1/100
Rare: >1/10 000, <1/1000

Nervous system disorders
Common: Listlessness, ataxia, visual disturbances, nystagmus.
Gastrointestinal disorders
Common: Nausea.
Uncommon: Vomiting.
Skin disorders
Uncommon: Allergic reactions particularly affecting the skin can include maculopapular, morbilliform or scarlatiniform rashes.
Rare: Severe skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and lupus erythematosus.
Psychiatric disorders
Rare: Personality changes, which may include psychotic reactions.
Blood disorders
Rare: Megaloblastic anaemia, blood dyscrasias.
Hepato-biliary disorders
Rare: Elevations in hepatic enzymes, including Gamma-GT and alkaline phosphatase.
Musculoskeletal disorders
Rare: Arthralgia, osteomalacia. Dupuytren’s contracture has been reported.
Renal disorders
Uncommon: Polyuria.
Reproductive system disorders
Uncommon: Impairment of sexual function.
General disorders
Common: Drowsiness.
Uncommon: Headache, dizziness, oedema of the legs, thirst.

Visual disturbances, headache, dizziness, nystagmus, ataxia, vomiting and nausea are usually transient 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 supplement may be needed during long-term MYSOLINE therapy, since vitamin D catabolism may be increased.
Exceptionally, megaloblastic anaemia may develop requiring discontinuation of MYSOLINE. This condition may respond to treatment with folic acid and/or Vitamin B12.
Special precautions
MYSOLINE should be given with caution and reduced dosage may be required in children, the elderly, debilitated patients or those with impaired renal, hepatic or respiratory function.
MYSOLINE can induce liver enzymes and although there is insufficient evidence to suggest a causal relationship, there is a theoretical risk of hepatic damage.
MYSOLINE is a potent CNS depressant and is metabolised to phenobarbitone, therefore the combination of both agents is contra-indicated. However, if patients are to be transferred from phenobarbitone to MYSOLINE, then it is recommended that the withdrawal of phenobarbitone should be done gradually over a period of two weeks, during which time it may be necessary to increase the MYSOLINE dosage to maintain control. After prolonged administration there is a potential for tolerance, dependence and a withdrawal reaction on abrupt cessation of treatment.
Effect on ability to drive or operate machinery
Patients who drive vehicles or operate machinery should be aware of the possibility of impaired reaction time.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Primidone is metabolised to phenobarbitone and overdosage leads to various degrees of CNS depression which, depending on the dose ingested, may include ataxia, loss of consciousness, respiratory depression and coma.
Crystalluria may occur in overdosage and could be used as a helpful diagnostic aid where MYSOLINE overdosage is suspected.
Depending on the severity of intoxication, therapy should include aspiration of stomach contents, administration of intravenous fluids, forced alkaline diuresis and general supportive measures. In more life threatening circumstances, heamoperfusion (if the patient is hypotensive) or haemodialysis are effective.
There is no specific antidote.

IDENTIFICATION
MYSOLINE tablets are round, white to almost white, biconvex, uncoated tablets, bisected on one side with 'M' impressed on either side of the breakline.

PRESENTATION
MYSOLINE tablets: Containers of 100.

STORAGE INSTRUCTIONS
Store below 25ºC.
Protect from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
MYSOLINE tablets: B/2.5/572

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
MIDRAND

DATE OF PUBLICATION OF THIS PACKAGE INSERT
9 October 2009

Updated on this site: May 2014
Source: Pharmaceutical Industry

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