PRIMIDONE AUDEN 250 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Primidone Auden 250 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg primidone.

Each tablet also contains 55.25 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Primidone 250 mg Tablets are white to off white, circular uncoated tablets, diameter 11.5 mm with ‘PR’ embossed on one side of the break line and ‘250’ on the other side of the break line.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Primidone is indicated in the management of grand mal and psychomotor (temporal lobe) epilepsy. It is also of value in the management of focal or Jacksonian seizures, myoclonic jerks and akinetic attacks.

Management of essential tremor.

4.2 Posology and method of administration

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

Primidone 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.

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, Primidone may be used to augment or replace existing treatment. First add Primidone to the current anticonvulsant treatment by the method of gradual introduction described previously. When a worthwhile effect has been achieved and the amount of Primidone 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 Primidone 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 Primidone substitution should be made earlier, so as to prevent excessive drowsiness from interfering with accurate assessment of the optimum dosage of Primidone.

Essential tremor: Initially a dose of 50 mg daily should be introduced using Primidone 50mg Tablets. 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 Primidone, 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).

4.3 Contraindications

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.

4.4 Special warnings and precautions for use

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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.

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.

Severe skin reactions

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of primidone.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS, TEN or DRESS is within the first weeks of treatment. If symptoms or signs of SJS, TEN or DRESS (e.g. progressive skin rash often with blisters or mucosal lesions) are present, primidone treatment should be discontinued.

The best results in managing SJS, TEN and DRESS come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS, TEN or DRESS with the use of primidone (or phenobarbital), primidone must not be re-started in this patient at any time (see section 4.8).

Women of childbearing , potential

Primidone may cause foetal harm when administered to a pregnant woman. Prenatal exposure to primidone may increase the risk for congenital malformations approximately 2– to 3-fold (see section 4.6).

Primidone should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following consideration of other suitable treatment options. Women of childbearing potential should be fully informed of the potential risk to the foetus if they take primidone during pregnancy.

A pregnancy test to rule out pregnancy should be considered prior to commencing treatment with primidone in women of childbearing potential.

Women of childbearing potential should use highly effective contraception during treatment and for 2 months after the last dose. Due to enzyme induction, primidone may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of childbearing potential should be advised to use other contraceptive methods (see sections 4.5 and 4.6).

Women planning a pregnancy should be advised to consult in advance with her physician so that adequate counselling can be provided and appropriate other treatment options can be discussed prior to conception and before contraception is discontinued.

Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant while on treatment with primidone.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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, cloazepine, chloramphenicol, corticosteroid­s/glucocorticos­teroids, cyclophosphamide, dicoumarins, digitoxin*, doxycycline, ethosuxamide, etoposide, felbamate, granisetron, lamotrigine, losartan, methadone*, metronidazole, mainserin, montelukast*, nelfinavir*, nimodipine, oralcontraceptives, 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.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception

Primidone should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.

A pregnancy test to rule out pregnancy should be considered prior to commencing treatment with primidone in women of childbearing potential.

Women of childbearing potential should use highly effective contraception during treatment with primidone and for 2 months after the last dose. Due to enzyme induction, primidone may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of childbearing potential should be advised to use other contraceptive methods while on treatment with primidone, e.g. two complementary forms of contraception including a barrier method, oral contraceptive containing higher doses of estrogen, or nonhormonal intrauterine device (see section 4.5).

Women of childbearing potential should be informed of and understand the risk of potential harm to the foetus associated with primidone use during pregnancy and the importance of planning a pregnancy.

Women planning a pregnancy should be advised to consult in advance with her physician so that specialist medical advice can be provided and appropriate other treatment options can be discussed prior to conception and before contraception is discontinued.

Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant.

Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant while on treatment with primidone.

Risk related to antiepileptic medicinal products in general

Specialist medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant.

Sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to seizures that could have serious consequences for the woman and the unborn child.

Monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated AEDs.

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.

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.

Risks related to , primidone

Primidone crosses the placenta. Animal studies (literature data) have shown reproductive toxicity in rodents (see section 5.3).

Data from meta-analysis and observational studies showed a risk of major malformations about 2 to 3 times higher than the baseline risk of major malformations in the general population (which is 2–3%). The risk is dose-dependent; however, no dose has been found to be without risk. Primidone monotherapy is associated with an increased risk of major congenital malformations, including cleft lip and palate and cardiovascular malformations. Other malformations involving various body systems including cases of hypospadias, facial dysmorphic features, neural tube effects, craniofacial dysmorphia (microcephaly) and digital abnormalities have also been reported.

Data from a registry study suggest an increase in the risk of infants born small for gestational age or with reduced body length, compared to lamotrigine monotherapy.

Neurodevelopmental disorders have been reported among children exposed to primidone during pregnancy. Studies related to the risk of neurodevelopmental disorders in children exposed to primidone during pregnancy are contradictory and a risk cannot be excluded. Pre-clinical studies have also reported adverse neurodevelopment effects (see section 5.3).

Primidone should not be used during pregnancy unless the potential benefit is judged to outweigh the risks following consideration of other suitable treatment options.

If, following re-evaluation of treatment with primidone, no other treatment option is suitable, the lowest effective dose of primidone should be used. The woman should be fully informed of and understand the risks related to the use of primidone during pregnancy.

When used in the third trimester of pregnancy, withdrawal symptoms may occur in the neonate, including sedation, hypotonia and sucking disorder.

Patients taking primidone should be adequately supplemented with folic acid before conception and during pregnancy.

In infants born of epileptic mothers treated with primidone, there have been reports of congenital abnormalities associated with maternal folate deficiency, including microencephaly and anencephaly.

During breast feeding the baby should be monitored for sedation.

There is insufficient fertility data available to indicate whether primidone has any effect on fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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.

Undesirable effects are listed by MedDRA System Organ Classes. Assessment of undesirable effects is based on the following frequency groupings:

■ 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

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Primidone is metabolised extensively to phenobarbitone and overdosage leads to varying 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 primidone overdosage is suspected.

Depending on the severity of intoxication, therapy should include aspiration of stomach contents, administration of activated charcoal, administration of intravenous fluids, forced alkaline diuresis (striving for a urine pH of 8.0), and general supportive measures. In more life threatening circumstances, haemoperfusion (if the patient is hypotensive) or haemodialysis are effective.

There is no specific antidote.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics (barbiturates and derivatives).

Therapeutic classification: N03AA03

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, in common with other anticonvulsants, effects on the neuronal membrane particularly with respect to alteration of ionic fluxes are likely to play a fundamental role.

Primidone, as with other anticonvulsants, can induce liver enzymes.

5.2 Pharmacokinetic properties

Primidone is absorbed rapidly from the gastrointestinal tract, peak plasma levels being 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. The pharmacokinetics of primidone are complex because of biotransformation into two metabolites, phenobarbitone and phenylethylma­lonamide, that have anticonvulsant activity and complex pharmacokinetic properties. Primidone has a plasma half-life of approximately 10 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.

5.3 Preclinical safety data

Primidone is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

Published studies reported teratogenic effects (morphological defects) in rodents exposed to primidone. Cleft palate is reported consistently in all preclinical studies but other malformations are also reported (e.g. umbilical hernia, spina bifida, exencephaly, exomphalos plus fused ribs) in single studies or species.

In addition, although data from the published studies are inconsistent, primidone given to rats/mice during gestation or early postnatal period was associated with adverse neurodevelopment effects, including alterations in locomotor activity, cognition and learning patterns.

6.1

6.2

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate (type A)

Povidone K30

Sodium lauryl sulfate

Colloidal anhydrous silica

Stearic acid

Magnesium stearate

None applicable.

6.3 Shelf life

24 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/aluminium blisters. Pack size of 100 tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited

Brampton Road

Hampden Park

Eastbourne

BN22 9AG

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/2329

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

22/05/2015