Primidone actavis

Overdose

Primidone Actavis 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 Actavis 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.

No information provided.

Contraindications

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

Primidone is contraindicated in: 1) patients with porphyria and 2) patients who are hypersensitive to phenobarbital (see Actions).

Incompatibilities

None known.

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.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Primidone Actavis. The mechanism by which Primidone Actavis 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.

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

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

The most frequently occurring early side effects are ataxia and vertigo. These tend to disappear with continued therapy, or with reduction of initial dosage. Occasionally, the following have been reported: nausea, anorexia, vomiting, fatigue, hyperirritability, emotional disturbances, sexual impotency, diplopia, nystagmus, drowsiness, and morbilliform skin eruptions. Granulocytopenia, agranulocytosis, and red-cell hypoplasia and aplasia, have been reported rarely. These and, occasionally, other persistant or severe side effects may necessitate withdrawal of the drug. Megaloblastic anemia may occur as a rare idiosyncrasy to Primidone Actavis and to other anticonvulsants. The anemia responds to folic acid without necessity of discontinuing medication.

Preclinical safety data

Primidone Actavis 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.

Primidone Actavis price

Therapeutic indications

'Primidone Actavis' 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.

Primidone Actavis, used alone or concomitantly with other anticonvulsants, is indicated in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy.

Pharmacodynamic properties

The activity of 'Primidone Actavis' is due to the anticonvulsant properties of three active moieties, namely Primidone Actavis 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 Actavis' 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 Actavis', as with other anticonvulsants, can induce liver enzymes.

Pharmacokinetic properties

'Primidone Actavis' is absorbed rapidly from the gastrointestinal tract, peak plasma levels being attained approximately 3 hours after ingestion. Primidone Actavis 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 Actavis are complex because of biotransformation into two metabolites, phenobarbitone and phenylethylmalonamide, that have anticonvulsant activity and complex pharmacokinetic properties. Primidone Actavis has a plasma half-life of approximately 10 hours which is considerably shorter than those of its principal metabolites. Primidone Actavis 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

'Primidone Actavis' 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 Actavis is a potent CNS depressant and is partially metabolised to phenobarbitone.

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 Actavis.

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.

The abrupt withdrawal of antiepileptic medication may precipitate status epilepticus. The therapeutic efficacy of a dosage regimen takes several weeks before it can be assessed.

Antiepileptic drugs (AEDS), including Primidone Actavis, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 : Risk by indication for antiepileptic drugs in the pooled analysis

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Primidone Actavis or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

To provide information regarding the effects of in utero exposure to Primidone Actavis, physicians are advised to recommend that pregnant patients taking Primidone Actavis enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334 , and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

The effects of Primidone Actavis in human pregnancy and nursing infants are unknown.

Recent reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship.

There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors leading to birth defects, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorders are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential. Neonatal hemorrhage, with a coagulation defect resembling vitamin K deficiency, has been described in newborns whose mothers were taking primidone and other anticonvulsants. Pregnant women under anticonvulsant therapy should receive prophylactic vitamin K1 therapy for one month prior to, and during, delivery.

The total daily dosage should not exceed 2 g. Since Primidone Actavis therapy generally extends over prolonged periods, a complete blood count and a sequential multiple analysis-12 (SMA-12) test should be made every six months.

There is evidence in mothers treated with primidone, the drug appears in the milk in substantial quantities. Since tests for the presence of primidone in biological fluids are too complex to be carried out in the average clinical laboratory, it is suggested that the presence of undue somnolence and drowsiness in nursing newborns of Primidone Actavis-treated mothers be taken as an indication that nursing should be discontinued.

Patients, their caregivers, and families should be counseled that AEDs, including Primidone Actavis, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see Usage in Pregnancy section).

Please refer to the Primidone Actavis Medication Guide provided with the product for more information.

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.

Dosage (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 Actavis' alone, but in some, 'Primidone Actavis' will need to be combined with other anticonvulsants or with supporting therapy.

'Primidone Actavis' 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 Actavis.

Patients on other anticonvulsants: Where a patient's attacks are not sufficiently well controlled with other anticonvulsants, or disturbing side effects have arisen, 'Primidone Actavis' may be used to augment or replace existing treatment. First add 'Primidone Actavis' 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 Actavis' 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 Actavis' 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 Actavis' substitution should be made earlier, so as to prevent excessive drowsiness from interfering with accurate assessment of the optimum dosage of 'Primidone Actavis'.

Essential tremor: Initially a dose of 50 mg daily should be introduced using Primidone Actavis 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 intolerance to 'Primidone Actavis', 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).

Patients 8 years of age and older who have received no previous treatment may be started on Primidone Actavis according to the following regimen using either 50 mg or scored 250 mg Primidone Actavis tablets:

Days 1 to 3: 100 to 125 mg at bedtime.

Days 4 to 6: 100 to 125 mg b.i.d.

Days 7 to 9: 100 to 125 mg t.i.d.

Day 10 to maintenance: 250 mg t.i.d.

For most adults and children 8 years of age and over, the usual maintenance dosage is three to four 250 mg Primidone Actavis tablets in divided doses (250 mg t.i.d. or q.i.d.). If required, an increase to five or six 250 mg tablets daily may be made but daily doses should not exceed 500 mg q.i.d.

INITIAL: ADULTS AND CHILDREN OVER 8

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations of primidone may be necessary for optimal dosage adjustment. The clinically effective serum level for primidone is between 5 to 12 μg/mL.

Primidone Actavis should be started at 100 to 125 mg at bedtime and gradually increased to maintenance level as the other drug is gradually decreased. This regimen should be continued until satisfactory dosage level is achieved for the combination, or the other medication is completely withdrawn. When therapy with Primidone Actavis alone is the objective, the transition from concomitant therapy should not be completed in less than two weeks.

For children under 8 years of age, the following regimen may be used:

Days 1 to 3: 50 mg at bedtime.

Days 4 to 6: 50 mg b.i.d.

Days 7 to 9: 100 mg b.i.d.

Day 10 to maintenance: 125 mg t.i.d. to 250 mg t.i.d.

For children under 8 years of age, the usual maintenance dosage is 125 to 250 mg three times daily or, 10 to 25 mg/kg/day in divided doses.

Special precautions for disposal and other handling

To be taken as directed by the prescriber.