SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Phenobarbital Sodium Injection BP 60mg/ml

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 60mg of Phenobarbital Sodium BP

3    PHARMACEUTICAL FORM

Solution for Injection

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

An anti-convulsant.

4.2    Posology and method of administration

Adults 50 - 200mg as a single dose by intramuscular, subcutaneous or, after dilution with 10 times its own volume of Water for Injection, by intravenous injection, repeated, if necessary, after 6 hours.

Children 3 - 5mg per kg body weight as a single dose by intramuscular injection.

4.3 Contraindications

Known hypersensitivity to barbiturates or any of the ingredients. Severe respiratory depression.

Acute intermittent porphyria.

Severe impairment of renal or hepatic function.

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 Phenobarbital Sodium.

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.

Phenobarbital should be used with caution in the young, elderly, senile or debilitated patient and those with renal impairment, existing liver disease or respiratory depression, (should be avoided if severe).

Prolonged use may result in dependence of the alcohol-barbiturate type and care must be taken in treating patients with a history of drug abuse or alcoholism.

Intravenous use must be preceded by dilution as described in section 4.2. Subcutaneous injection can cause tissue necrosis.

To prevent rebound seizures withdrawal from the drug should be cautious and gradual.

Herbal preparations containing St John’s wort ( Hypericum perforatum) should not be used while taking phenobarbital due to the risk of decreased plasma concentrations and reduced clinical effects of phenobarbital

4.5 Interaction with other medicinal products and other forms of interaction

Phenobarbital should not be taken concomitantly with CNS depressants including alcohol as this may lead to additive CNS depressant effect.

Phenobarbital causes hepatic microsomal enzyme induction which increases the rate of metabolism of some drugs and consequently serum concentrations of certain drugs may be reduced. These include coumarin anticoagulants, digitoxin, disopyramide, quinidine, leukopritrionine antagonist montelukast, phenytoin, lamotrigine, carbamazepine, phenylbutazone, systemic steroids leading to a reduced effect and oral contraceptives (possibly leading to contraceptive failure), phenothiazines, tricyclic antidepressants, griseofulvin and voriconozole, rifampicin, chloramphenicol, doxycycline, metronidazole, cyclosporin, calcium channel blocking agents (especially felodipine, verapamil, nimodipine and nifedipine - may require an increase in dosage) and theophylline.

The plasma concentrations of indinavir, lopinavir, nelfinavir and saquinavir may be reduced by concomitant administration with phenobarbital.

Phenobarbital therapy may increase vitamin D requirements.

The effect of phenobarbital may possibly be reduced by memantine.

The metabolism of toremifene may be accelerated by phenobarbital.

The convulsive threshold may be lowered by simultaneous use of antipsychotic drugs. Phenobarbital also accelerates the metabolism of haloperidol.

Telithromycin should not be given during or within 2 weeks of discontinuation of treatment with phenobarbital due to reduced plasma concentrations of the antibiotic.

The plasma concentration of tropisetron is reduced by concomitant use of phenobarbital.

Folic acid or folinic acid may possibly reduce plasma concentrations of phenobarbital.

Increased sedative effects may occur with phenytoin and sodium valproate.

Phenobarbital has been shown to reduce the response to thyroxine. Prescribers should be alert for changes in thyroid status if barbiturates are added or withdrawn from patients being treated for hypothyroidism.

The effect of phenobarbital can be reduced by concomitant use of the herbal preparation St John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St. John’s wort. Herbal preparations containing St. John’s wort should therefore not be combined with phenobarbital. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John’s wort. If a patient is already taking St. John’s wort check the anticonvulsant levels and stop St John’s wort. Anticonvulsant levels may increase on stopping St. John’s wort. The dose of anticonvulsant may need adjusting.

4.6 Pregnancy and lactation

The use of phenobarbital within the 1st and 3rd trimesters should be avoided unless considered essential. Phenobarbital can cross the placental barrier and the risk of teratogenicity is increased. Neonatal bleeding may occur due to depletion of foetal vitamin K₁ reserves and prophylactic treatment with vitamin K₁ for the mother before delivery may be necessary. Vitamin K₁ should also be given to the neonate immediately after delivery. Neonates may develop withdrawal symptoms.

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

Phenobarbital is excreted into breast milk and may cause sedation in the infant though the risk is probably small. Breastfeeding is therefore not recommended.

4.7 Effects on ability to drive and use machines

Phenobarbital may effect the mental and/or physical abilities of the patient. If affected patients should not drive or operate machinery.

4.8 Undesirable effects

•    Megaloblastic anaemia (due to folate deficiency). Agranulocytosis, aplastic anaemia and macrocytic anaemia are rare but severe effects.

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

•    Osteomalacia, hypocalcaemia and Dupuytren’s contracture are rare effects associated with continued use of the drug.

•    Mental depression and confusion, Memory and cognitive impairment, hyperactivity and behavioural disturbance. Paradoxical excitement, irritability and hyperexcitabilty may sometimes occur particularly in the elderly and children.

•    Drowsiness and lethargy.

•    Nystagmus.

•    Ataxia and respiratory depression.

•    Allergic skin reactions, maculopapular, morbilliform or scarlatiniform rashes can occur in a small proportion of patients. Severe reactions such as widespread exfoliate dermatitis, erythema multiforme and toxic epidermal necrolysis are extremely rare.

•    Hepatitis and cholestasis have been associated with barbiturate administration.

4.9 Overdose

Symptoms. These include drowsiness, coma, hypotension, hypothermia, and

respiratory and cardiovascular depression. The duration and depth of cerebral depression varies with the dose and the tolerance of the patient.

Treatment. Supportive measures alone may be sufficient if symptoms are mild. If an overdose is taken by mouth and within 4 hours of ingestion, gastric aspiration or lavage may be of benefit to adults. The prime objective of treatment is to maintain vital functions, respiration, cardiovascular and renal functions and the electrolyte balance while the majority of the drug is metabolised by hepatic enzymes. Given normal renal function, forced alkaline diuresis (maintaining the urinary pH at approximately 8 by intravenous infusion) may enhance the excretion of the drug from the kidneys. Charcoal haemoperfusion is the treatment of choice for the majority of patients with severe barbiturate poisoning who fail to improve or who deteriorate despite good supportive care.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Phenobarbital is a long acting barbiturate with hypnotic and anti-convulsant properties.

5.2 Pharmacokinetic properties

The plasma half-life (T _1/2) is about 75 hours in children and about 100 hours in adults.

It is about 40% plasma bound.

Excretion is mainly in the urine (and is increased in alkaline urine) with about 30% of the drug unchanged. The remainder is inactivated in the liver.

Phenobarbital crosses the placenta and is secreted in the milk of nursing mothers.

5.3 Preclinical safety data

No additional pre-clinical data of relevance to the prescriber is available.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Disodium Edetate BP, Propylene Glycol BP and Water for Injection BP.

6.2    Incompatibilities

None stated.

6.3    Shelf life

24 months.

6.4    Special precautions for storage

Protect from light.

6.5    Nature and contents of container

Clear type 1 Ph Eur glass ampoules each containing sufficient product to allow removal of 1ml. Sold in cardboard outers of 10 ampoules.