PHENOBARBITAL SODIUM Solution for injection Ref.[7809] Active ingredients: Phenobarbital

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 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.

Steven-Johnson syndrome and toxic epidermal necrolysis

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of phenobarbital. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Phenobarbital treatment should be discontinued. The best results in managing SJS and TEN 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 or TEN with the use of phenobarbital, phenobarbital must not be re-started in this patient at any time.

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) pregnancy, breastfeeding and porphyria.

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.

Sudden withdrawal should be avoided as severe withdrawal syndrome (rebound insomnia, anxiety, tremor, dizziness, nausea, fits and delirium) may be precipitated.

Acute chronic pain – paradoxical excitement may be induced or important symptoms masked.

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

Excipient warning

The maximum daily dose contains 177.9mg of propylene glycol.

Propylene glycol in high doses may cause central nervous system side-effects, lactic acidosis, kidney and liver toxicity, increase in plasma osmolarity, and haemolytic reactions.

Effects on Phenobarbital:

• Alcohol: concurrent administration with alcohol may lead to an additive CNS depressant effect. This is likely with concurrent administration with other CNS depressants.
• Antidepressants: including MAOIs, SSRIs and tricyclics may antagonise the antiepileptic activity of phenobarbital by lowering the convulsive threshold
• Antiepileptics: phenobarbital plasma concentrations increased by oxcarbazepine, phenytoin and sodium valproate. Vigabatrin possibly decreases phenobarbital plasma concentrations.
• Antipsychotics: concurrent use of chlorpromazine and thioridazine with phenobarbital can reduce the serum levels of either drug.
• Folic acid: if folic acid supplements are given to treat folate deficiency, which can be caused by the use of phenobarbital, the serum phenobarbital levels may fall, leading to decreased seizure control in some patients. (see section 4.6).
• Memantine: the effect of Phenobarbital is possibly reduced.
• Methylphenidate: plasma concentration of Phenobarbital is possibly increased.
• St John’s wort (Hypericum perforatum): the effect of phenobarbital can be reduced by concomitant use of the herbal remedy St John’s wort.

Effects of phenobarbital on other medicines:

Phenobarbital increases the rate of metabolism reducing serum concentrations of the following drugs:

• Anti-arrhythmics: disopyramide and quinidine loss of arrhythmia control is possible. Plasma levels of antiarrhymics should be monitored, if phenobarbital is added or withdrawn. Changes in dosage may be necessary.
• __Antibacterials – chloramphenicol, doxycycline, metronidazole and rifampicin. Avoid concomitant use of telithromycin during and for 2 weeks after Phenobarbital.
• Anticoagulants.
• Antidepressants: paroxetine, mianserin and tricyclic antidepressants.
• Antiepileptics: carbamazepine, lamotrigine, tiagabine, zonisamide, primidone and possibly ethosuxamide.
• Antifungals: the antifungal effects of griseofulvin can be reduced or even abolished by concurrent use. Phenobarbital possibly reduces plasma concentrations of itraconazole or posaconazole. Avoid concomitant use of voriconazole.
• Antipsychotics: phenobarbital possibly reduces concentration of aripiprazole.
• Antivirals: phenobarbital possibly reduces plasma levels of abacavir, amprenavir, darunavir, lopinavir, indinavir, nelfinavir, saquinavir.
• Anxiolytics and Hypnotics: clonazepam.
• Aprepitant: phenobarbital possibly reduces plasma concentration of aprepitant.
• Beta-blockers: metoprolol, timolol and possibly propranolol.
• Calcium channel blockers: phenobarbital causes reduced levels of felodipine, isradipine, diltiazem, verapamil, nimodipine and nifedipine and an increase in dosage may be required.
• Cardiac Glycosides: blood levels of digitoxin can be halved by concurrent use.
• Ciclosporin or tacrolimus.
• Corticosteroids.
• Cytotoxics: phenobarbital possibly reduces the plasma levels of etoposide or irinotecan.
• Diuretics: concomitant use with eplerenone should be avoided.
• Haloperidol: serum levels are approximately halved by concurrent used with phenobarbital.
• Hormone Antagonists: gestrinone and possibly toremifene.
• Methadone: levels can be reduced by concurrent use of phenobarbital and withdrawal symptoms have been reported in patients maintained on methadone when phenobarbital has been added. Increases in the methadone dosage may be necessary.
• Montelukast.
• Oestrogens: reduced contraceptive effect.
• Progestogens: reduced contraceptive effect.
• Sodium oxybate: enhanced effects, avoid concomitant use.
• Theophylline: may require an increase in theophylline dose.
• Thyroid hormones: Phenobarbital has been shown to accelerate the metabolism of levothyroxine and liothyronine. Prescribers should be alert for changes in thyroid status if barbiturates are added or withdrawn from patients being treated for hypothyroidism.
• Tibolone
• Tropisetron
• Vitamins: barbiturates possibly increase requirements for vitamin D

Phenobarbital may interfere with some laboratory tests including metyrapone test, phentolamine tests and serum bilirubin estimation.

Pregnancy

Phenobarbital therapy in epileptic pregnant women presents a risk to the foetus in terms of major and minor congenital defects such as congenital craniofacial, digital abnormalities and, less commonly, cleft lip and palate. The risk of teratogenic effects developing appears to be greater if more than one antiepileptic drug is administered. The risk to the mother however is greater if phenobarbital is withheld and seizure control is lost. The risk: benefit balance, in this case, favours continued use of the drug during pregnancy at the lowest possible level to control seizures

Patients taking phenobarbital should be adequately supplemented with folic acid before conception and during pregnancy (see section 4.5). Folic supplementation during pregnancy can help to counteract the risk of neural tube defects.

Phenobarbital readily crosses the placenta following oral administration and is distributed throughout foetal tissue, the highest concentrations being found in the placenta, foetal liver and brain. Adverse effects on neurobehavioral development have also been reported.

Haemorrhage at birth is also a risk. Prophylactic treatment with vitamin K₁ for the mother before delivery (as well as the neonate) is recommended, the neonate should be monitored for signs of bleeding.

Breast-feeding

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

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

Antiepileptic hypersensitivity syndrome may occur. Symptoms include fever, rash, lymphadenopathy and hepatitis.

Blood and the lymphatic system disorders: megaloblastic anaemia (due to folate deficiency), agranulocytosis, thrombocytopenia.

Metabolism and nutritional disorders: osteomalacia, rickets.

Psychiatric disorders: paradoxical reaction (unusual excitement), hallucinations, restlessness and confusion in the elderly, mental depression, memory and cognitive impairment, drowsiness, lethargy.

Nervous system disorders: hyperactivity, behavioural disturbances in children, ataxia, nystagmus.

Cardiac disorders: hypotension.

Respiratory disorders: respiratory depression.

Hepato-bilary: hepatitis, cholestasis.

Skin and subcutaneous tissue disorders: allergic skin reactions (maculopapular morbilliform or scarlatiniform rashes), other skin reactions such as exfoliative dermatitis, erythema multiforme. Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4) very rarely.

Musculoskeletal, connective tissue and bone disorders: 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.

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 at: www.mhra.gov.uk/yellowcard.

None stated.