Pentobarbital

Category D.

Risk summary statement

Anaesthetic and sedative agents are a necessary part of the care of children and pregnant women needing surgery, other procedures or tests that cannot be delayed, and no specific medicines have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anaesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Preclinical data

Published studies in pregnant primates demonstrate that the administration of anaesthetic and sedative agents that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.

Barbiturates readily cross the placenta and are distributed throughout foetal tissues. The highest concentrations are found in the placenta and in the foetal liver and brain. Prenatal exposure to barbiturates has been reported to increase the risk of foetal abnormalities and of brain tumours.

The risk of giving birth to a child with an abnormality as a result of antiepileptic medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.

It is recommended that:

• women on antiepileptic drugs (AEDs) receive pre pregnancy counselling with regard to the risk of foetal abnormalities;
• AEDs should be continued during pregnancy and mono therapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
• folic acid supplementation (5mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
• specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

The risk of a mother with epilepsy giving birth to a child with an abnormality is about three times that of the general population.

The use in pregnancy of phenobarbital has been associated with minor craniofacial defects, fingernail hypoplasia and developmental disability. Barbiturates can give rise to hypotension, respiratory depression and hypothermia in the new born infant. Continuous treatment during pregnancy and administration during labour should be avoided.

The use of phenobarbital in pregnancy alone, or in combination with other anticonvulsants, can cause coagulation defects in the new born infant which may be preventable by the prophylactic administration of vitamin K to the mother prior to delivery.

The serum level of phenobarbital may decline during pregnancy requiring adjustments in dosage. Postpartum restoration of the original dose will probably be indicated.

Barbiturate withdrawal has been reported in neonates who have been exposed to the drug in utero. Withdrawal may occur 1 to 14 days after birth and symptoms include seizures, irritability, disturbed sleep, tremor, hypotonia, vomiting and hyperreflexia.

Phenobarbital is not recommended in breastfeeding mothers. Phenobarbital is distributed into breast milk and use by breastfeeding mothers may cause CNS depression.

Fertility

Carcinogenesis, mutagenesis, impairment of fertility

Phenobarbital is carcinogenic in mice and rats after lifetime administration. In mice it produced benign and malignant liver cell tumours. In rats, benign liver cell tumours were observed.

Phenobarbital was negative in a 26 week bioassay in p53 heterozygous mice. Genotoxicity studies for gene mutations and chromosome aberrations have given mixed results, however tests for DNA damage or repair have been negative. In a 29 year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included Phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma. Previously some of the patients had been treated with thorotrast, a drug known to cause hepatic carcinomas. When patients who had received thorotrast had been included, there was a non-significant increase in the number of liver tumours and, unlike the mouse liver tumours, were mostly associated with cirrhosis.

Phenobarbital causes drowsiness and is likely to impair the patient’s ability to concentrate and react constituting a risk in the ability to drive and use machines. Patients taking Phenobarbital, should not take charge of vehicles, or machinery where loss of attention could cause accidents.

Adverse effects include the following:

• Suicidal Behaviour
• Suicidal Ideation
• Emergence or worsening of existing depression

The most frequent adverse effect following administration of Phenobarbital is sedation, but this often becomes less marked with continued administration. Like some other antiepileptic agents Phenobarbital may produce subtle mood changes and impairment of cognition and memory, which may not be apparent without testing.

Prolonged administration may occasionally result in folate deficiency or hypocalcaemia; rarely, megaloblastic anaemia or osteomalacia have been reported.

At high dose nystagmus and ataxia may occur and the typical barbiturate-induced respiratory depression may become severe. Overdosage may result in coma, severe respiratory and cardiovascular depression, hypotension and shock leading to renal failure, and death. Hypothermia may occur, with associated pyrexia during recovery. Skin blisters (bullae) reportedly occur in about 6% of patients with barbiturate overdose.

Owing to their extreme alkalinity necrosis has followed subcutaneous injection or extravasation of sodium salts of barbiturates. Intravenous injections can be hazardous and cause hypotension, shock, laryngospasm, and apnoea.

Phenobarbital and other anticonvulsants that have been shown to induce the CYP450 enzymes are thought to affect bone mineral metabolism directly by increasing the metabolism of vitamin D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcaemia, and hypophosphataemia in chronically treated epileptic patients.

Hypersensitivity reactions occur in a small proportion of patients; skin reactions are reported in 1 to 3% of patients receiving Phenobarbital, and are most commonly maculopapular, morbilliform, or scarlatiniform rashes. More severe reactions such as exfoliative dermatitis, erythema multiform (or Stevens-Johnson syndrome), and toxic epidermal necrolysis are extremely rare. Hepatitis and disturbances of liver function have been reported.

Paradoxical excitement, irritability and hyperexcitability may sometimes occur, particularly in children or the elderly.

Neonatal drug dependence and symptoms resembling vitamin K deficiency have been reported in infants born to mothers who received Phenobarbital during pregnancy.

Congenital malformations have been reported in children of women who received Phenobarbital during pregnancy but the casual role of the drug is a matter of some debate.