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31/01/2012 Phenobarbital Elixir BP - electronic Medicines Compendium (eMC) - print fri…

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Summary of Product Characteristics last updated on the eMC: 22/11/2011

Phenobarbital Elixir BP

1. NAME OF THE MEDICINAL PRODUCT

Phenobarbital Elixir BP

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Phenobarbital BP 0.3% w/v

3. PHARMACEUTICAL FORM

Elixir

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

As an anticonvulsant in the treatment of all forms of epilepsy except absence seizures.

4.2 Posology and method of administration

Oral

RECOMMENDED DOSE AND DOSAGE SCHEDULE

Usual adult daily dose: 60-200mg phenobarbital taken in 2 or 3 divided portions.

Children: initially 3-6mg per kg body weight per day taken in 2 or 3 divided portions.

Label states: for use as directed by the practitioner

4.3 Contraindications

Contra-indicated in patients with known hypersensitivity to barbiturates or any other ingredient, with severerespiratory depression, with severely impaired hepatic or renal function, and in cases of acute intermittentporphyria. Also in hyperkinetic children.

4.4 Special warnings and precautions for use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in severalindications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has shown a smallincreased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the availabledata do not exclude the possibility of an increased risk for Phenobarbital Elixir BP.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriatetreatment should be considered. Patients (and caregivers of patients) should be advised to seek medicaladvice should signs of suicidal ideation or behaviour emerge.

Thornton & Ross Ltd

Telephone: +44 (0)1484 842217 Fax: +44 (0)1484 847301 WWW: http://www.thorntonandross.com Medical Information Direct Line: +44(0)1484 848 251 Medical Information e-mail: [email protected] Customer Care direct line: +44(0)1484 842 217 Medical Information Fax: +44(0)1484 847 301

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Barbiturates are frequently used in suicidal attempts. In the presence of severe pain, barbiturates may fail toexert their hypnotic action and may cause wakefulness, excitement and delirium unless accompanied by ananalgesic. Phenobarbital should be used with caution in the young, debilitated or senile patients and thosewith renal impairment, existing liver disease or respiratory depression (should be avoided if severe).

Prolonged use may result in the dependence of the alcohol-barbiturate type and particular care should betaken in treating patients with a history of drug abuse or alcoholism. Avoid sudden withdrawal to preventrebound seizures.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of phenobarbital are enhanced by concurrent administration of other sedatives, monoamineoxidase inhibitors and some tranquillizers and may be enhanced by anticholinesterases, sodium valproate,sulphonylurea, antidiabetics and tricyclic antidepressants. Increased sedative effects may occur withphenytoin and sodium valproate. The concommitant administration of barbiturates and alcohol may lead toan additive CNS depressant effect, may produce very serious respiratory depression and a lowering of thelethal dose of phenobarbital.

The effects of other depressants of the central nervous system such as anaesthetics, antihistamines andnarcotic analgesics may also be enhanced.

The effects of phenobarbital may be diminished by rendering the urine alkaline and possibly byantidepressants, antipsycotics, reserpine and folic acid. Phenobarbital may enhance the activity ofmethotrexate, cyclophosphamide and sulphonylureas.

Phenobarbital increases the rate of metabolism of many drugs by induction of drug-metabolising enzymes inliver microsomes. This may result in a reduction in activity. Drugs affected include carbamazepine, coumarinanticoagulants, doxycyline, folic acid, phenylbutazone, phenazone, phenytoin, corticosteroids and othersystemic steroids including oral contraceptives (which may lead to oral contraceptive failure), lamotrigine,rifampicin, phenothiazines, tricyclic antidepressants, calcium channel antagonists (especially felodipine,verapamil, nimodipine and nifedipine – may require an increase in dosage) and theophylline. The activity ofgriseofulvin may be reduced if it is given by mouth with phenobarbital. Plasma concentrations are reducedwhen used with alprenolol, amfebutamone, chloramphenicol, clonazepam, ciclosporin, dicoumarol, digitoxin,disopyramide, doxorubicin, ethosuximide, etopside, fenoprofen, folate, gestrinone, haloperidol, indinavir,itraconazole, lidocaine, methadone, metoprolol, metronidazole, mianserin, montelukast, nelfinavir,paroxetine, phenothiazines (eg. chlorpromazine, mesoridazine, thiodorazine), phenylbutazone, pyridoxine,propafenone, propranolol, quinidine, saquinavir, sodium valproate, tibolone, tiagabine, topisetron, timolol,toremifene and tricyclic antidepressants (eg. imipramine, amitriptyline).

Increased phenobarbital levels may occur when used concomitantly with chloramphenicol,dextropropoxyphene, furosemide, quinine and the influenza vaccine.

Phenobarbital has been shown to reduce the response to thyroxine. Prescribers should be alert for changesin 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 remedy St. John's wort(Hypericum perforatum).

A marked increase in serious skin reactions has been seen in children given cefotaxime and phenobarbital.Phenobarbital may increase the risk of hypersensitivity reactions with the antineoplastic, procarbazine.

Two cases of hepatotoxicity have been reported in patients on phenobarbital after taking paracetamol.

Encephalopathy has been reported in a patient taking phenobarbital and the alkylating cytotoxic drug,ifosfamide.

Interactions between antiepileptics are complex. Concomitant administration of phenobarbital with otherantiepileptics may enhance toxicity without a corresponding increase in antiepileptic effect. Interactions areusually caused by hepatic enzyme induction or hepatic enzyme inhibition. Oxcarbazepine, phenytoin andvalproate often raise the plasma concentration of phenobarbital. As primadone is substantially converted intophenobarbital within the body elevated phenobarbital levels will arise if they are given concurrently. Incontrast, vigabatrin sometimes lowers the plasma concentration of phenobarbital.

4.6 Pregnancy and lactation

The use of phenobarbital in pregnancy, especially the first and third trimesters should be avoided unless it isconsidered to be essential. Phenobarbital can cross the placental barrier and there is an increased risk ofteratogenicity. Neonatal bleeding may occur and prophylactic treatment with vitamin k1 for mother before

delivery (as well as for the neonate) is recommended.

Patients taking phenobarbital should be adequately supplemented with folic acid before conception andduring pregnancy.



Phenobarbital is excreted into breast milk and there is a small risk of neonatal sedation. Breast-feeding istherefore not advisable.

4.7 Effects on ability to drive and use machines

May cause drowsiness. Phenobarbital may impair the mental and/or physical abilities required for theperformance of potentially hazardous tasks such as driving or operating machinery. If patients are affectedthey should not drive or operate machinery.

4.8 Undesirable effects

The side effects of therapeutic doses are mild and include headache, insomnia, subtle mood changes,respiratory depression, sedation, drowsiness, lethargy, mental depression, allergic skin reactions –maculopapular morbilliform or scarlatiniform rashes; fixed-drug eruptions and photosensitivity may occur.Severe reactions such as purpura exfoliative dermatitis, erythema multiforme and toxic epidermal necrolysisare extremely rare. Nystagmus and ataxia may occur with excessive doses. Paradoxical excitement,restlessness and confusion may occur in the elderly or in the presence of pain. Memory and cognitiveimpairment, hyperactivity and behavioural disturbance, irritability and hyperexcitability may occur inchildren. Megaloblastic anaemia (due to folate deficiency) has developed during chronic administration ofphenobarbital for epilepsy and hypoprothrombinaemia has occurred in infants of mothers who have receivedphenobarbital during pregnancy. Hepatitis, cholestasis and osteomalacia have been associated withbarbiturate administration. Continued use of phenobarbital, even in therapeutic doses, may result in psychicor physical dependence. Abrupt withdrawal of the drug may result in a severe abstinence syndrome whichincludes grand mal seizures and delirium; withdrawal should be cautious and gradual.

Disturbances of liver function have been reported and there is some evidence that phenobarbital interfereswith vitamin D metabolism.

Rare effects include macrocytic anaemia, Dupuytren's contracture, Stevens-Johnson syndrome,hypocalcaemia, hypophosphataemia and metabolic bone disease in children on poor diets receiving longterm phenobarbital.

4.9 Overdose

The toxic effects of overdosage include drowsiness, prolonged coma, respiratory depression andcardiovascular depression, with hypotension and shock leading to renal failure. The duration and depth ofcerebral depression varies with the dose and tolerance of the patient. Absent bowel sounds are a sign ofsevere poisoning. Hypothermia is common, with associated pyrexia during recovery. Characteristicerythematous or haemorrhagic blisters occur in about 6% of patients. Death is usually due to respiratory andcirculatory failure. The chronic effects of phenobarbital on neurological and psychic functions closelyresemble those of alcohol. The symptoms of chronic poisoning include disorientation, mental confusion,ataxia, dizziness, depression and skin rashes. The aims in treating poisoning with phenobarbital are tomaintain respiration, treat shock and prevent further absorption of the drug. Supportive measures alonemay be sufficient if symptoms are mild.

Analeptics should generally be avoided. However a single dose of nikethamide may be given in anemergency. If within 4 hours of ingestion, gastric aspiration or lavage may be of benefit in adults. Thestomach should be emptied by lavage with warm water to leave the stomach empty, but only afterprecautions have been taken to avoid aspiration. Apomorphine – induced emesis evacuates the stomachmore rapidly and reliably than doses of ipecacuanha. After lavage, a saline cathartic should be administeredand repeated every 1 to 2 hours, as long as bowel sounds are present. The prime objective of treatment isto maintain vital functions while the majority of the drug is metabolised by hepatic enzymes. Given normalrenal function, forced alkaline diuresis (maintaining the urinary pH at approximately 8 by intravenous fusion)may enhance the excretion of the drug from the kidneys. The potentially fatal dose of phenobarbital is 6 to10g. Attention should be paid to maintenance of a patient's airway and to the prevention of hypostaticpneumonia. Measures should be taken to prevent further loss of body heat.

In severe acute intoxication circulatory collapse is a major threat. Dehydration is often severe. Hypovolemiamust be corrected and if necessary the blood pressure can be supported with dopamine.

Should renal failure occur, haemodialysis or charcoal haemoperfusion may be used to dispose of the poison.Charcoal haemoperfusion is the treatment of choice for the majority of patients with very severe barbituratepoisoning who fail to improve, or who deteriorate despite good supportive care.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The barbiturates reversibly depress the activity of all excitable tissues. Not all tissues are affected at thesame dose or concentration and when barbiturates are given in sedative or hypnotic doses there is very littleeffect on skeletal, cardiac or smooth muscle.



Phenobarbital is a barbiturate drug which has selective anticonvulsant activity and is used to control tonic-clonic seizures in the treatment of epilepsy. In a dose that has only minor effects on the reticular system,phenobarbital elevates the threshold for the initiation of afterdischarges, shortens the period ofafterdischarge, and suppresses the spread of seizures.

5.2 Pharmacokinetic properties

Oral absorption of phenobarbital is complete but slow, peak plasma concentrations occur several hours aftera single dose. It is about 40% bound to plasma proteins and bound to a similar extent in tissues. The volume

of distribution is approximately 0.9 lkg-1 . About 25% of phenobarbital is eliminated by pH-dependent renalexcretion, the remainder is inactivated by the hepatic microsomal enzymes.

The major metabolite is the para hydroxyphenyl derivative, which is inactive and is excreted in the urinepartly as the sulphate conjugate.

Phenobarbital has a plasma half-life of up to about 75 hours in children and 100 hours in adults. This isincreased in the elderly, in overdosage and in renal or hepatic disease.

5.3 Preclinical safety data

No data of relevance, which is additional to that included in other sections of the SPC

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Anise oil BP, coriander oil BP, ethanol (96%) BP, glycerol BP, orange oil terpeneless BP, lemon oilterpeneless BP, tartrazine solution compound BP, purified water BP.

6.2 Incompatibilities

No major incompatibilities known.

6.3 Shelf life

500ml: 36 months unopened.

6.4 Special precautions for storage

Store below 25°C

Protect from light.

6.5 Nature and contents of container

500ml: amber glass bottle with plastic cap with EPE/Saranex liner or white plastic child resistant cap withEPE/Saranex liner.

6.6 Special precautions for disposal and other handling

None.

7. MARKETING AUTHORISATION HOLDER

THORNTON & ROSS LTD

HUDDERSFIELD

HD7 5QH

ENGLAND

8. MARKETING AUTHORISATION NUMBER(S)

PL 00240/6313R

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/5/82, 8/7/97

10. DATE OF REVISION OF THE TEXT

18/09/08



11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

phenobarbital elixir bp - electronic medicines compendium (emc) - print friendly

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