Phenobarbitone Injection

Phenobarbitone sodium.20mg/0.5ml

Presentation
Phenobarbitone Injection is a clear, colourless to pale yellow, sterile solution of phenobarbitone sodium in Water for Injections. Each 0.5 mL contains 20 mg of phenobarbitone sodium and 2% w/v benzyl alcohol in a mixture of nine volumes of propylene glycol and one volume of Water for Injections.

Uses
Actions
Phenobarbitone is a non-selective central nervous system depressant with a long duration of action. It is mainly used for its anticonvulsant properties. The mechanism of action of barbiturates is not completely known. They may act by enhancing and/or mimicking the synaptic action of gamma-aminobutyric acid (GABA). The anticonvulsant properties are believed to be due to depression of monosynaptic and polysynaptic transmission and increasing the threshold for electrical stimulation of the motor cortex. Phenobarbitone is reported to have anticonvulsant activity at subhypnotic doses.

Pharmacokinetics
The onset of action of phenobarbitone is usually seen within 5 minutes after IV administration. IM administration of the drug results in a slightly slower onset of action. Phenobarbitone is rapidly distributed to all tissues and fluids, with the highest concentrations appearing in the brain, liver and kidneys. Maximal CNS depression may not occur for 15 minutes or more after IV administration. Phenobarbitone is about 45% bound to plasma proteins and is only partly metabolised in the liver. About 25% is excreted in the urine unchanged at normal urinary pH. It is known that urinary pH and rate of urine flow can affect the renal circulation of unchanged phenobarbitone, with a greater quantity being eliminated in alkaline urine and at increased flow rates. There is considerable interindividual variation in phenobarbitone kinetics, with metabolic elimination being influenced by age, chronic liver disease and other drugs. The plasma half-life is 90 to 100 hours in adults, and 65 to 70 hours in children, but is greatly prolonged in neonates. When used as an anticonvulsant monitoring of plasma concentrations has been performed as an aid in assessing control. The therapeutic range of plasma
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phenobarbitone is usually quoted as being 15 to 40 micrograms per mL (65 to 170 micromol per litre). Barbiturates readily cross the placenta and, if administered IV, foetal blood concentrations are approximately equal to maternal serum concentrations. Phenobarbitone is excreted into breast milk.

Indications
Phenobarbitone Injection is used in the emergency treatment of certain acute convulsive episodes such as those associated with status epilepticus, eclampsia, meningitis, and toxic reactions to strychnine; as adjunctive treatment for acute convulsive episodes associated with tetanus; and in the treatment of febrile seizures. Case reports have suggested that neonates suffered a toxic syndrome (such as metabolic acidosis) which appears to be associated with the use of benzyl alcohol. In view of this, the use of this preparation, which contains benzyl alcohol, is not recommended in neonates.

Dosage and Administration

Phenobarbitone sodium is administered by Intramuscular (IM) or slow Intravenous (IV) injection. The solution for IM injection is highly alkaline and may cause tissue damage; limit injection volume to 5mL at any one site (see Precautions). For IV injection, the solution should be diluted 1 in 10 with water for injection, dextrose 5%, sodium chloride/dextrose solutions, lactated ringer's solution or sodium chloride 0.9%. The rate of IV injection should not exceed 60mg per minute to avoid the risk of serious respiratory depression and/or cardiovascular collapse. Intravenous administration should not to be attempted without adequate provisions for supporting respiration and circulation (see Precautions). When phenobarbitone is administered IV, the onset of action usually occurs within 5 minutes and maximum effects are achieved within 30 minutes (see Pharmacokinetics). Dosage reduction is required in the elderly and in patients with decreased renal or hepatic function. No solution containing a precipitate, or that is more than slightly discoloured should be used. Anticonvulsant: Adults: 100 to 320 mg IV with additional doses if necessary to a maximum dose of 600 mg in a 24 hour period.

Children: As a loading dose, 10 to 20 mg/kg IV; maintenance, 1 to 6 mg/kg/day IV. Status epilepticus: Adults: 10 to 20 mg/kg by slow IV injection. Repeat if necessary at 20 minute intervals, until the seizure is controlled or a total dose of 1 to 2 g is given. Children: 15 to 20 mg/kg by slow IV injection over 10 minutes. Repeat if necessary at a dose of 5 to 10 mg/kg every 20 minutes until the seizure is controlled or a total dose of 40 mg/kg is given.

Contraindications
Phenobarbitone is contraindicated in patients with known barbiturate sensitivity. It is contradicted in patients with a history of manifest or latent porphyria patients with severe respiratory depression or pulmonary insufficiency, marked hepatic impairment or sleep apnoea. Large doses of phenobarbitone are contraindicated in patients with nephritis. Phenobarbitone should not be administered to persons with known previous addiction to the sedative-hypnotic group since ordinary doses may be ineffectual and may contribute to further addiction. Intra-arterial administration is contraindicated. Its consequences vary from transient pain to gangrene. Subcutaneous administration is not recommended because it produces tissue irritation, ranging from tenderness and redness to necrosis. Phenobarbitone should not be administered to patients showing the premonitory signs of hepatic coma. Phenobarbitone should not to be used in the presence of uncontrolled pain as paradoxical excitement may be produced.

Warnings and Precautions

General
Emergency facilities such as resuscitative equipment, oxygen, drugs required for treatment of overdosage (eg. vasopressor), devices for haemodialysis or haemoperfusion and personnel resources needed for proper management of toxic reactions must all be readily available whenever phenobarbitone is used (see Overdosage -Treatment). Prolonged use of phenobarbitone may result in psychological and/or physical dependence. Phenobarbitone withdrawal may occur when the medication is discontinued. Major symptoms include convulsions and hallucinations, which may occur within 16 hours
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and last up to 5 days. Minor symptoms may occur within 8 to 12 hours and usually occur in the following sequence: anxiety or restlessness; muscle twitching; trembling of hands; weakness; dizziness; vision problems; nausea; vomiting; trouble in sleeping, increased dreaming or nightmares; and orthostatic hypotension. The intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Blood counts in patients should be determined prior to and periodically during therapy with phenobarbitone. Patients should be instructed to report immediately symptoms such as sore throat, fever, easy bruising, petechiae, epistaxis, or other signs of infection or bleeding tendency which may be indications of haematologic toxicity. Therapy should be discontinued if blood dyscrasias occur. Caution is essential when phenobarbitone is administered in the presence of any respiratory difficulty. Caution is recommended in elderly or debilitated patients because they may react to phenobarbitone with marked excitement, depression, or confusion. In some persons, especially children, phenobarbitone may produce excitement rather than depression. Alcohol should not be consumed while taking phenobarbitone. The concurrent use of phenobarbitone with other CNS depressants (eg alcohol, narcotics, tranquilisers, and antihistamines) may result in additional CNS-depressant effects; caution is recommended and dosage reduction of either or both medications may be needed. Intramuscular injection should not exceed a volume of 5 mL at any one site because of the possibility of tissue damage. Phenobarbitone solution is highly alkaline. Extreme care should be taken to avoid perivascular extravasation or intra-arterial injection. Extravascular injection may cause local tissue damage, with subsequent necrosis. The consequences of intraarterial injection may vary from transient pain along the course of the artery to gangrene of the limb. Signs of accidental injection by this route include, in addition to pain, pallor and cyanosis of the extremity and patchy discolouration of the skin. Any complaint of pain in the limb warrants stopping the injection. Caution should be paid when phenobarbitone is used in patients with a tendency to hypersensitivity reactions. Phenobarbitone causes some type of skin reaction in 13% of all patients. Hypersensitivity reactions to phenobarbitone include urticaria, angioedema, mild maculopapular, morbilliform, or scarlatiniform rashes which resolve quickly when the drug is discontinued. Fever, serum sickness, exfoliative dermatitis, erythema multiforme, or Stevens-Johnson syndrome have also been reported. Since skin eruptions can precede potentially fatal reactions, barbiturates should be discontinued whenever dermatologic reactions occur. Hypersensitivity reactions are more likely to occur in patients with asthma, urticaria, or angioedema. Caution should be paid when phenobarbitone is used in patients with a history of asthma because the use of phenobarbitone may increase the risk of bronchospastic reactions.

Intravenous administration of phenobarbitone may result in vasodilatation and hypotension, particularly in patients with hypertension. Rapid injection can cause cardiovascular collapse. Slow administration will usually prevent this occurrence, but may cause apnea, laryngospasm, coughing, or other respiratory difficulties. To avoid the risk of serious respiratory depression and/or cardiovascular collapse, the rate of intravenous injection should not exceed 60 mg per minute. Phenobarbitone should be used with caution in patients with acute or chronic pain, since paradoxical excitement may occur or important symptoms might be masked. Caution should be exercised when using phenobarbitone in children because the drug may exacerbate existing hyperkinetic behaviour, which is sometimes severe enough to necessitate a change to a different barbiturate derivative or another anticonvulsant. The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbitone. Thus, this product should be administered with caution in patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin. Caution should be paid in patients with hyperthyroidism because symptoms may be exacerbated as a result of barbiturates displacing thyroxine from plasma proteins. Although rare, rickets and osteomalacia have been reported following prolonged usage of barbiturates due to increased metabolism of vitamin D.

Impaired renal function

Phenobarbitone is excreted via the kidneys; reduction in phenobarbitone dosage may be necessary in patients with renal function impairment. Dosage may need to be reduced in elderly patients where age-related renal function impairment is common.

Impaired hepatic function

Phenobarbitone should be administrated with caution and initially in reduced doses in patients with hepatic damage. In case of severely impaired liver function, Phenobarbitone should be used with extreme caution.

Pregnancy and Lactation

Use In Pregnancy Category D. 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 fetal tissues. The highest concentrations are found in the placenta and in the fetal liver and brain.

Prenatal exposure to barbiturates has been reported to increase the risk of fetal abnormalities and of brain tumors. The risk of having an abnormal child as a result of medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy. The risk of a mother with epilepsy giving birth to a baby with an abnormality is about three times that of the general population. Mothers taking more than one anticonvulsant drug have a higher risk of having a baby with a malformation than mothers taking one drug. The use of phenobarbitone in pregnancy has been associated with minor craniofacial defects, fingernail hypoplasia and development of disability. The use of phenobarbitone in pregnancy, alone or in combination with other anticonvulsants, can cause coagulation defects in the newborn infant that may be preventable by the prophylactic administration of vitamin K to the mother prior to delivery. The serum level of phenobarbitone may decline during pregnancy requiring adjustments in dosage. Postpartum restoration of the original dosage will probably be indicated. Barbiturate withdrawal has been reported in neonates who have been exposed to the drug in-utero. Withdrawal may occur from 1-14 days after birth, and symptoms include seizures, irritability, disturbed sleep, tremor, hypotonia, vomiting and hyperreflexia. Use in Lactation Phenobarbitone is distributed into breast milk and may cause CNS depression in the infant. Breast milk concentrations are 35 to 50% of maternal serum concentrations. Breast fed infants should be observed for excessive drowsiness, feeding problems, rash or other adverse effects. If any of these occur, breast-feeding should be discontinued. When breast-feeding is discontinued there exists a potential for withdrawal symptoms in the infant. Barbiturates are eliminated slowly in neonates and the drug may accumulate. Monitor serum concentrations in infant if possible.

Effects on ability to drive and use machines

Phenobarbitone and other barbiturates cause drowsiness and may impair the patient's ability to concentrate and react and therefore constitute a risk in the ability to drive and use machines. Patients receiving them, if affected should not take charge of vehicles, or machinery where loss of attention could cause accidents.

Other
Carcinogenecity and Mutagenecity Phenobarbitone 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 very late in life. While there is no sufficient evidence to suggest that
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phenobarbitone is carcinogenic in humans, one retrospective case-control study has suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Adverse Effects
Nervous system
Common: sedation. Uncommon: agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, thinking abnormality, subtle mood changes, impairment of concentration, judgement, memory and fine motor skills. Disturbances of sleep, vertigo, headache and depression.

Respiratory system
Uncommon: severe respiratory depression, apnea, laryngospasm or bronchospasm. This may occur with IV administration, especially if dose is administered too rapidly (see Precautions).

Cardiovascular system:
Uncommon: bradycardia, vasodilatation, hypotension, syncope. Hypotension is generally related to the rate of IV administration (see Precautions)

Digestive system:
Uncommon: nausea, vomiting, diarrhoea and constipation.

Haematological:
Uncommon: folate deficiency or hypocalcaemia, megaloblastic anaemia and lymphocytosis Rare: Agranulocytosis and thrombocytopenia.

Dermatological:
Very common: skin blisters (bullae) in patients with barbiturate overdose, evidence of connective tissue changes. Uncommon: injection site reactions, erythroderma, hypersensitivity reactions such as angioedema and skin rashes. Rare: exfoliative dermatitis, erythema multiforme (or Stevens-Johnson syndrome) and toxic epidermal necrolysis.
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Hepatic
Uncommon: liver damage Rare: toxic hepatitis and jaundice

Metabolic
Uncommon: increased vitamin D requirements, possibly due to increased vitamin D metabolism. Rare: rickets and osteomalacia

Musculoskeletal
Very common: development of Dupuytren's contracture, frozen shoulder, Ledderhose syndrome, Peyronie's disease, fibromas and general joint pain.

Endocrine System
Uncommon: effects on sex hormone; increased baseline levels of prolactin and its reduced response to stimulation, reduced baseline levels of luteinising and folliclestimulating hormones as well as increased bound serum level of testosterone as a result of increased synthesis of the specific transport protein, namely sex hormonebinding globulin.

Other Adverse Effects

Uncommon: fever and menstrually related mood disorder

Interactions
Pharmacokinetic interactions
Phenobarbitone appears to increase the rate of metabolism of many drugs by induction of hepatic microsomal enzymes. Consequently, concurrent use with phenobarbitone may result in lowered blood levels and reduced effects of these drugs. Subsequent discontinuation of phenobarbitone may result in enhanced effects or even toxicity of some of these drugs. Oral anticoagulants: Barbiturates may increase the metabolism of oral anticoagulants resulting in decreased anticoagulant response (eg. warfarin and phenindione). Correspondingly, if phenobarbitone is discontinued from a stabilised dosage, the hypoprothrombinaemic response may be greatly increased, potentially resulting in haemorrhagic complications. Prothrombin times should be monitored closely if phenobarbitone is added or deleted from a regimen that includes oral anticoagulants.

Tricyclic antidepressants (TCAs): Phenobarbitone may increase the metabolism of TCAs, resulting in lack of effect. Plasma TCA levels should be monitored if possible, especially if the patient is not responding to standard dosages of antidepressants. Anticonvulsants: Carbamazepine: Phenobarbitone usually accelerates the metabolism of carbamazepine, resulting in decreased plasma concentrations. Phenytoin: When phenobarbitone is used with phenytoin, concentrations of either or both drugs may be affected. While phenobarbitone may induce the metabolism of phenytoin, it may also decrease it because both drugs compete for the same metabolic pathway. Therefore, plasma concentrations of both drugs should be monitored when they are used concomitantly. Sodium valproate: The metabolism of phenobarbitone may be decreased by sodium valproate, resulting in increased CNS depressant effects. Phenobarbitone potentiates the hepatotoxicity of sodium valproate by increasing the metabolism of sodium valproate to form valproate-4-ene, a known hepatotoxin. Therefore, plasma concentrations of sodium valproate and phenobarbitone should be monitored when any change in the therapeutic regimen occurs. Lamotrigine: Phenobarbitone may enhance the metabolism of lamotrigine. Adjustment of lamotrigine dose may be required following withdrawal of phenobarbitone from the therapeutic regimen. Corticosteroids: Barbiturates increase the metabolism of corticosteroids, and may exacerbate asthma and other conditions when added to regimens containing corticosteroids. Oral contraceptives: Barbiturates may accelerate the metabolism of both the oestrogenic and progestogenic components of the contraceptive, resulting in decreased effectiveness that may or may not be signalled by breakthrough bleeding. Another form of contraception is advisable if phenobarbitone is given on a regular basis. Opioid analgesics: Phenobarbitone may increase the metabolism of opioid analgesics such as methadone leading to decreased plasma level and opioid withdrawal symptoms. Thus, when phenobarbitone is used with methadone the plasma methadone level must be monitored. Concurrent administration of dextropropoxyphene and phenobarbitone may increase serum phenobarbitone concentration. Dosage adjustments of phenobarbitone may be required. Antipsychotics: Barbiturates have been reported to increase the metabolism of phenothiazines and chlorpromazine. Antibiotics: Barbiturates has been shown to increase the metabolism and correspondingly reduce the effectiveness of chloramphenicol. Phenobarbitone has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued.

Anaesthetics, halogenated hydrocarbon: Barbiturates may increase the metabolism of anaesthetics, such as enflurane, halothane or methoxyflurane leading to increased risk of hepatotoxicity. Chronic use of barbiturates prior to methoxyflurane anaesthesia may increase the formation of nephrotoxic metabolites resulting in increased risk of nephrotoxicity. Cardiovascular: Barbiturates have been reported to increase the metabolism and correspondingly reduce the effectiveness of digitoxin, quinidine, disopyramide, mexiletine and propranolol. MAO (monoamine oxidase) inhibitors: MAO inhibitors may inhibit barbiturate metabolism, resulting in increased CNS depressant effects. A reduction in phenobarbitone dosage may be necessary. Phenobarbitone should be avoided in patients who are on tranylcypromine because concomitant use of barbiturate and tranylcypromine has been reported to result in semicomatose for 36 hours in one case study. Other drugs: Barbiturates have also been reported to increase the metabolism and correspondingly reduce the effectiveness of corticotrophin, theophylline, dihydropyridine calcium channel blockers, chenodeoxycholic acid, paracetamol, calcium antagonists and cyclosporin. Methylphenidate appears to raise the levels of phenobarbitone. Chronic use of phenobarbitone may increase the risk of hepatotoxicity with single toxic doses or prolonged high doses of paracetamol. Miscellaneous: Phenobarbitone may decrease blood griseofulvin concentrations, probably by impairing griseofulvin absorption. Blood griseofulvin concentrations should therefore be monitored and dosage increased if necessary. Concurrent administration of disulfiram with barbiturates may result in inhibition of metabolism of the barbiturates and an increased incidence of barbiturate toxic effects. Concurrent use of flu vaccine and phenobarbitone may increase the serum concentration of the barbiturate, and dosage adjustments may be necessary. There are concerns that concurrent administration of St John's Wort (Hypericum perforatum) may reduce the efficacy of phenobarbitone by reducing phenobarbitone plasma concentrations.

Pharmacodynamic interactions
Concurrent administration of phenobarbitone with other drugs may result in increased effect of the other drugs or the barbiturate itself. CNS depressants: Excessive CNS depressant effects may result from concurrent administration of barbiturates and other CNS depressants such as alcohol, benzodiazepines, phenothiazines, antihistamines, anaesthetics and opioids.

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Tricyclic antidepressants (TCAs): Concomitant use of phenobarbitone and TCAs may result in additive respiratory depressant effects. TCA may decrease seizure control, epileptic patients receiving phenobarbitone should be watched closely when TCA is administered and the dosage of phenobarbitone should be adjusted if necessary. Anaesthetics: Ketamine anaesthesia following administration of a barbiturate has been reported to produce profound respiratory depression. Carbonic anhydrase inhibitors: Concurrent administration of carbonic anhydrase inhibitors with phenobarbitone may enhance osteopenia induced by phenobarbitone. Patients receiving concurrent therapy should be monitored for early signs of osteopenia, and carbonic anhydrase inhibitor should be discontinued, with appropriate treatment initiated if required. Hypothermia-producing medicines: Concurrent use of hypothermia-producing medicines with phenobarbitone in high doses or acute overdose may increase the risk of hypothermia.

Effects on Laboratory Tests

Phenobarbitone may interfere with diagnostic test results when the following agents are used: cyanocobalamin Co, metyrapone and phentolamine. It may also decrease serum bilirubin concentrations presumably due to induction of glucuronyltransferase, the enzyme responsible for the conjugation of bilirubin.

Overdosage
Clinical Features
Acute overdosage with barbiturates is manifested by CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur. In extreme overdosage, all electrical activity in the brain may cease. In this case there may be a "flat" EEG, but this does not necessarily indicate clinical death, since this effect is fully reversible unless hypoxic damage occurs. Complications such as pneumonia, pulmonary oedema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uraemia may increase CNS sensitivity to barbiturates if renal function is impaired. Potentially lethal blood concentrations are those in excess of 80 mcg/mL. Hypothermia may occur, with associated pyrexia during recovery. Skin blisters (bullae) reportedly occur in about 6% of patients with barbiturate overdose.
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Treatment
No specific antidote is known. Treatment of overdose is mainly supportive and consists of the following: To enhance elimination - multiple dose activated charcoal may be used for the enhancement of phenobarbitone elimination. If renal and cardiac function are satisfactory and the patient is hydrated, forced diuresis and IV sodium bicarbonate may be used to enhance urinary excretion of phenobarbitone. Alkalinisation of the urine increases renal excretion of phenobarbitone. Haemodialysis or haemoperfusion is not recommended but may be used in severe barbiturate poisoning or if the patient is anuric or in shock. Specific treatment - Fluid therapy and other standard treatment for shock, if needed. A vasopressor may be required if hypotension occurs. Fluid or sodium overload should be avoided. Supportive care - Protect the patient's airway and support ventilation. Maintain an adequate airway, with assisted respiration and oxygen administration as needed. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes. Patient should be rolled from side to side every 30 minutes. If pneumonia is suspected, antibiotics should be given. Appropriate care should be taken to prevent hypostatic pneumonia, decubiti, aspiration, and other complications that may occur with altered states of consciousness.

Pharmaceutical Precautions
Incompatibilities
The solution has a pH of 10.0-11.0 and is incompatible with many alkaline-labile drugs, such as penicillin G, noradrenaline, isoprenaline, thiamine and atracurium. Phenobarbitone may be precipitated when the injection is mixed with acidic solutions such as tetracyclines or metaraminol bitartrate. This precipitation is dependent upon the concentration and the pH, and also on the presence of other solvents.

Special Precautions for Storage

Store below 25C. Protect from light.

Medicine Classification
Controlled Drug C5

Package Quantities

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Phenobarbitone Injection is available as a 20 mg/0.5 mL presentation in packs of 5 ampoules.

Further Information
Phenobarbitone sodium occurs as a white, odourless crystalline hygroscopic powder. It may appear as granules or flakes. It is freely soluble in carbon dioxidefree water and alcohol but is insoluble in ether and methylene chloride. Phenobarbitone sodium is a sodium derivative of 5-ethyl-5-phenyl-1- H,3H,5H pyrimidine-2,4,6-trione. The structure of Phenobarbitone sodium is shown below:

C12H11N2NaO3 MW: 254 CAS - 57-30-7

Name and Address

Mayne Pharma (NZ) Limited 23 Haining Street Te Aro Wellington New Zealand

Date of Preparation
1 October 2006

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