Consumer medicine information

Phenobarbitone Injection

Phenobarbital (phenobarbitone)

BRAND INFORMATION

Brand name

Phenobarbitone Injection (Aspen Pharmacare)

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

SUMMARY CMI

PHENOBARBITONE INJECTION

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using PHENOBARBITONE INJECTION?

PHENOBARBITONE INJECTION contains the active ingredient phenobarbital sodium. PHENOBARBITONE INJECTION is used for treatment of grand mal and psychomotor epilepsy and sedation.

For more information, see Section 1. Why am I using PHENOBARBITONE INJECTION? in the full CMI.

2. What should I know before I use PHENOBARBITONE INJECTION?

Do not use if you have ever had an allergic reaction to phenobarbital sodium or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use PHENOBARBITONE INJECTION? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PHENOBARBITONE INJECTION and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use PHENOBARBITONE INJECTION?

The recommended dose of PHENOBARBITONE INJECTION varies depending on your condition. Your doctor will determine how much is appropriate.

More instructions can be found in Section 4. How do I use PHENOBARBITONE INJECTION? in the full CMI.

5. What should I know while using PHENOBARBITONE INJECTION?

Things you should do	Remind any doctor that you are using PHENOBARBITONE INJECTION, especially if you need any medical tests as it may affect the results of some tests. Tell your doctor if you become pregnant while you are using this medicine.
Things you should not do	Do not use any other medicines while you are being given PHENOBARBITONE INJECTION without first telling your doctor.
Driving or using machines	Do not drive or operate machinery while being given this medicine.
Drinking alcohol	Your doctor may suggest that you avoid alcohol completely or reduce the amount of alcohol you drink while PHENOBARBITONE INJECTION is being given.
Looking after your medicine	PHENOBARBITONE INJECTION is stored in the hospital pharmacy or on the ward. The injection is kept in a cool dry place, where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using PHENOBARBITONE INJECTION? in the full CMI.

6. Are there any side effects?

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

PHENOBARBITONE INJECTION

Active ingredient: phenobarbital sodium

Consumer Medicine Information (CMI)

This leaflet provides important information about using PHENOBARBITONE INJECTION. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using PHENOBARBITONE INJECTION.

Where to find information in this leaflet:

1. Why am I using PHENOBARBITONE INJECTION?
2. What should I know before I use PHENOBARBITONE INJECTION?
3. What if I am taking other medicines?
4. How do I use PHENOBARBITONE INJECTION?
5. What should I know while using PHENOBARBITONE INJECTION?
6. Are there any side effects?
7. Product details

1. Why am I using PHENOBARBITONE INJECTION?

PHENOBARBITONE INJECTION contains the active ingredient phenobarbital sodium. It belongs to a group of medicines called barbiturates, which act by inducing sleep and stopping convulsions.

PHENOBARBITONE INJECTION is used for treatment of grand mal and psychomotor epilepsy and sedation.

2. What should I know before I use PHENOBARBITONE INJECTION?

Warnings

Do not use PHENOBARBITONE INJECTION if you:

are allergic to phenobarbital sodium, any other barbiturate or any of the ingredients listed at the end of this leaflet.

Do not use if you have or have had any of the following medical conditions:

porphyria (a rare blood pigment disorder)
severe anaemia (a disease of the blood with reduced number of red blood cells) if it is due to folate deficiency
uncontrolled severe asthma
severe respiratory depression
uncontrolled diabetes mellitus or sugar diabetes
acute intoxication with alcohol, hypnotics or analgesics
intoxication with stimulants or depressant psychotropic agents
alcoholism or drug dependence
severe liver or kidney problems
severe depression or suicidal tendencies
short or long term serious or chronic pain.

PHENOBARBITONE INJECTION should not be given to unusually overactive children.

Do not use after the expiry date (EXP) printed on the pack.

Do not use if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

are allergic to any other medicines or any foods, dyes or preservatives
have or have had any other medical conditions or health problems, including:
- high/low blood pressure
- heart problems
- lung problems
- hyperthyroidism, an overactive thyroid gland
- hypoadrenalism (borderline), an underfunction of the adrenal gland
- a depressive illness
- asthma.
are a heavy drinker
have a drug dependency.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor immediately if you become pregnant or think you may be pregnant while on treatment with PHENOBARBITONE INJECTION.

PHENOBARBITONE INJECTION may affect your developing baby if you take it during pregnancy. However, it is very important to control your fits while you are pregnant. If it is necessary for you to use PHENOBARBITONE INJECTION, your doctor can help you decide whether or not to use it during pregnancy.

Tell your doctor if you intend to become pregnant.

Your doctor may ask you to:

undergo a pregnancy test to rule out pregnancy prior to starting on this medicine.
use other effective contraceptive methods instead of the ‘pill’ as this medicine can interact with the oral contraceptive pill making it less effective.

Your doctor will advise you about other possible medication options prior to conception and before contraception is discontinued.

Use during breastfeeding

Tell your doctor if you are breastfeeding or plan to breastfeed.

This medicine is not recommended for use while breastfeeding as it passes into breast milk and may cause serious side effects to your baby.

Use in the elderly

Elderly patients are more likely to have less effective kidney or liver function. This may increase the risk of side effects.

If you have not told your doctor about any of the above, tell them before PHENOBARBITONE INJECTION is used.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with this medicine. These include:

other medications used to treat epilepsy
anticoagulants, medicines used to treat clots eg. warfarin
painkillers, paracetamol and stronger narcotic agents
antidepressants, medicines used to treat depression
anti-arrhythmics, medicines used to treat irregular heart beats eg. quinidine, disopyramide
antibiotics and antifungal agents, medicines used to treat infections including AIDS
calcium channel blockers, medicines used to treat high blood pressure and angina
antipsychotics, medicines used to treat certain mental and emotional conditions
chemotherapy drugs, used to treat cancer
corticosteroids, such as prednisolone, cortisone
medicines used to treat heart failure eg. digoxin
oral contraceptives
immunosuppressive medicines, used to lower your body's resistance to disease e.g. cyclosporin, tacrolimus
medicines used to stop you from feeling pain, e.g. anaesthetic agents
disulfiram, a medicine used to treat alcoholism
urinary alkalinisers
antihistamines, medicines used to prevent or relieve symptoms of allergy
theophylline, a medicine used to treat asthma
beta-blockers e.g. propranolol, used to treat high blood pressure and heart conditions
other medications that interact with alcohol.

Some medicines may interfere with PHENOBARBITONE INJECTION and affect how it works.

You may need different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist has more information on medicines to be careful with or avoid while being given PHENOBARBITONE INJECTION.

4. How do I use PHENOBARBITONE INJECTION?

How much to use

The recommended dose of PHENOBARBITONE INJECTION varies depending on your condition. Your doctor will determine how much is appropriate.

How long to have it for

PHENOBARBITONE INJECTION should be given for as long as recommended by your doctor.

If symptoms persist, see your doctor.

How it is given

Except under unusual circumstances, PHENOBARBITONE INJECTION should be administered by a health care professional.

If too much is given (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to casualty at your nearest hospital, if you think that you or anyone else may have been given too much PHENOBARBITONE INJECTION.

Do this even if there are no signs of discomfort or poisoning.

Also report any other medicine or alcohol (including any barbiturates or narcotics) which has been taken. You may need urgent medical attention.

Symptoms of overdose may include weakness, dizziness, lethargy, nausea, vomiting, sweating, underbreathing, shock, impairment of consciousness, collapse of circulation, mental confusion and hypotension.

5. WHAT SHOULD I KNOW WHILE USING PHENOBARBITONE INJECTION?

Things you should do

Tell your doctor if you become pregnant while you are being given PHENOBARBITONE INJECTION.

Tell your doctor if you want to take oral contraceptives while being given PHENOBARBITONE INJECTION.

You may need a higher dose of oral contraceptives than usual to prevent pregnancy or you may need to consider other forms of contraception.

If you need any medical tests while you are being given PHENOBARBITONE INJECTION, tell your doctor as it may affect the results of some tests.

Your doctor may want to take some tests from time to time to help prevent unwanted side effects.

Always discuss with your doctor any problems or difficulties during or after being given PHENOBARBITONE INJECTION.

Things you should not do

Do not use any other medicines while you are being given PHENOBARBITONE INJECTION without first telling your doctor.

Do not drive or operate machinery while being given this medicine.

PHENOBARBITONE INJECTION may cause drowsiness or dizziness in some people and therefore may affect alertness.

Drinking alcohol

Be careful drinking alcohol while using PHENOBARBITONE INJECTION. If you drink alcohol, it could make some of the unwanted side effects of this medicine worse. Your doctor may suggest that you avoid alcohol completely or reduce the amount of alcohol you drink while PHENOBARBITONE INJECTION is being given.

Driving or using machines

Some people may experience side effects such as nausea, vomiting, constipation, drowsiness and dizziness, which may further affect the risk when driving or using dangerous machinery.

Storage

PHENOBARBITONE INJECTION is stored in the pharmacy or on the hospital ward. The injection is kept in a cool dry place, where the temperature stays below 25°C.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
pain or irritation at the site of injection rapid heartbeat nausea (feeling sick) constipation dizziness lethargy vomiting skin rashes sweating dry mouth confusion faintness irritability restlessness dependency (habit-forming) mood changes drowsiness hyperexcitability hangover sleep disturbances.	Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
signs of infection e.g. fever, chills, sore throat, swollen glands, mouth ulcers easy or unusual bleeding or bruising under the skin nosebleed yellowing of the skin and eyes (jaundice) other sudden signs of allergy severe skin rash, itching, hives, blisters or peeling skin harming yourself or committing suicide.	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

The use of barbiturates may lead to dependence on this medicine.

What PHENOBARBITONE INJECTION contains

Active ingredient (main ingredient)	Phenobarbital sodium 219 mg (equivalent to phenobarbitone 200 mg) per 1 mL ampoule
Other ingredients (inactive ingredients)	Ethanol Propylene glycol Water for injections
Potential allergens	Ethanol.

Do not take this medicine if you are allergic to any of these ingredients.

What PHENOBARBITONE INJECTION looks like

PHENOBARBITONE INJECTION is a clear, colourless solution in a clear glass 1 mL ampoule.

It is for single use in one patient only.

Available in packs of 5 ampoules (AUST R 175471).

Who distributes PHENOBARBITONE INJECTION

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

This leaflet was revised in April 2024.

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Phenobarbitone Injection (Aspen Pharmacare)

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

1 Name of Medicine

Phenobarbital sodium.

2 Qualitative and Quantitative Composition

Phenobarbitone Injection contains phenobarbital sodium 219 mg (equivalent to phenobarbitone 200 mg) per 1 mL ampoule.
Excipients include ethanol. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Phenobarbitone Injection is a clear, colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of grand mal and psychomotor epilepsy; sedation.

4.2 Dose and Method of Administration

Phenobarbitone Injection is for single use in one patient only. Discard any residue.
Phenobarbitone Injection has been administered by intramuscular (IM) or slow intravenous (IV) injection.
Intravenous administration requires a delivery of a diluted (1/10) solution in water for injections at a rate not exceeding 60 mg/minute to reduce the risk of significant respiratory depression and circulatory collapse. Extravasation of solution especially if concentrated may cause tissue damage. Adequate provisions for supporting respiration and circulation should be present if the intravenous route is contemplated.
The subcutaneous route should be avoided as it may cause tissue necrosis.
Phenobarbitone dosage reduction is recommended in the elderly and in patients with decreased renal or hepatic function.
The solution should be inspected for discolouration or the presence of particulate matter.
The sponsor recommends that Phenobarbitone Injection be given by the intramuscular (IM) route.
The following dosage regimen is a guide only.

Anticonvulsant.

Adults.

Intramuscular, 100 to 300 mg, repeated if necessary up to a total dose of 600 mg during a 24 hour period.

Paediatric.

Initial: intramuscular, 10 to 20 mg per kg bodyweight as a single loading dose.
Maintenance: intramuscular, 1 to 6 mg per kg bodyweight per day.

Status epilepticus.

Adults.

Intramuscular, 10 to 20 mg per kg of bodyweight, repeated if necessary until seizures are controlled or a total dose of 1 to 2 g is given.

Paediatric.

Intramuscular, 15 to 20 mg per kg of bodyweight, repeated if necessary at a dose of 5 to 10 mg/kg every 20 minutes until seizures are controlled or a total dose of 40 mg/kg is given.
Plasma concentrations of phenobarbitone for the control of epilepsy are usually in the range 15 to 40 microgram/mL (65 to 170 micromole per L). Drug levels should be monitored so as to keep within the therapeutic range.

Sedative.

Adults.

Intramuscular, 30 to 120 mg a day in two or three divided doses.

Paediatric.

Intramuscular, 1 to 3 mg per kg of bodyweight a day if needed.

4.3 Contraindications

Phenobarbitone is not recommended in the presence of the following conditions:
A history of porphyria, either acute intermittent or variegata.
Hypersensitivity to the active substance, to other barbiturates or to any of the excipients in the injection solution.
Severe anaemia (if it is due to folate deficiency).
Severe asthma (if uncontrolled).
Severe respiratory depression.
Diabetes mellitus (if uncontrolled).
Acute intoxication with alcohol, hypnotics or analgesics or intoxication with stimulants or depressant psychotropic agents.
A history of drug abuse or dependence.
Severe hepatic or renal impairment.
Hyperkinetic children.
Severe depression or suicidal tendencies.
Acute or chronic pain (paradoxical excitement may result or other symptoms may be masked).

4.4 Special Warnings and Precautions for Use

Parenteral administration.

Care should be taken during parenteral administration of phenobarbitone to avoid extravasation. Owing to the extreme alkalinity of sodium salts of barbiturates, subcutaneous injection or extravasation can lead to tissue necrosis.

Dependence, tolerance and withdrawal.

Prolonged use may lead to physical dependence and tolerance hence phenobarbitone should not be discontinued abruptly. Symptoms of withdrawal are characterised after several hours by apprehension and weakness, followed by anxiety, headache, dizziness, irritability, tremors, nausea, vomiting, insomnia, visual problems, muscle twitching and tachycardia. Hallucinations, orthostatic hypotension and convulsions may develop after a day or two, sometimes leading to status epilepticus. Sudden withdrawal of phenobarbitone from an epileptic patient should be avoided as it may precipitate status epilepticus.
Phenobarbitone dose should be reduced gradually over a period of days or weeks. For example, the total daily dose can be reduced by 30 mg daily as long as no signs of withdrawal occur, or alternatively the phenobarbitone dose can be reduced daily by 10% if tolerated by the patient.

Suicidal behaviour and ideation.

Antiepileptic drugs, including phenobarbitone, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any antiepileptic drugs for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono and adjunctive therapy) of 11 different antiepileptic drugs showed that patients randomised to one of the antiepileptic drugs had approximately twice the risk (adjusted relative risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 antiepileptic drug treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with antiepileptic drugs was observed as early as one week after starting drug treatment with antiepileptic drugs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with antiepileptic drugs of varying mechanisms of action and across a range of indications suggests that the risk applies to all antiepileptic drugs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1 shows absolute and relative risk by indication for all evaluated antiepileptic drugs.

The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing phenobarbitone or any other antiepileptic drugs must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptic drugs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence of worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Haematological disease.

Phenobarbitone should be used with caution in patients with a history of haematological disease, especially chronic anaemia (folate requirements are increased in patients on long-term anticonvulsant therapy). The blood count should be monitored during long-term therapy. Patients should be instructed to immediately report symptoms such as sore throat, fever, easy bruising, epistaxis or other signs of infection or bleeding tendency (note that megaloblastic anaemia and thrombocytopenia have been reported rarely).

Intra-arterial injection.

Intra-arterial injection should be avoided. The consequences range from pain in the region of the artery to pallor, patchy discolouration of the skin and even gangrene.

Asthma, urticaria and angioedema.

Barbiturates should be used with caution in patients with a history of asthma, urticaria or angioedema. Milder hypersensitivity reactions have been reported in 1 to 3% of patients treated with phenobarbitone. These include urticaria, and maculopapular, erythematous and morbilliform rashes which resolve on discontinuation. More serious reactions include serum sickness, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Section 4.8 Adverse Effects (Undesirable Effects)). Phenobarbitone should be discontinued in the presence of dermatological reactions or other manifestations of hypersensitivity such as bronchospasm.

Hypotension, cardiovascular disease and respiratory disease.

Parenteral barbiturates should be administered with caution in patients with a history of hypotension, cardiovascular disease or respiratory disease.

Bone mineral density and fractures.

Chronic administration of phenobarbitone may decrease bone mineral density and increase the risk of fractures. Periodic monitoring of bone mineral density and the use of supplemental calcium and vitamin D are advisable. Patients should be advised to have adequate sunlight exposure, regular weightbearing exercise and avoid other risk factors associated with bone disease, such as alcohol use and smoking.

Corticosteroids, hypoadrenalism and hyperthyroidism.

The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbitone. The drug should be administered with caution in patients with borderline hypoadrenalism regardless of whether it is the pituitary or adrenal in origin. Patients with hyperthyroidism should be treated with caution as symptoms may be exacerbated through the displacement of thyroxine from plasma proteins.

CNS depressants.

Concurrent use of phenobarbitone with other CNS depressant drugs and alcohol can lead to potentiation of the CNS depressant effects of either these substances or phenobarbitone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Withdrawal of these drugs should be slow and cautious, as the condition "severe abstinence syndrome" (grand mal seizures, delirium) may occur.

Women of childbearing potential.

Phenobarbital may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenobarbital may increase the risk of congenital malformations and adverse developmental outcomes (see Section 4.6).
Phenobarbital should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following consideration of other suitable treatment options. Women of childbearing potential, women planning pregnancy and pregnant women should be fully informed of the potential risk to the fetus if they take phenobarbital during pregnancy.
A pregnancy test to rule out pregnancy should be considered prior to commencing treatment with phenobarbital in women of childbearing potential.
Women of childbearing potential should use highly effective contraception during treatment and for 2 months after the last dose. Due to enzyme induction, phenobarbital may result in a failure of the therapeutic effect of oral contraceptive drugs (see Section 4.5; Section 4.6).
Women planning a pregnancy should be advised to consult in advance with her physician so that adequate counselling can be provided and appropriate other treatment options can be discussed prior to conception and before contraception is discontinued.
Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant while on treatment with phenobarbital.

Use in hepatic impairment.

Phenobarbitone is metabolised in the liver, therefore hepatic dysfunction may theoretically lead to increased blood levels. The dose may need to be reduced.
Medical monitoring is required in patients with hepatic impairment because various adverse events attributed to the excipient, propylene glycol, used in Phenobarbitone Injection have been reported such as liver dysfunction.

Use in renal impairment.

Unchanged phenobarbitone is excreted by the kidneys, therefore a reduction in dose may be required in patients with renal dysfunction.
Medical monitoring is required in patients with renal impairment because various adverse events attributed to the excipient, propylene glycol, used in Phenobarbitone Injection have been reported such as renal dysfunction (acute tubular necrosis) and acute renal failure.

Use in the elderly.

Phenobarbitone and other barbiturates should be administered cautiously to the elderly; reduced dosage should be employed until tolerance is assessed. Age related hepatic and/or renal impairment may require reduction in dosage. Elderly patients may react with excitement, confusion or mental depression. The risk of barbiturate induced hypothermia may be increased especially with high doses or in acute overdose.

Paediatric use.

Some children may react with paradoxical excitement.

Paediatric neurotoxicity.

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined with inhalation or infusion of such drugs, exposure is longer than the period of inhalation or infusion. Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration.

Effects on laboratory tests.

The following changes in laboratory determinations have been reported in patients using phenobarbitone:
Absorption of radioactive cyanocobalamin may be impaired.
Metyrapone may have its metabolism enhanced thus decreasing the observed response.
False positives may be returned from Phentolamine tests.
Serum bilirubin concentrations may be decreased possibly due to induction of glucuronyl transferase, the enzyme responsible for the conjugation of bilirubin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Phenobarbitone is metabolised via the cytochrome P450 system within the gut wall and the liver. Therefore most of its interactions with other medicines are due to the competition between phenobarbitone and other medicines for the specific isoenzymes within this system.

Induction.

Phenobarbitone is a potent inducer of the isoenzymes CYP3A4, CYP1A2 and CYP2C. Discontinuation of phenobarbitone may result in enhanced effects of concomitant medications or even their potential toxicity. Upon phenobarbitone commencement appearance of overt signs of drug interactions due to enzyme induction occurs in approximately one week.
The major medicines affected by induction of the CYP450 isoenzymes by phenobarbitone are:
Analgesics.

Paracetamol.

The therapeutic effects of paracetamol may be decreased due to enzyme induction of CYP3A4 and subsequent increased metabolism of the drug. This may also lead to increased risk of hepatotoxicity.

Opioid analgesics.

Dosage of these analgesics may need to be increased due to increased metabolism. Withdrawal symptoms may develop due to lowered plasma levels. In a well documented interaction between phenobarbitone and methadone, there was a 50% reduction in methadone concentrations with signs of narcotic withdrawal. Methadone levels must be monitored if phenobarbitone is introduced.
Antidepressants. Tricyclic antidepressants and selective serotonin reuptake inhibitor plasma levels may be lowered resulting in compromised efficacy through the possible induction of isoenzyme CYP2D6.
Antiarrhythmics such as quinidine and disopyramide. Concurrent barbiturate use may reduce serum levels to ineffective concentrations due to induction of CYP3A4.

Digoxin.

Induction may result in decreased blood levels of digoxin when taken with barbiturates. Careful monitoring of dosage is required if barbiturates are given in patients on digoxin therapy.
Anticoagulants. Phenobarbitone may increase the metabolism of coumarin anticoagulants such as warfarin resulting in a substantial decrease in anticoagulant activity. Initiation of barbiturate therapy in patients stabilised on anticoagulants must be accompanied by monitoring of anticoagulant activity and adjustment of anticoagulant dose if required. Patients maintained on both a coumarin and barbiturates have a risk of bleeding if the barbiturate is discontinued and the dose of the anticoagulant is not adjusted. The long half-life of phenobarbitone must be taken into account when commencing and ceasing treatment. Combination with phenindione should be treated in the same manner.
Antifungal agents. Poor clinical response to antifungals such as itraconazole and ketoconazole results from enzyme induction of isoenzyme CYP3A4 by phenobarbitone. Fluconazole does not appear to be much affected. The absorption of griseofulvin may be decreased resulting in decreased serum concentrations.
Antibiotics. The half-life of doxycycline may be decreased by phenobarbitone due to induction of metabolism. The dosage and/or dosing interval of doxycycline may need to be adjusted. Metronidazole metabolism is enhanced resulting in reduced plasma levels.
Calcium channel blockers. Efficacy may be compromised when combining these agents with phenobarbitone. A reduction in efficacy has been documented with nifedipine via induction of CYP3A4.
Antipsychotics. Haloperidol and the phenothiazines lower the seizure threshold and hence combination with phenobarbitone may compromise the efficacy of phenobarbitone. Phenobarbitone may induce the metabolism of haloperidol and phenothiazines through cytochrome enzyme induction.
Chemotherapeutic agents. Clearance of etoposide has been shown to increase by 170% when given with phenobarbitone. Be alert for the need to increase etoposide dose if used concurrently with phenobarbitone.
Corticosteroids. Reduction in serum levels of corticosteroids may compromise their effectiveness in the treatment of steroid responsive disorders such as asthma.
Oral contraceptives. Reductions in serum levels with breakthrough bleeding and lowered contraceptive efficacy may occur when these agents are combined with phenobarbitone.
Immunosuppressants. Cyclosporin and tacrolimus have been shown to have clearance increased by barbiturates.
The effect on corticosteroids, oral contraceptives and immunosuppressants is via CYP3A4 induction.
Protease inhibitors. Increased metabolism by the action of phenobarbitone on CYP3A4 may result in reduced plasma levels.
Theophylline. Induction of isoenzyme CYP1A2 by phenobarbitone may result in lowered plasma levels and loss of efficacy. Serum theophylline levels should be monitored because theophylline has a narrow therapeutic index.
Anaesthetics, halogenated hydrocarbon. Barbiturates may increase the metabolism of anaesthetic agents such as halothane and enflurane leading to increased risk of hepatotoxicity.
Vitamin D. The effects of vitamin D may be reduced by barbiturates including phenobarbitone because of accelerated metabolism by hepatic microsomal enzymes. Vitamin D supplementation may be required in patients on long-term anticonvulsant therapy with phenobarbitone to prevent osteomalacia. The effect of phenobarbitone on vitamin D may be enhanced by the concomitant use of carbonic anhydrase inhibitors.
Beta-blockers. The plasma concentration of some beta-blockers, e.g. propranolol may be reduced by barbiturates.
Anticonvulsants. Variable effects are seen on the activity of phenytoin when combined with barbiturates. When phenobarbitone is used with phenytoin, concentrations of either or both medicines may be affected. Even though phenobarbitone may induce phenytoin metabolism, it may also decrease it because both medicines compete for the same metabolic pathway. It is recommended that plasma concentrations of both drugs be monitored when they are used concomitantly. Phenobarbitone may accelerate the metabolism of carbamazepine resulting in decreased plasma concentration. Phenobarbitone may enhance the metabolism of lamotrigine. Adjustment of lamotrigine dose may be required following withdrawal of phenobarbitone.

Inhibition.

Several drugs inhibit the isoenzymes CYP3A4, CYP1A2 and CYP2C which can lead through competition to decreased metabolism of phenobarbitone. This in turn leads to elevated blood levels of the medicine, respiratory depression and lowering of the lethal dose of phenobarbitone. The effects of inhibition can usually be seen immediately rather than delayed as in induction.
Medicines which inhibit these isoenzymes and could lead to accumulation of phenobarbitone are:

Antidepressants.

Monoamine oxidase (MAO) inhibitors may inhibit barbiturate metabolism resulting in increased CNS depressant effects. A reduction in phenobarbitone dosage may be indicated. Concomitant use of barbiturate and tranylcypromine has been reported to result in semicoma for 36 hours in one case study.
Selective serotonin reuptake inhibitors (SSRI) may inhibit a number of important cytochrome P450 isoenzymes (CYP1A2, CYP2C9/10, CYP2C19, CYP2D6 and CYP3A3/4) although they differ in their potency. Combination with phenobarbitone may result in increased plasma levels and enhanced activity of phenobarbitone.

Disulfiram.

Concurrent administration of disulfiram with barbiturates may result in inhibition of metabolism of barbiturates and an increased incidence of barbiturate toxicity.

Valproic acid/ sodium valproate.

The metabolism of phenobarbitone may be decreased by valproic acid/ sodium valproate resulting in increased CNS depressant effects. Phenobarbitone may potentiate the hepatotoxicity of valproic acid/ sodium valproate by increasing the metabolism of this drug to form valproate-4-ene, a known hepatotoxin. Co-administration of valproate and phenobarbital increases the risk of valproate-associated encephalopathy and/or increased ammonia levels.
It is recommended that plasma concentrations of valproate and phenobarbitone be monitored when any change in the therapeutic regimen occurs.

Other interactions.

Amphetamines.

Concurrent use with phenobarbitone may result in delays in the intestinal absorption of phenobarbitone.

CNS depressants.

Phenobarbitone is a potent CNS depressant so will tend to enhance or potentiate the effects of other CNS depressants. This includes other sedatives and hypnotics, antihistamines, tranquillisers and alcohol.

Ketamine.

Concurrent use of ketamine, especially in high doses or when rapidly administered with barbiturates may result in hypotension and/or respiratory depression, and prolonged recovery time. Ketamine and barbiturates are chemically incompatible hence must not be mixed in the same solution.

Urinary alkalinisers.

Alkalinising the urine may diminish the effects of barbiturates due to increased excretion.

St John's wort (Hypericum perforatum).

Concurrent use of barbiturates and St John's wort may result in decreased serum barbiturate levels resulting in diminished efficacy. In patients who are taking barbiturates and St John's wort, the serum barbiturate levels should be closely monitored and the administration of St John's wort should be stopped. The serum barbiturate levels may increase when the administration of St John's wort is stopped, therefore resulting in a need to adjust the dose of the barbiturate.

Stiripentol.

Phenobarbital should not be used in conjunction with stiripentol (medicinal product used to treat Dravet's syndrome). If co-administration is inevitable, clinical monitoring of phenobarbital serum concentrations with possible dose adjustments is recommended.

Information on excipients.

Due to the alcohol used in the solution for injection as a solvent, interactions with medicinal products that show harmful interactions with alcohol must be kept in mind (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Use in renal impairment).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.

Women of childbearing potential/contraception.

Phenobarbital should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.
A pregnancy test to rule out pregnancy should be considered prior to commencing treatment with phenobarbital in women of childbearing potential.
Women of childbearing potential should use highly effective contraception during treatment with phenobarbital and for 2 months after stopping treatment. Due to enzyme induction, phenobarbital may result in a failure of the therapeutic effect of oral contraceptive drugs (see Section 4.5). Women of childbearing potential should be advised that at least one highly effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case involving the patient in the discussion when choosing the contraception method.
Women of childbearing potential should be informed of and understand the risk of potential harm to the fetus associated with phenobarbital use during pregnancy and the importance of planning a pregnancy.
Women planning a pregnancy should be advised to consult in advance with her physician so that specialist medical advice can be provided and appropriate other treatment options can be discussed prior to conception and before contraception is discontinued.
Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant.
Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant while on treatment with phenobarbital.
(Category D)

Risk related to antiepileptic medicinal products in general.

Specialist medical advice regarding the potential risks to a fetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment and especially to women planning pregnancy and women who are pregnant.
Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant. In pregnant women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to seizures that could have serious consequences for the woman and the unborn child.
It is recommended that:
women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of congenital malformations and adverse developmental outcomes;
AEDs should be continued during pregnancy at the lowest effective dose and monotherapy should be considered if appropriate;
adequate folic acid supplementation should be discussed as part of pre-pregnancy and pregnancy counselling;
specialist prenatal diagnosis including detailed mid-trimester ultrasound should be considered.

Pregnancy risks related to phenobarbital.

Phenobarbital readily crosses the placenta following oral administration and is distributed throughout fetal tissue the highest concentrations being found in the placenta, fetal liver and brain. Animal studies (literature data) have shown reproductive toxicity in rodents (see Section 5.3).
Phenobarbital therapy in pregnant women with epilepsy presents a risk to the fetus in terms of major and minor congenital defects including congenital craniofacial and cardiac defects, digital abnormalities and less commonly cleft lip and palate. Studies in women with epilepsy who were exposed to phenobarbital during pregnancy identified a frequency of major malformations of 6-7% in their offspring compared to the background rate in the general population of 2-3%. Studies have found the risk of congenital malformations following in utero exposure to phenobarbital to be dose-dependent, however no dose has been found to be without risk. Therefore the lowest effective dose should be used.

In neonates.

Data from a registry study suggest an increase in the risk of infants born small for gestational age or with reduced body length, to women with epilepsy who were exposed to phenobarbital during pregnancy compared to women exposed to lamotrigine monotherapy during pregnancy.
Adverse effects on neurobehavioral development have also been reported. Studies investigating neurobehavioral development have also been reported. Studies investigating neurodevelopmental effects of prenatally administered phenobarbital were mostly small in numbers; however significant negative effects on neurodevelopment and IQ were found following in utero and postnatal exposure. Pre-clinical studies have also reported adverse neurodevelopment effects (see Section 5.3).
Haemorrhage at birth and addiction are also a risk. Prophylactic treatment with vitamin K₁ for the mother before delivery (as well as the neonate) is recommended and the neonate should be monitored for signs of bleeding.
Use of barbiturates throughout the third trimester of pregnancy may result in physical dependence and subsequent withdrawal symptoms in the neonate such as sedation, hypotonia and sucking disorder. In infants experiencing long term exposure in utero, the acute withdrawal syndrome of seizures and hyperirritability has been reported to occur up to 14 days after birth. Use of the barbiturates during labour may cause respiratory depression in the neonate. Elimination of phenobarbitone is slow in the newborn especially in premature infants.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.
Phenobarbitone is not recommended in breastfeeding mothers. Phenobarbitone is distributed into breast milk and use by breastfeeding mothers may cause CNS depression in the infant.

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned that barbiturates may impair their ability to perform potentially hazardous activities requiring mental alertness and physical coordination such as driving and operating machinery.
The sedative action of phenobarbitone in epileptic patients can be reduced by using a lower dose supplemented by phenytoin or primidone.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.
Undesirable effects are presented below by MedDRA system organ class, using the following frequency convention.
Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
The most frequent adverse effect following administration of phenobarbitone is sedation which often becomes less marked with continued administration. Phenobarbitone may produce mood changes and impairment of cognition and memory. Continued use of barbiturates even in therapeutic doses may result in psychological or physical dependence. Abrupt withdrawal may lead to a series of neurological symptoms culminating in seizures and delirium (see Section 4.4 Special Warnings and Precautions for Use regarding withdrawal symptoms). Tolerance to the hypnotic effects may develop. See Section 4.9 Overdose, for the effects of excessive doses.
The following adverse effects have been reported with the use of phenobarbitone (see Table 2).

4.9 Overdose

Clinical features.

Overdosage of barbiturates produces CNS depression ranging from sleep to profound coma to death; respiratory depression which may progress to Cheyne-Stokes respiration, central hypoventilation, and cyanosis; cold, clammy skin and/or hypothermia or later fever, areflexia, tachycardia, hypotension, and decreased urine formation. Pupils are usually slightly constricted but may be dilated in severe poisoning. Patients with severe overdosage often experience typical shock syndrome; apnea, circulatory collapse, respiratory arrest and death may occur. Complications such as pneumonia, pulmonary oedema or renal failure may also prove fatal. Other complications which may occur are congestive heart failure, cardiac arrhythmias and urinary tract infections. Some patients have developed bullous cutaneous lesions which heal slowly.

Treatment.

Treatment of overdosage is mainly supportive including maintenance of an adequate airway and assisted respiration and oxygen administration if needed. Standard treatment for shock should be administered if necessary. Activated charcoal may reduce absorption of phenobarbitone if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Multiple dose, nasogastric administration of activated charcoal has been used effectively to treat phenobarbitone overdose; activated charcoal enhances the elimination of the drug and shortens the duration of coma. The patient's vital signs and fluid intake should be monitored closely. Analeptic drugs should not be administered because they may produce paroxysmal cerebral activity which may result in generalised seizures. In addition, it has been demonstrated that analeptics are incapable of stimulating respiration and exerting an arousal effect in patients with severe barbiturate poisoning and profound CNS depression. If renal function is normal, forced diuresis may be of benefit. In addition, alkalinisation of the urine increases renal excretion of phenobarbitone. Peritoneal dialysis or haemodialysis may be useful in severe barbiturate intoxication and/or if the patient is anuric or in shock.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Phenobarbitone is a long acting barbiturate used as a sedative hypnotic and as an anticonvulsant in the treatment of epilepsy.
Recent studies have suggested that the sedative hypnotic and anticonvulsant effects of barbiturates may be related to their ability to enhance and/or mimic the inhibitory synaptic action of gamma-aminobutyric acid (GABA). Phenobarbitone inhibits seizure activity at doses which cause relatively little sedation.
The barbiturates are general central nervous system depressants, the effect ranging from mild sedation to general anaesthesia.
Onset of action after IV dosage is usually within 5 minutes and maximum effects are achieved within 30 minutes. Orally administered phenobarbitone has an onset of action that varies from 20 to 60 minutes. IM injection results in somewhat slower distribution compared with IV administration. The duration of action of parenterally administered phenobarbitone sodium is usually 4-6 hours.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

About 70-90% of an oral dose is absorbed as in the case of other barbiturates. The oral preparation is relatively lipid insoluble; hence attainment of peak concentrations in the blood may take several hours.

Distribution.

Phenobarbitone sodium is rapidly distributed to all tissues and fluids with high concentrations in the brain, kidney and liver. As lipid solubility is low, phenobarbitone is slower than other barbiturates in penetrating the tissues. Phenobarbitone is approximately 40% bound to plasma proteins. The plasma half-life is approximately 90 to 100 hours in adults but is significantly prolonged in neonates. The half-life in children is shorter than in adults (about 65 to 70 hours). Phenobarbitone crosses the placenta and is excreted in breast milk.

Metabolism.

Metabolism is primarily via the hepatic microsomal enzyme system. Phenobarbitone is converted via oxidative hydroxylation to p-hydroxyphenobarbitone, an inactive metabolite.

Excretion.

Approximately 25% of a dose is excreted unchanged in the urine and about 75% of the dose is excreted via the kidneys as p-hydroxyphenobarbitone and its glucuronide and sulfate conjugates. Alkalinisation of the urine and/or increasing urinary flow rate substantially increases the rate of excretion of unchanged phenobarbitone. Unmetabolised drug can accumulate in patients with oliguria or uraemia. Phenobarbitone is a potent inducer of enzymes of the cytochrome P450 system (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Therapeutic monitoring.

When used as an anticonvulsant, monitoring of plasma concentrations has been performed as an aid in assessing control. The therapeutic range is usually quoted as being 15 to 40 microgram per mL (65 to 170 micromol per litre).

5.3 Preclinical Safety Data

Published studies reported teratogenic effects (morphological defects) in rodents exposed to phenobarbital. Cleft palate is reported consistently in all preclinical studies, but other malformations are also reports (e.g. umbilical hernia, spina bifida, exencephaly, exomphalos plus fused ribs) in single studies or species. In addition, although data from the published studies are inconsistent, phenobarbital given to rats/mice during gestation or early postnatal period was associated with adverse neurodevelopment effects, including alterations in locomotor activity, cognition and learning patterns.

Genotoxicity.

Genotoxicity studies for gene mutations and chromosome aberrations have given mixed results, however, tests for DNA damage or repair have been negative.

Carcinogenicity.

Phenobarbitone sodium is carcinogenic in mice and in rats after lifetime administration. In mice, it produced benign and malignant liver cell tumours; in rats, benign liver cell tumours were observed. Phenobarbitone was negative in a 26 week bioassay in p53 heterozygous mice.
In a 29 year epidemiologic study of 9,136 patients who were treated on an anticonvulsant protocol that included phenobarbitone, results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug known to produce hepatic carcinomas. When patients who had received thorotrast were excluded, there was a nonsignificant increase in the number of liver tumours, and, unlike the mouse liver tumours, were mostly associated with cirrhosis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol, propylene glycol and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Clear glass type 1 ampoule. 5 ampoules per pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Phenobarbital sodium is a white, odourless, hygroscopic powder, granules or flakes. It is very soluble in water and soluble in alcohol, practically insoluble in chloroform and ether. A 10% solution in water has a pH of not more than 10.2. Store in airtight containers.

Chemical structure.

Its molecular formula is C₁₂H₁₁N₂NaO₃. The molecular weight is 254.2.

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