Consumer medicine information

Phenobarb

Phenobarbital (phenobarbitone)

BRAND INFORMATION

Brand name

Phenobarb

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Phenobarb.

SUMMARY CMI

PHENOBARB Tablets

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 Phenobarb?

Phenobarb contains the active ingredient Phenobarbital. Phenobarb is used for epileptic fits and sedation.

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

2. What should I know before I use Phenobarb?

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

Talk to your doctor or pharmacist 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 Phenobarb? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Phenobarb 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 Phenobarb?

  • Take your medicine as directed by your doctor.

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

5. What should I know while using Phenobarb?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Phenobarb, 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 taking this medicine.
Things you should not do
  • Do not take any other medicines while you are taking Phenobarb tablets without first telling your doctor
Driving or using machines
  • Do not drive or operate machinery until you know how this medicine affects you.
Drinking alcohol
  • Be careful drinking alcohol while taking Phenobarb tablets. Your doctor may suggest that you avoid alcohol completely or reduce the amount of alcohol you drink while you are taking Phenobarb tablets.
Looking after your medicine
  • Keep this medicine in a cool dry place, protected from light where the temperature stays below 25°C.

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

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Phenobarb tablets.

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

PHENOBARB Tablets

Active ingredient(s): Phenobarbital

Consumer Medicine Information (CMI)

This leaflet provides important information about using Phenobarb. 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 Phenobarb.

Where to find information in this leaflet:

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

1. Why am I using Phenobarb?

Phenobarb contains the active ingredient Phenobarbital, which belongs to a group of medicines called barbiturates. Barbiturates act by inducing sleep and stopping convulsions.

Phenobarb is used for:

  • epileptic fits
  • sedation.

Ask your doctor if you have any questions about why Phenobarb tablets have been prescribed for you. Your doctor may have prescribed it for another purpose.

It is available only with a doctor's prescription.

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

2. What should I know before I use Phenobarb?

Warnings

Do not use Phenobarb if:

  • you are allergic to Phenobarbital, other barbiturates or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include red, itchy skin rashes, difficulty breathing, hayfever, swelling of the face or throat or faintness.

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

  • porphyria, a rare blood pigment disorder
  • anaemia, a disease of the blood with reduced number of red blood cells
  • severe breathing difficulties
  • uncontrolled severe asthma
  • uncontrolled diabetes mellitus or sugar diabetes
  • alcoholism or drug dependence
  • sleep apnoea
  • severe liver or kidney problems
  • severe depression or suicidal tendencies
  • acute or chronic pain.

Phenobarb tablets should not be given to unusually overactive children.

Check with your doctor if you:

  • are allergic to any other medicines or any other substances, such as foods, preservatives or dyes
  • are young, run down or senile
  • have any other medical or health problems including:
    - high/low blood pressure
    - heart problems
    - lung problems
    - hyperthyroidism (an overactive thyroid gland)
    - hypoadrenalism (borderline), an underfunctioning adrenal gland
    - a depressive illness
    - asthma
    - a heavy drinker or have a history of alcoholism
    - a drug dependency
    - have severe or long-term pain.

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 if you are pregnant or intend to become pregnant.

Phenobarb tablets may harm your developing baby if you take it during pregnancy. However, it is very important to control your fits while you are pregnant. Phenobarbital should not be used during pregnancy unless the potential benefit is judged to outweigh the risks following consideration of other suitable treatment options.

If you become pregnant while taking Phenobarb, call your doctor.

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

Breastfeeding is not recommended while taking this medicine 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 due to age. This may increase the risk of side effects.

If you have not told your doctor about any of the above, tell them before you take any Phenobarb tablets.

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 interfere with Phenobarb tablets. These include:

  • other medications used to treat epilepsy
  • anticoagulant medicines used to treat clots, e.g. warfarin
  • painkillers, paracetamol and stronger narcotic agents
  • antidepressants, medicines used to treat depression
  • anti-arrhythmics, medicines used to treat irregular heartbeats e.g. 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 e.g. digoxin
  • oral contraceptives
  • folic acid or Vitamin D
  • immunosuppressive medicines, used to lower your body's resistance to disease e.g. ciclosporin, tacrolimus
  • medicines used to stop you from feeling pain, e.g. anaesthetic agents
  • disulfiram, a medicine used to treat alcoholism
  • diuretics
  • thyroid replacement therapy medications, e.g. levothyroxine
  • urinary alkalinisers
  • antihistamines, medicines used to prevent or relieve symptoms of allergy
  • theophylline, medicine used to treat asthma
  • beta-blockers e.g. propranolol, used to treat high blood pressure and heart conditions.
  • Hormone antagonist e.g. Gestrinone

The above medicines may reduce the effectiveness of Phenobarb tablets, reduce their own effectiveness and/ or react with it resulting in untoward or sometimes dangerous side effects.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Phenobarb tablets.

4. How do I use Phenobarb?

How much to take / use

Take your medicine as directed by your doctor.

The usual doses of Phenobarb tablets are:

Adults:

  • Sedative dose

1-4 tablets as a single daily dose or as 2 to 3 divided doses per day.

  • Anticonvulsant dose

2-8 tablets as a single daily dose or as 2 to 3 divided doses per day.

Children:

  • Your doctor will advise you of the correct dose, depending on the weight of your child.

How to take it

Swallow the tablets whole with a glass of water.

How long to take it

Continue taking Phenobarb tablets as long as your doctor recommends to.

Do not stop taking Phenobarb tablets without checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.

Stopping this medicine suddenly may cause unwanted effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

If you forget to take it

Take your dose as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are unsure about whether to take your next dose, speak to your doctor or pharmacist.

Do not try to make up for missed doses by taking more than one dose at a time.

This may increase the chance of you getting an unwanted effect.

If you take too much (overdose)

If you think that you have used too much Phenobarb, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should 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.

Symptoms of overdose include weakness, dizziness, lethargy, nausea, vomiting, sweating, underbreathing, impairment of consciousness, collapse of circulation, mental confusion and low blood pressure.

5. What should I know while using Phenobarb?

Things you should do

Take Phenobarb tablets exactly as directed by your doctor.

Tell your doctor if you want to take oral contraceptives while taking Phenobarb tablets.

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

Tell your doctor if you become pregnant while you are taking Phenobarb tablets.

If you need any medical tests while you are taking Phenobarb tablets, tell your doctor as it may affect the results of some tests.

Always discuss with your doctor any problems or difficulties during or after taking this medicine.

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

Things you should not do

Do not take any other medicines while you are taking Phenobarb tablets without first telling your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Do not drive or operate machinery until you know how this medicine affects you.

Phenobarb may cause dizziness in some people and therefore may affect alertness.

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.

Drinking alcohol

Be careful drinking alcohol while taking Phenobarb tablets.

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 you are taking Phenobarb tablets.

Storage

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep this medicine in a cool dry place, protected from light where the temperature stays below 25°C.

Do not store it or any other medicines in a bathroom or near a sink. Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking this medication or it has passed its expiry date, ask your pharmacist what to do with any tablets that are left over.

Do not take this medicine after the expiry date (EXP.) printed on the pack.

Do not take it if the packaging shows signs of tampering or the tablets do not look quite right.

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.

Less serious side effects

Less serious side effectsWhat to do
  • rapid heartbeat
  • nausea (feeling sick)
  • constipation
  • dizziness
  • lethargy
  • vomiting
  • skin rashes
  • sweating
  • dry mouth
  • confusion or confusion in the elderly
  • unusual excitement
  • depression
  • memory impairment
  • hallucinations
  • faintness
  • irritability
  • restlessness
  • dependency (habit-forming)
  • mood changes
  • drowsiness
  • hyperexcitability
  • jerky movements, jerky eye movements
  • 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 effectsWhat to do
  • signs of infection, e.g. sore throat, fever, chills, swollen glands, mouth ulcers
  • easy or unusual bleeding or bruising under the skin
  • nosebleed
  • yellowing of the skin and eyes (jaundice)
  • sudden signs of allergy, e.g. severe skin rash (Steven-Johnson syndrome, toxic epidermal necrolysis), 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 immediately or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

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.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

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.

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 Phenobarb contains

Active ingredient
(main ingredient)		Each Phenobarb tablet contains 30 mg Phenobarbital.
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • acacia
  • wheat starch
  • magnesium stearate
Potential allergensPhenobarb tablets contain gluten and lactose monohydrate.

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

Phenobarb tablets do not contain sucrose, tartrazine or any other azo dyes.

What Phenobarb looks like

Phenobarb tablets are uncoated, white, round and scored. Available in bottles of 200 tablets. (Aust R 19758).

Who distributes Phenobarb

Arrotex Pharmaceuticals Pty Ltd
15–17 Chapel Street
Cremorne VIC 3121
Australia

www.arrotex.com.au

This leaflet was prepared in December 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Phenobarb

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

S4

 

1 Name of Medicine

Phenobarbital.

2 Qualitative and Quantitative Composition

Phenobarb tablets contain phenobarbital 30 mg.

Excipients with known effect.

Gluten and lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Phenobarb tablets are white, round uncoated biconvex tablets with a scoreline on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Epilepsy, sedation.

4.2 Dose and Method of Administration

Anticonvulsant.

Adults.

60 to 240 mg per day in 2 to 3 divided doses.

Paediatric.

1 to 6 mg per kg per day in 2 to 3 divided doses.
Phenobarbital may be given as a single daily dose as it has a long half-life. Doses must be individualised.

Sedative.

Adults.

30 to 120 mg per day in 2 to 3 divided doses.

Paediatric.

1 to 2 mg per kg 2 to 3 times a day.
Alternatively phenobarbital may be given as a single daily dose.
Geriatric and debilitated patients may exhibit excitement, confusion or depression with usual therapeutic doses. Lower doses are recommended.

4.3 Contraindications

Phenobarbital is not recommended in the presence of the following conditions:
a history of porphyria, either acute intermittent or variegate;
hypersensitivity to barbiturates or the excipients in the tablets;
severe anaemia (if it is due to folate deficiency);
severe respiratory depression or pulmonary insufficiency;
severe asthma (if uncontrolled);
diabetes mellitus (if uncontrolled);
a history of drug abuse or dependence;
alcoholism;
severe hepatic or renal impairment;
sleep apnoea;
hyperkinetic children;
severe depression or suicidal tendencies;
acute or chronic pain (paradoxical excitement may result or other symptoms may be masked).
Phenobarbital should not be administered to elderly patients who exhibit nocturnal confusion or restlessness from sedative hypnotic drugs or to persons who are known to be, or are likely to become, dependent on sedative hypnotic medications.

4.4 Special Warnings and Precautions for Use

Women of childbearing potential.

Phenobarbital may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenobarbital may increase the risk for congenital malformations and adverse developmental outcomes (see Section 4.6 Fertility, Pregnancy and Lactation).
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 Interactions with Other Medicines and Other Forms of Interactions; Section 4.6 Fertility, Pregnancy and Lactation).
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.

Stevens-Johnson syndrome and toxic epidermal necrolysis.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of phenobarbital. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, phenobarbital treatment should be discontinued. The best results in managing SJS or TEN come from early diagnosis and immediate discontinuation of any suspected drug. Early withdrawal is associated prognosis.
If a patient has developed SJS or TEN with the use of phenobarbital, phenobarbital must not be restarted in this patient at any time.

Dependence, tolerance and withdrawal.

Prolonged use may lead to physical dependence and tolerance hence phenobarbital 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 phenobarbital from an epileptic patient should be avoided as it may precipitate status epilepticus.
Phenobarbital 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 phenobarbital dose can be reduced daily by 10% if tolerated by the patient.

Suicidal behaviour and ideation.

Antiepileptic drugs, including phenobarbital, 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 phenobarbital 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.

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.
Anaesthetic and sedative agents are a necessary part of the care of children and pregnant women needing surgery, other procedures or tests that cannot be delayed. Decisions regarding the timing of any elective procedures requiring anaesthesia should take into consideration the benefits of the procedure weighed against the potential risks (also see Section 4.6 Fertility, Pregnancy and Lactation).
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.
Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration resulting in longer exposure to the drug.

Haematological disease.

Phenobarbital 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).

Asthma, urticaria and angioedema.

Barbiturates should be used with caution in patients with a history of asthma, urticaria or angio-oedema. Milder hypersensitivity reactions have been reported in 1 to 3% of patients treated with phenobarbital. These include urticaria, and maculopapular, erythematous and morbilliform rashes which resolve on discontinuation. More serious reactions include serum sickness, exfoliative dermatitis, erythema multiforme and Stevens-Johnson syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)). Phenobarbital 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 phenobarbital 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 weight-bearing exercise, and avoid other risk factors associated with bone disease, such as alcohol use and smoking.

Corticosteroids, hypoadrenalism and hyperthyroidism.

Phenobarbital is metabolised in the liver, therefore hepatic dysfunction may theoretically lead to increased blood levels. The dose may need to be reduced.
The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbital. 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 phenobarbital with other CNS depressant drugs and alcohol can lead to potentiation of the CNS depressants effects of either these substances or phenobarbital (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.

Use in renal impairment.

Unchanged phenobarbital is excreted by the kidneys, therefore a reduction in dose may be required in patients with renal dysfunction.

Use in the elderly.

Phenobarbital 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.

Effects on laboratory tests.

The following changes in laboratory determinations have been reported in patients using phenobarbital:
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.
Care should be used in the following situations:
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Young, debilitated or senile patients.
Existing liver disease.
Sudden withdrawal should be avoided as severe withdrawal syndrome (rebound insomnia, anxiety, tremor, dizziness, nausea, fits and delirium) may be precipitated.
Acute chronic pain - paradoxical excitement may be induced or important symptoms masked.
Prolonged use may result in dependence of the alcohol-barbiturate type. Care should be taken in treating patients with a history of drug abuse or alcoholism.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Phenobarbital 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 phenobarbital and other medicines for the specific isoenzymes within this system.
There are complex interactions between antiepileptics, and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy.

Induction.

Phenobarbital is a potent inducer of the isoenzymes CYP3A4, CYP1A2 and CYP2C. Discontinuation of phenobarbital may result in enhanced effects of concomitant medications or even their potential toxicity. Upon phenobarbital 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 CYP-450 isoenzymes by phenobarbital 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 phenobarbital and methadone, there was a 50% reduction in methadone concentrations with signs of narcotic withdrawal. Methadone levels must be monitored if phenobarbital is introduced.

Pethidine.

Barbiturates can be expected to have addictive CNS depressants effects. Prolonged sedation with pethidine in the presence of phenobarbital has also been attributed to induction of N-demethylation of pethidine resulting in the enhanced formation of the potentially neurotic metabolite norpethidine.
Antidepressants. Monoamine oxidase (MAO) inhibitors may inhibit barbiturate metabolism resulting in increased CNS depressant effects. A reduction in phenobarbital 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 phenobarbital may result in increased plasma levels and enhanced activity of phenobarbital.
Tricyclic antidepressants and selective serotonin reuptake inhibitor plasma levels may be lowered resulting in compromised efficacy through the possible induction of isoenzyme CYP2D6. Interaction with tricyclic antidepressants - resulting in increased sleep time and duration of anaesthesia meant that lower doses of barbiturates should be used.

Amitriptyline.

Antidepressants may antagonise the antiepileptic activity of some barbiturates by lowering the convulsive threshold. Barbiturates can increase the metabolism if tricyclic antidepressants and thereby produce lower plasma concentrations.

Bupropion.

Bupropion may induce seizures and consequently is contraindicated in patients with epilepsy. Phenobarbital may induce the metabolism of bupropion.

Fluoxetine.

Antidepressants may antagonize the activity of antiepileptics by lowering the convulsive threshold. Phenobarbital has been reported to reduce serum concentrations of paroxetine.

Lithium.

Severe CNS toxicity despite 'normal' serum lithium concentrations has been described in a patient also taking phenobarbital.

Mianserin.

Reduced plasma concentrations and half-lives of mianserin and desmethylmianserin were seen in 6 patients also receiving antiepileptic therapy consisting of phenytoin with either carbamazepine or phenobarbital. Mianserin may antagonise the action of antiepileptics by lowering the convulsive threshold.
Memantine. The effect of phenobarbital is possibly reduced.
Methylphenidate. Plasma concentration of phenobarbital is possibly increased.
Anti-arrhythmics such as quinidine and disopyramide. Concurrent barbiturate use may reduce serum levels to ineffective concentrations due to induction of CYP3A4. Plasma levels of antiarrhythmics should be monitored.

Lidocaine.

Studies in healthy subjects and patients with epilepsy suggest that long-term use of drugs such as barbiturates may increase dosage requirements for lidocaine due to induction of drug metabolising microsomal enzymes.

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.
Antibacterial.

Chloramphenicol.

Serum concentrations of phenytoin and phenobarbital in a previously stabilized patient were increase when they took chloramphenicol. Subsequent monitoring revealed in a similar effect when chloramphenicol was taken with phenobarbital alone. In turn, phenobarbital may affect serum concentrations of chloramphenicol. The metabolism of chloramphenicol may be increased by inducers of hepatic enzymes such as phenobarbital. Serum concentrations of chloramphenicol are usually reduced by the hepatic enzyme induction that occurs with phenobarbital.
Anticonvulsants. Patients treated concomitantly with valproate and phenobarbital should be monitored for signs of hyperammonemia. In half of the reported cases hyperammonaemia was asymptomatic and does not necessarily result in clinical encephalopathy. See also subsection Valproic acid/sodium valproate below.
Anticoagulants. Phenobarbital 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 phenobarbital 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 phenobarbital. Fluconazole does not appear to be much affected. The absorption of griseofulvin may be decreased resulting in decreased serum concentrations. Avoid concomitant use of voriconazole.
Antineoplastics.

Teniposide.

Clearance of teniposide was markedly increased by phenobarbital; the resultant decrease in systemic exposure to the antineoplastic might reduce it efficacy, and increased dosage would be needed in patients receiving this drug to guarantee equivalent exposure.
Antibiotics. The half-life of doxycycline may be decreased by phenobarbital due to induction of metabolism. The dosage and/or dosing interval of doxycycline may need to be adjusted. Metronidazole and rifampicin metabolism is enhanced resulting in reduced plasma levels.
Calcium channel blockers. Efficacy may be compromised when combining these agents with phenobarbital. A reduction in efficacy has been documented with nifedipine via induction of CYP3A4, felodipine, isradipine, diltiazem, verapamil, nimodipine.

Verapamil.

Phenobarbital is a hepatic enzyme inducing drug and has been reported to increase the clearance of oral and intravenous verapamil and to reduce oral bioavailability in healthy subjects. Plasma protein binding of verapamil was also reduced. Dosage adjustment of verapamil may be needed in patients also taking phenobarbital.
Cardiac glycosides.

Digitoxin.

Phenobarbital may greatly accelerate the metabolism of digitoxin. Since digitoxin is significantly metabolized in the liver it may be affected by drugs than induce microsomal enzymes, including antiepileptics such as phenobarbital.
Antipsychotics. With all antiepileptics, antipsychotics may antagonise the antiepileptics activity of phenobarbital by lower the convulsive threshold.

Chlorpromazine.

Phenobarbital are potent enzyme inducers and may decrease plasma concentrations of antipsychotics or their active metabolite when used together. The clinical effect of any interaction has not been consistent; worsening; improvement, or no change in psychotic symptoms have all been noted.
Haloperidol and the phenothiazines lower the seizure threshold and hence combination with phenobarbital may compromise the efficacy of phenobarbital. Phenobarbital may induce the metabolism of haloperidol and phenothiazines through cytochrome enzyme induction.

Aripiprazole.

Phenobarbital possibly reduces concentration of aripiprazole.
Aprepitant. Phenobarbital possibly reduces concentration of aprepitant.
Antivirals. A patient stabilised on phenobarbital 100 mg daily has an episode of seizures 4 weeks after starting HAART therapy with abacavir, didanosine, ritonavir-boosted tipranavir, and enfuvirtide. The patient's phenobarbital plasma concentrations had fallen from 16 to 8 micrograms/mL and an increase in the phenobarbital dosage to 150 mg daily was required to restore concentrations. The tipranavir/ritonavir component of HAART therapy was considered to be responsible.
Phenobarbital possibly reduces plasma levels of amprenavir, darunavir, lopinavir, indinavir, nelfinavir and saquinavir.

HIV-protease inhibitors.

Reduced plasma concentrations of HIV-protease inhibitors may be anticipated if the enzyme inducer phenobarbital is given concurrently.
Chemotherapeutic agents. Clearance of etoposide has been shown to increase by 170% when given with phenobarbital. Be alert for the need to increase etoposide dose if used concurrently with phenobarbital.
Corticosteroids. Reduction in serum levels of corticosteroids may compromise their effectiveness in the treatment of steroid-responsive disorders such as asthmatics, arthritic, renal transplant and other patients who receive phenobarbital.
Cytotoxics. Phenobarbital possibly reduces the plasma levels of etoposide or irinotecan.
Diuretics. Serum-phenobarbital concentrations were raised in 8 to 10 epileptic patients taking phenobarbital and additional antiepileptics when give frusemide 40 mg three times daily for 4 weeks. This might have been the cause of drowsiness in 5 to 14 patients. 3 of whom had to stop furosemide.
Concomitant use with eplerenone should be avoided.
Levothyroxine. Enzyme induction by drugs such as barbiturates enhances thyroid hormone metabolism resulting in reduced serum concentrations of thyroid hormones. Therefore patients on thyroid replacement therapy may require an increase in their dose of thyroid hormone if these drugs are also given and a decrease if the enzyme-inducing drug is withdrawn.
Montelukast. Licensed product information recommends caution when potent inducers of the cytochrome P450 isoenzyme CYP3A4 such as phenobarbital are given with montelukast. Montelukast - Peak serum concentrations after a single dose of montelukast 10 mg were reduced by 20% in 14 healthy subjects who took phenobarbital 100 mg daily for 14 days, and area under the serum concentration-time curve was reduced by 38%. However, it was not thought that montelukast doses would need adjustment if given with phenobarbital.
Oral contraceptives. Reductions in serum levels with breakthrough bleeding and lowered contraceptive efficacy may occur when these agents are combined with phenobarbital.
Immunosuppressants. Ciclosporin 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 phenobarbital on CYP3A4 may result in reduced plasma levels.
Sodium oxybate. Enhanced effects, avoid concomitant use.
Theophylline. Induction of isoenzyme CYP1A2 by phenobarbital 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 halogenated hydrocarbon anaesthetic agents leading to increased risk of hepatotoxicity.
Vaccines. Influenza vaccinations can cause prolonged rises in serum-phenobarbital concentrations in some patients.
Vitamin D. The effects of vitamin D may be reduced by barbiturates including phenobarbital because of accelerated metabolism by hepatic microsomal enzymes. Vitamin D supplementation may be required in patients on long-term anticonvulsant therapy with phenobarbital to prevent osteomalacia. The effect of phenobarbital 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. metoprolol, timolol and propranolol may be reduced by barbiturates.
Anticonvulsants. Variable effects are seen on the activity of phenytoin when combined with barbiturates. When phenobarbital is used with phenytoin, concentrations of either or both medicines may be affected. Even though phenobarbital 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. Phenobarbital may accelerate the metabolism of carbamazepine resulting in decreased plasma concentration. Phenobarbital may enhance the metabolism of lamotrigine. Adjustment of lamotrigine dose may be required following withdrawal of phenobarbital.
Vigabatrin has been reported to lower plasma concentrations of phenobarbital in some patients, although dosage changes were not necessary in these patients.
High dose of oxcarbamazepine may increase the plasma concentrations of phenobarbital but this was thought unlikely to be clinically significant, conversely strong inducers of cytochrome P450 coenzymes, such a phenobarbital may reduce the plasma concentrations of the active metabolite of oxcarbamazepine.

Carbamazepine.

The metabolism of carbamazepine is enhanced by enzyme inducers such as phenobarbital interactions of varying degrees of clinical significance have been reported between carbamazepine and other antiepileptics. Serum concentrations of carbamazepine are reported to be reduced by phenobarbital, but without loss of seizure control; this reduction is probably due to induction of carbamazepine metabolism.

Diazepam.

Phenobarbital is an inducer of hepatic drug metabolizing enzymes. Therefore, in patients receiving long term therapy of these drugs the metabolism of benzodiazepines may be enhanced.

Ethosuximide.

Since ethosuximide has a limited spectrum of antiepileptic action, patients with mixed seizure syndromes may require addition of other antiepileptics. Phenobarbital has been shown to increase the clearance of ethosuximide and thus reduce plasma concentration. This interaction is likely to be clinically relevant and higher ethosuximide dosages may be necessary to achieve therapeutic drug levels.

Tiagabine.

The hepatic metabolism of tiagabine is accelerated by antiepileptics that include enzymes of the cytochrome P450 system such as phenobarbital. Plasma concentrations of tiagabine may be reduced up to threefold by use with phenobarbital.

Zonisamide.

There are complex interactions between antiepileptics and toxicity may be enhanced without a corresponding increase in antiepileptic activity. Such interactions are very variable and unpredictable and plasma monitoring is often advisable with combination therapy. Use with drugs that induce or inhibit the cytochrome P450 isoenzyme CYP3A4 may alter plasma concentrations of zonisamide. Phenobarbital reduces the half-life of zonisamide.

Inhibition.

Several drugs inhibit the isoenzymes CYP3A4, CYP1A2 and CYP2C which can lead through competition to decreased metabolism of phenobarbital. This in turn leads to elevated blood levels of the medicine, respiratory depression and lowering of the lethal dose of phenobarbital. 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 phenobarbital are:

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 phenobarbital may be decreased by valproic acid/sodium valproate resulting in increased CNS depressant effects. Valproate appears to inhibit both the direct N-glycosylation of phenobarbital and the O-glucuronidation of p-hydroxyphenobarbital.
Phenobarbital may potentiate the hepatotoxicity of valproic acid/sodium valproate by increasing the metabolism of this drug to form valproate-4-ene, a known hepatotoxin. It is recommended that plasma concentrations of valproate and phenobarbital be monitored when any change in the therapeutic regimen occurs.
Progabide has also been reported to cause significant increase in phenobarbital concentrations when two were given together to healthy subjects. Neurotoxicity, attributed to an increase in plasma concentrations of phenobarbital, has been seen in one patients taking phenobarbital and sodium valproate when felbamate was added to the treatment. The dosage of phenobarbital had already been reduced before treatment with felbamate was started.
And data from a pharmacokinetic study indicated that the interaction may result from the inhibition of phenobarbital hydroxylation by felbamate.

Other interactions.

Amphetamines.

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

CNS depressants.

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

Oestrogen and progestogens.

Oestrogen and progestogens have a reduced contraceptive effect (see Section 4.6 Fertility, Pregnancy and Lactation).

Folic acid.

If folic acid supplements are given to treat folate deficiency, which can be caused by the use of phenobarbital, the serum phenobarbital levels may fall, leading to decreased seizure control in some patients (see Section 4.6 Fertility, Pregnancy and Lactation).

Hormone antagonist.

Gestrinone and possibly toremifene.

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.

Tibolone and tropisetron.

Phenobarbital may have an effect on tibolone and tropisetron.

Urinary alkalinisers.

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

Vitamins.

Barbiturates may possibly increase requirements for vitamin D.

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.

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 Interactions with Other Medicines and Other Forms of Interactions). 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 prepregnancy counselling with regard to the 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 concentration being found in the placenta fetal liver and brain. Animal studies (literature data) have shown reproductive toxicity in rodents (see Section 5.3 Preclinical Safety Data).
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 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 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).
Other malformations involving various body systems including cases of hypospadias, facial dysmorphic features, neural tube effects, craniofacial dysmorphia (microcephaly) and digital abnormalities have also been reported.
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.
The highest concentrations are found in the placenta and in the foetal liver and brain. Prenatal exposure to barbiturates have been reported to increase the risk of foetal abnormalities and of brain tumours. 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 phenobarbital is slow in the newborn especially in premature infants.
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.
Published animal studies of some anaesthetic/analgesic and 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. The clinical significance of these findings is not clear. However, based on the available data across species, the window of vulnerability to these changes is believed to correlate with exposure in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans.
 Phenobarbital is not recommended in breastfeeding mothers. Phenobarbital 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 phenobarbital in epileptic patients can be reduced by using a lower dose supplemented by phenytoin or primidone.

4.8 Adverse Effects (Undesirable Effects)

The most frequent adverse effect following administration of phenobarbital is sedation which often becomes less marked with continued administration. Phenobarbital 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.
Table 2 - The following adverse effects have been reported with the use of phenobarbital.
The following are also reported:

Musculoskeletal and connective tissue disorders.

Dupuytren's contracture, osteopenia, frozen shoulder and arthralgia.

Reproductive and breast disorders.

Peyronie's disease.

Psychiatric disorders.

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

Nervous system disorder.

Hyperactivity, behavioural disturbances in children, ataxia and nystagmus.

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 www.tga.gov.au/reporting-problems.

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.
Barbiturates decrease gut motility, which may lead to slow onset and worsening of symptoms or cyclical improvement and worsening of symptoms.

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 phenobarbital 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 phenobarbital 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 phenobarbital. 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.

Phenobarbital 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). Phenobarbital 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 phenobarbital 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 phenobarbital 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.

Phenobarbital sodium is rapidly distributed to all tissues and fluids with high concentrations in the brain, kidney and liver. As lipid solubility is low, phenobarbital is slower than other barbiturates in penetrating the tissues. Phenobarbital 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). Phenobarbital crosses the placenta and is excreted in breast milk.

Metabolism and excretion.

Metabolism is primarily via the hepatic microsomal enzyme system. Phenobarbital is converted via oxidative hydroxylation to p-hydroxyphenobarbital, an inactive metabolite. Approximately 25% of a dose is excreted unchanged in the urine and about 75% of the dose is excreted via the kidneys as p-hydroxyphenobarbital and its glucuronide and sulphate conjugates. Alkalinisation of the urine and/or increasing urinary flow rate substantially increases the rate of excretion of unchanged phenobarbital. Unmetabolised drug can accumulate in patients with oliguria or uraemia. Phenobarbital is a potent inducer of enzymes of the Cytochrome P-450 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 reported (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.

Phenobarbital 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. Phenobarbital 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 phenobarbital, 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 non-significant 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

Phenobarb tablets contain the following excipients: lactose monohydrate, acacia, wheat starch and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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. Protect from light.

6.5 Nature and Contents of Container

Phenobarb tablets are available in white HDPE bottles with a polypropylene child-resistant closure of 200 tablets.

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 presents as colourless crystals or a white odourless crystalline powder. It may exhibit polymorphism. It is soluble 1 in 1000 of water and 1 in 10 of alcohol; sparingly soluble in chloroform; soluble in ether. A saturated solution in water has a pH of about 5.

Chemical structure.

Phenobarbital has the following chemical structure:
Its molecular formula is C12H12N2O3. The molecular weight is 232.2.

CAS number.

CAS-50-06-6.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes