Consumer medicine information

Orion Phenobarbital Elixir

Phenobarbital (phenobarbitone)

BRAND INFORMATION

Brand name

Orion Phenobarbital Elixir

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

Important information about your medicine

This medicine the doctor has prescribed for you is called Orion Phenobarbital Elixir.

The information in this leaflet will answer some of the questions you may have about Orion Phenobarbital Elixir. This leaflet does not tell you everything. Your doctor or pharmacist has been provided with full information and can answer any questions you may have.

This leaflet does not replace the advice given to you by your doctor. Talk to your doctor or pharmacist.

You should read this leaflet before taking Orion Phenobarbital Elixir and keep it in a safe place to refer to later.

What Orion Phenobarbital Elixir is used for

Orion Phenobarbital Elixir is used to treat people with epilepsy. It is a barbiturate which belongs to a group of medicines called central nervous system depressants (medicines that cause drowsiness). Your doctor however may have prescribed Orion Phenobarbital Elixir for another purpose. Ask you doctor if you have any questions about why Orion Phenobarbital Elixir has been prescribed for you.

Before taking this medicine

When deciding to take a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For barbiturates the following should be considered:

Allergies: Tell your doctor if you have ever had any unusual or allergic reactions to phenobarbital or barbiturates, or any of the ingredients in Orion Phenobarbital Elixir (see Product Description). Symptoms of an allergic reaction may include red itchy skin rashes, difficulty breathing, hay fever, swelling of the face, lips, tongue or other parts of the body. Tell your doctor if you are allergic to any other substances such as food, preservatives or dyes.

Medical Conditions: Do not take Orion Phenobarbital Elixir if you have, or have had any of the following medical conditions:

Porphyria, a rare blood pigment disorder
Anaemia, a condition of the blood with a reduced number of red blood cells
Lung, liver or kidney problems
Sleep apnoea
Uncontrolled diabetes
Severe depression or suicidal tendencies
Alcoholism or drug dependence
Uncontrolled pain

Orion Phenobarbital Elixir should not be given to unusually overactive children.

Do not take Orion Phenobarbital Elixir after the expiry date printed on the bottle. If you take it after the expiry date has passed, it may have no effect at all, or worse, an entirely unexpected effect.

Do not take Orion Phenobarbital Elixir if the packaging is torn or shows signs of tampering.

Pregnancy: Barbiturates have been shown to increase the chance of birth defects in humans. However this medicine may be needed in serious illnesses or other situations that threaten the mothers life. Discuss this with your doctor if you are pregnant or plan a pregnancy.

If you plan a pregnancy you should take a folic acid supplement (5mg) four weeks before you get pregnant and take the folic acid (5mg) for 12 weeks after you fall pregnant. While pregnant you should have additional ultrasound checks, please discuss this with your doctor.

Breastfeeding: Discuss with your doctor if you are breastfeeding or plan to breastfeed. Orion Phenobarbital Elixir passes into breast milk and can affect the breastfed baby. Phenobarbital is thus not recommended in breastfeeding mothers.

Children: Excitement may occur in children who are more sensitive to the effects of barbiturates than adults.

Older Adults: Confusion, mental depression and unusual excitement may occur in the elderly who are usually more sensitive than younger adults to the effects of barbiturates. Also, elderly patients are more likely to have less effective kidney or liver function due to age. This may increase the risk of side effects. You should discuss with your doctor how much Orion Phenobarbital Elixir to take.

Before you take Orion Phenobarbital Elixir for the first time you should tell your doctor

If you are taking other medicines or treatment
If you are or may become pregnant
If you are breast feeding
If you have any other medical conditions/health problems, including:
- Blood problems
- Short or long-term pain

Precautions while taking this medicine

If you are taking this medicine regularly for a long time your doctor should check your progress at regular intervals.

Be careful when drinking alcohol while taking Orion Phenobarbital Elixir. Combining this medicine with alcohol can make you more sleepy, dizzy or light headed. Your doctor may suggest you avoid alcohol while you are being treated with this medicine.

Orion Phenobarbital Elixir may be habit-forming if taken in high doses for a long period of time. Talk to your doctor or pharmacist if you are concerned about this.

If you have to take any medical tests while you are taking Orion Phenobarbital Elixir tell your doctor that you are taking this medicine as it may affect the results of some tests.

Be sure to keep all your doctor’s appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time to help prevent unwanted side effects.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking Orion Phenobarbital Elixir. If you are about to be started on any new medicine, tell your doctor, dentist or pharmacists that you are taking this medicine.

Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

Driving or operating machinery while taking Orion Phenobarbital Elixir

Orion Phenobarbital Elixir may cause drowsiness. You should be sure how you react to Orion Phenobarbital Elixir before you drive your car or operate machinery or do anything else that could be dangerous if you are dizzy or not alert.

How to take Orion Phenobarbital Elixir

Take this medicine as directed by your doctor. Your doctor will decide on the best dose of Orion Phenobarbital Elixir for you. It will depend on your age, weight and illness. Do not take more of it or take it more often. Do not take it for longer than told to by your doctor. If taken too much it may become habit forming.

The number of doses you take each day and the time between each dose will depend on your medical problem.

Do not stop taking the medicine without talking to your doctor, it must be taken regularly to control your epilepsy, do not miss any doses. Stopping Orion Phenobarbital Elixir suddenly may cause unwanted effects or make your condition worse. Your doctor will slowly reduce your dose before you stop taking it completely.

If you forget to take it
If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise take it 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.

Taking Orion Phenobarbital Elixir with other medicines

Some medicines can affect the way Orion Phenobarbital Elixir works. It is important that you tell your doctor before taking any other medicine even those bought without a prescription from your pharmacy, supermarket or health food shop.

It is especially important to tell your doctor if you are taking any of the following medicines and to talk to him before you take them for the first time:

Other medications used to treat epilepsy
Anticoagulants, medicines used to treat clots eg warfarin
Painkillers, paracetamol and stronger narcotic medicines
Anaesthetic agents
Antidepressants, medicines used to treat depression
Antipsychotics, medicines used to treat certain mental and emotional conditions
Stimulants such as amphetamines, dexamphetamines
Immunosuppressive medicines used to lower your body’s resistance to disease eg Cyclosporin, tacrolimus
Antibiotics, antivirals and antifungals, medicines used to treat infections including AIDS
Medicines used to treat heart conditions, irregular heart beats, high blood pressure, angina
Disulfram, a medicine used to treat alcoholism
Urinary alkalisers
Carbonic anhydrase inhibitors eg acetazolamide, medicines used to treat glaucoma, oedema (fluid build up)
Antihistamines, medicines used to treat or prevent the treatment of allergy
Theophylline, a medicine used to treat asthma
Corticosteroids such as prednisolone, cortisone
Oestrogens, hormones used in oral contraceptive pills and in hormone replacement therapy
St John’s Wort (Hypercium perforatum)

These medicines may be affected by Orion Phenobarbital Elixir or affect how well it works. You may need different amounts of medicine, or may need to take different medicine. Your doctor or pharmacist will advise you.

Your doctor may advise you to use an additional form of contraception while taking Orion Phenobarbital Elixir.

If you are going to have a flu vaccine, tell your doctor that you are taking Orion Phenobarbital Elixir. Your doctor may need to adjust your dose of Orion Phenobarbital Elixir.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking Orion Phenobarbital Elixir.

Side Effects

All medicines including Orion Phenobarbital Elixir can cause unwanted effects.

The most common side effect with Orion Phenobarbital Elixir is likely to be drowsiness.

Tell your doctor if you notice any of the following and they worry you:

Rapid heartbeat
Nausea (feeling sick)
Constipation
Dizziness
Lethargy
Vomiting
Skin rashes
Sweating
Dry mouth
Confusion
Faintness
Irritability
Restlessness
Mood changes
Drowsiness
Hyperexcitability
Hangover
Sleep disturbances

Tell your doctor immediately or go to the Accident and Emergency at your nearest hospital if you notice any of the following:

Sore throat
Fever
Easy or unusual bleeding or bruising under the skin
Nosebleed
Other signs of infections eg swollen glands, mouth ulcers
Sudden signs of allergy (listed on page 1)
Severe skin rash, itching, hives, blisters or peeling skin

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Overdose

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Orion Phenobarbital Elixir. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Taking an overdose of Orion Phenobarbital Elixir or taking alcohol or medicines such as sleeping tablets, sedatives, tranquillizers and strong painkillers with Orion Phenobarbital Elixir may lead to unconsciousness.

Some signs of overdose are severe drowsiness, dizziness, confusion, weakness, nausea, vomiting, trouble breathing, slurred speech and staggering.

Other information about Orion Phenobarbital Elixir

Do not give your Orion Phenobarbital Elixir to anyone else.

Taking barbiturates may lead to dependence on the medicine.

This medicine is available only with your doctor’s prescription.

Storing Orion Phenobarbital Elixir

Keep out of reach of children since overdose is especially dangerous in children.

Do not keep out of date medicine.

Store Orion Phenobarbital Elixir below 30°C.

Product description

Orion Phenobarbital Elixir is an elixir flavoured with butterscotch flavour, it also contains phenobarbital, ethanol, glycerol, sorbitol and water.

Sponsor

This product is supplied by

Orion Laboratories Pty Ltd T/A
Perrigo Australia
25 - 29 Delawney Street
Balcatta WA 6021
Phone: 1800 805 546

Australian Registration Number Orion Phenobarbital Elixir 15mg/5mL: AUST R 21187

This leaflet was prepared January 2002

Last Amendment: May 2023

END OF CONSUMER MEDICINE INFORMATION

ACC04156P:3

Published by MIMS August 2023

BRAND INFORMATION

Brand name

Orion Phenobarbital Elixir

Active ingredient

Phenobarbital (phenobarbitone)

Schedule

1 Name of Medicine

Phenobarbital.

2 Qualitative and Quantitative Composition

Orion Phenobarbital Elixir contains 15 mg phenobarbital per 5 mL (0.3% w/v) in a sweetened sucrose free base. It contains butterscotch flavour, ethanol, glycerol, sorbitol solution (70% noncrystallising) and water.

3 Pharmaceutical Form

Oral liquid, solution. Clear, syrupy liquid; characteristic butterscotch odour.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of epilepsy.

4.2 Dose and Method of Administration

The dose of phenobarbital must be adjusted to the individual giving consideration to the patient's age, weight and condition.
Plasma concentrations required to control epilepsy are usually about 15 to 40 micrograms/mL (65 to 170 micromoles per L). Drug levels should be monitored so as to keep within the therapeutic range.

Recommended dosage.

Adult.

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 individualized. Geriatric and debilitated patients may exhibit excitement, confusion or depression with usual therapeutic doses, thus lower doses are recommended.
Phenobarbital should be withdrawn slowly in order to avoid precipitating seizures or status epilepticus.

4.3 Contraindications

Not to be administered to:
Patients who are known to be hypersensitive to barbituric acid derivatives.
Patients with porphyria, severe respiratory depression or pulmonary insufficiency, renal impairment, hepatic impairment, sleep apnoea, uncontrolled diabetes mellitus, severe anaemia due to folate deficiency, hyperkinetic children, suicidal potential, alcoholism and drug dependency.
Not to be used in the presence of uncontrolled pain as paradoxical excitement may be produced.
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).
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.

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 and 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.

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) (see Section 4.3 Contraindications). The blood count should be monitored during long-term therapy. Patients should be instructed to report symptoms such as sore throat, fever, easy bruising, epistaxis or other signs of infection or bleeding tendency (note that megaloblastic anaemia and thrombocytopaenia have been reported rarely).

Asthma, urticaria and angioedema.

Barbiturates should be used with caution in patients with a history of asthma, urticaria or angioedema. Mild hypersensitivity reactions have been reported in 1-3% of patients 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.
Phenobarbital should be used with caution in the presence of any respiratory difficulty (see Section 4.3 Contraindications).

Rickets and osteomalacia.

Although rare, rickets and osteomalacia have been reported following prolonged usage of barbiturates due to increased metabolism of vitamin D.

Chronic pain.

Phenobarbital should be used with caution in patients with acute or chronic pain, since paradoxical excitement may occur or important symptoms might be masked (see Section 4.3 Contraindications).

Corticosteroids, hypoadrenalism and hyperthyroidism.

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 pituitary or adrenal in origin. Patients with hyperthyroidism should be treated with caution as symptoms may be exacerbated through displacement of thyroxine from plasma proteins.

CNS depressants.

Concurrent use of phenobarbital with other CNS depressant drugs (e.g. alcohol, narcotics, tranquillisers and antihistamines) and alcohol may result in additional CNS depressant effects. Caution is recommended and dosage reduction of either or both medications may be needed.

Use in hepatic impairment.

Phenobarbital is metabolised in the liver, therefore hepatic dysfunction may theoretically lead to increased blood levels. The dose may need to be reduced.

Use in renal impairment.

Phenobarbital is excreted in 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. The incidence of fractures due to falls may be increased.

Paediatric use.

Caution should be exercised when using phenobarbital in children because the drug may exacerbate existing hyperkinetic behaviour, which is severe enough to necessitate a change to a different barbiturate derivative or another anticonvulsant (see Section 4.3 Contraindications).

Effects on laboratory tests.

Phenobarbital may interfere with diagnostic test results when the following agents are used:
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 possible 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

Pharmacodynamic interactions.

Concurrent administration of phenobarbital with other drugs may result in increased effect of the other drugs or the barbiturate itself.

Pharmacokinetic interactions.

Phenobarbital is an inducer of hepatic microsomal enzymes and is capable of increasing the clearance of many hepatically metabolised drugs. This can result in a decrease in or a loss of effectiveness of other drugs during phenobarbital use and/or increase in effect and even frank toxicity on discontinuation of phenobarbital.

Anticoagulants.

Barbiturates may increase the metabolism of oral anticoagulants resulting in decreased anticoagulant response. Correspondingly, if phenobarbital is discontinued from a stabilised dosage, the hypoprothrombinaemic response may be greatly increased, potentially resulting in haemorrhagic complications. Prothrombin times should be monitored closely if phenobarbital is added or deleted from a regimen that includes oral anticoagulants.

Anticonvulsants.

Carbamazepine - Phenobarbital usually accelerates the metabolism of carbamazepine, resulting in decreased plasma concentrations.
Lamotrigine - Phenobarbital may enhance the metabolism of lamotrigine. Adjustment of lamotrigine dose may be required following withdrawal of phenobarbital from the therapeutic regimen.
Phenytoin - When phenobarbital is used with phenytoin concentrations of either or both drugs may be affected. While phenobarbital may induce the metabolism of phenytoin it may also decrease it because both drugs compete for the same metabolic pathway. Therefore, plasma concentrations of both drugs should be monitored when these are used concomitantly.
Sodium valproate - The metabolism of phenobarbital may be decreased by sodium valproate, resulting in increased CNS depressant effects. Phenobarbital potentiates the hepatotoxicity of sodium valproate by increasing the metabolism of sodium valproate to form valproate-4-ene, a known hepatotoxin. Therefore, plasma concentrations of sodium valproate and phenobarbital should be monitored when any change in the therapeutic regimen occurs.

Corticosteroids.

Barbiturates increase the metabolism of corticosteroids, and may exacerbate asthma and other conditions when added to regimens containing 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 phenobarbital (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).

Antidepressants.

Phenobarbital may increase the metabolism of tricyclic antidepressants and selective serotonin reuptake inhibitor through the possible induction of CYP2D6, resulting in a lack of effect. Plasma TCA or SSRI levels should be monitored if possible, especially if the patient is not responding to standard dosages of antidepressants.

Monoamine oxidase inhibitors.

MAOIs may inhibit barbiturate metabolism, resulting in increased CNS depressant effects. A reduction in phenobarbital dosage may be necessary. Phenobarbital should be avoided in patients who are on tranylcypromine because concomitant use of barbiturate and tranylcypromine has been reported to result in semi-comatose for 36 hours in one case study.

Opioid analgesics.

Phenobarbital may increase the metabolism of opioid analgesics such as methadone leading to a decreased plasma level and opioid withdrawal symptoms. Methadone levels must be monitored if phenobarbital is introduced.

Paracetamol.

The therapeutic effects of paracetamol may be reduced due to enzyme induction of CYP3A4 and subsequent increased metabolism of the drug to its toxic metabolite, leading to increased hepatotoxicity. Chronic use of phenobarbital may increase the risk of hepatotoxicity with single toxic doses or prolonged high doses of paracetamol.

Antipsychotics.

Phenobarbital may induce the metabolism of haloperidol and phenothiazines. Haloperidol and phenothiazines lower the seizure threshold and hence combination with phenobarbital may compromise the efficacy of phenobarbital.

Cardiovascular.

Barbiturates have been reported to increase the metabolism (due to the induction of CYP3A4) and correspondingly reduce the effectiveness of digoxin, anti-arrhythmics (e.g. quinidine, disopyramide and mexiletine), β-blockers (e.g. propranolol) and calcium channel blockers (e.g. nifedipine).

Antifungals.

Poor clinical response to antifungals such as itraconazole and ketoconazole results from enzyme induction of CYP3A4 by phenobarbital. 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 phenobarbital 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. Barbiturates have been shown to increase the metabolism and correspondingly reduce the effectiveness of chloramphenicol.

Disulfiram.

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

Flu vaccine.

Concurrent use of flu vaccine and phenobarbital may increase the serum concentration of the barbiturate, and dosage adjustments may be necessary.

Chemotherapeutic agents.

Clearance of etoposide has been shown to increase by 170% when given with phenobarbital. Be alert for the need to increase the etoposide dose if used concurrently with phenobarbital.

Immunosuppressants.

Cyclosporin and tacrolimus have been shown to have clearance increased by barbiturates.

Protease inhibitors.

Increased metabolism by the action of phenobarbital on CYP3A4 may result in reduced plasma levels.

Theophylline.

Induction of CYP1A2 may result in lowered plasma levels and loss of efficacy. Serum theophylline levels should be monitored as 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 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.

Urinary alkalinisers.

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

Hypericum perforatum (St John's wort).

Concomitant 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. Serum barbiturate levels may increase when the administration of St John's wort is stopped, thus resulting in a need to adjust the dose of barbiturate.

Pharmacodynamic interactions.

Concurrent administration of phenobarbital with other drugs may result in increased effect of the other drugs or the barbiturate itself.

CNS depressants.

Excessive CNS depressant effects may result from concurrent administration of barbiturates and other CNS depressants such as alcohol, benzodiazepines, phenothiazines, antihistamines, anaesthetics and opioids.

Amphetamines.

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

Tricyclic antidepressants.

Concomitant use of phenobarbital and tricyclic antidepressants may result in additive respiratory depressant effects. Tricyclic antidepressants may decrease seizure control; epileptic patients receiving phenobarbital should be watched closely when tricyclic antidepressants are administered and the dose of phenobarbital should be adjusted if necessary.

Anaesthetics.

Ketamine anaesthesia following administration of a barbiturate has been reported to produce profound respiratory depression.

Carbonic anhydrase inhibitors.

Concurrent administration of carbonic anhydrase inhibitors with phenobarbital may enhance osteopaenia induced by phenobarbital. Patients receiving concurrent therapy should be monitored for early signs of osteopaenia, and carbonic anhydrase inhibitor should be discontinued, with appropriate treatment initiated if required.

Hypothermia producing medicines.

Concurrent use of hypothermia producing medicines with phenobarbital in high doses or acute overdose may increase the risk of hypothermia.

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)
Pregnancy Category D - drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.

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.
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.
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 67% 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).
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 serum level of phenobarbital may decline during pregnancy requiring adjustments in dosage. Postpartum restoration of the original dose will probably be indicated.
Prenatal exposure to barbiturates has been reported to increase the risk of fetal abnormalities and of brain tumours. Barbiturate withdrawal has been reported in neonates who have been exposed to the drug in utero. Use of barbiturates throughout the third trimester of pregnancy may result in physical dependence and subsequent withdrawal symptoms in the neonate, including sedation, hypotonia and sucking disorder. Withdrawal may occur 1-14 days after birth, and symptoms include seizures, irritability, hyperirritability, disturbed sleep, tremor, hypotonia, vomiting and hyperreflexia. Use of barbiturates during labour may cause respiratory depression in the neonate.
Elimination of phenobarbital is slow in the newborn especially in premature infants. 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 12 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.
Phenobarbital is not recommended in breastfeeding mothers. Phenobarbital is distributed into breast milk and use by breastfeeding mothers may cause CNS depression.

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 the administration of phenobarbital is sedation that often becomes less marked with continued administration.
Phenobarbital may induce 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 number 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 effect may develop. See Section 4.9 Overdose for the effects of excessive doses.
The following adverse reactions have been reported with the use of phenobarbital:

Neurological.

Common: drowsiness, sedation (appears to lessen with use).
Uncommon: agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, thinking abnormality, subtle mood changes, impairment of concentration, judgment, memory and fine motor skills. Disturbances of sleep, vertigo, headache and depression.

Cardiovascular.

Uncommon: hypotension, syncope, bradycardia, vasodilation.
Rare: peripheral vascular collapse, feeble heartbeat, circulatory failure.

Respiratory.

Uncommon: severe respiratory depression, apnoea, bronchospasm or laryngospasm.

Haematological.

Uncommon: folate deficiency or hypocalcaemia, megaloblastic anaemia and lymphocytosis.
Rare: thrombocytopaenia, agranulocytosis.

Digestive system.

Uncommon: nausea, vomiting, diarrhoea and constipation.

Dermatological.

Very common: 1-3% incidence of relatively mild skin reactions in the form of maculopapular, morbilliform and scarlatiniform rashes; skin blisters (bullae) in patients with barbiturate overdose, evidence of connective tissue changes.
Uncommon: erythroderma, hypersensitivity reactions such as angioedema and skin rashes.
Rare: exfoliative dermatitis, erythema multiforme (or Stevens-Johnson syndrome) and toxic epidermal necrolysis.

Hepatic.

Uncommon: liver damage.
Rare: toxic hepatitis and jaundice.

Metabolic.

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

Neonates exposed to phenobarbital in utero.

Common: drug dependency, symptoms resembling vitamin K deficiency.

Other.

Uncommon: fever and menstrually related mood disorder.

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

Overdosage of barbiturates produce 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; apnoea, 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 of overdosage is primarily 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 is an effective barbiturate absorbent when administered within 30 minutes following ingestion of the drug. 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 the coma. The patient's vital signs and fluid intake should be monitored closely. Analeptic drugs should not be administered because these may produce paroxysmal cerebral activity which may result in generalized 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 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 nonselective central nervous system depressant with a long duration of action. The mechanism of action of the barbiturates is not completely known. They may act by enhancing and/or mimicking the synaptic action of gamma-aminobutyric acid (GABA). Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function and produce drowsiness, sedation and hypnosis. Phenobarbital is reported to have anticonvulsant activity at sub-hypnotic doses.
The anticonvulsant properties are believed to be due to depression of monosynaptic and polysynaptic transmission and increasing the threshold for electrical stimulation of the motor cortex.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Phenobarbital is readily absorbed (about 70-90% of an oral dose) from the gastrointestinal tract. It is relatively lipid insoluble and may require up to an hour or longer to achieve effective concentrations. Absorption is increased if barbiturates are taken well diluted or on an empty stomach. Its duration of action ranges from 10-12 hours.

Distribution.

Following the absorption phenobarbital 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, and thus has a slower onset and longer duration of action.
Phenobarbital is about 45% bound to the plasma proteins.
Therapeutic monitoring of plasma concentrations has been performed as an aid in assessing control of its anticonvulsant activity. The therapeutic range is usually quoted as being 15-40 micrograms per mL (65-170 micromol per L).

Metabolism.

The plasma half-life is about 90-100 hours in adults but is greatly prolonged in neonates. The half-life in children is about 65-70 hours.
Phenobarbital is metabolised primarily in the liver by the hepatic microsomal enzyme system and is a potent inducer of the CYP450 system and thus may accelerate metabolism of other concomitantly administered drugs metabolised by these enzymes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The pharmacokinetics of phenobarbital is affected by the concomitant administration of other antiepileptics.

Excretion.

Phenobarbital is hydroxylated by the liver to form p-hydroxyphenobarbital, an inactive metabolite. About 25-50% of a dose is excreted unchanged in the urine at normal urinary pH. About 75% of the dose is excreted via the kidneys as the p-hydroxy metabolite and its glucuronide and sulfate conjugates.
Alkalisation 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.

5.3 Preclinical Safety Data

Teratogenicity.

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 is carcinogenic in mice and rats after lifetime administration. In mice it produced benign and malignant liver cell tumours. In rats, benign liver cell tumours were observed. Phenobarbital was negative in a 26 week bioassay in p53 heterozygous mice. In a 29 year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma. Previously some of the patients had been treated with thorotrast, a drug known to cause hepatic carcinomas. When patients who had received thorotrast were included, 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

See Section 2 Qualitative and Quantitative Composition.

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 30°C.

6.5 Nature and Contents of Container

Orion Phenobarbital Elixir, phenobarbital 15 mg/5 mL, comes in 100 mL and 500 mL bottle.

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 is a barbituric acid derivative. It occurs as colourless crystals or a white odourless crystalline powder. Soluble 1 in 1000 of water and 1 in 10 of alcohol. It is soluble in alcohol, in ether and in solutions of fixed alkali hydroxides and carbonates, it is sparingly soluble in chloroform. Phenobarbital is 5-ethyl-5-phenylbarbituric acid and has the molecular formula C₁₂H₁₂N₂O₃ and molecular weight 232.2.

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Phenobarbital (phenobarbitone)

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