Consumer medicine information

Carbamazepine Sandoz

Carbamazepine

BRAND INFORMATION

Brand name

Carbamazepine Sandoz

Active ingredient

Carbamazepine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Carbamazepine Sandoz.

What is in this leaflet

This leaflet answers some common questions about Carbamazepine Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Carbamazepine Sandoz is used for

Carbamazepine Sandoz has several uses:

  • to control epilepsy, a condition in which there are repeated seizures (fits). There are many different types of seizures, ranging from mild to severe
  • to control sudden, repeated attacks of facial pain, known as trigeminal neuralgia
  • to control mania, a mental condition with episodes of overactivity, elation or irritability
  • to control bipolar mood disorder where periods of mania alternate with periods of depression.

Carbamazepine Sandoz belongs to a group of medicines called anticonvulsants. These medicines are thought to work by regulating the way messages in the brain are passed on by nerves so that seizures do not happen. This medicine also regulates other nerve functions in the body.

Carbamazepine Sandoz may be used alone or in combination with other medicines to treat your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription. There is no evidence that this medicine is addictive.

Before you take Carbamazepine Sandoz

When you must not take it

Do not take this medicine if you have an allergy to:

  • carbamazepine, the active ingredient, or any of the other ingredients listed at the end of this leaflet
  • any other medicine containing carbamazepine
  • tricyclic antidepressants, which are medicines used to treat depression.

Tell your doctor if you are allergic to oxcarbazepine or to phenytoin. These two medicines are also used to treat epilepsy. Some people who are allergic to oxcarbazepine or phenytoin are also allergic to carbamazepine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, eyelids, throat, mouth, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are taking a medicine called a monoamine oxidase inhibitor (MAOI) or have been taking it within the past 14 days. Taking this medicine with a MAOI, or within 14 days of taking a MAOI, may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions.

Do not take this medicine if you have or have had any of the following medical conditions:

  • severe liver or heart disease
  • a disease of the blood with a reduced number of red or white blood cells or platelets (risk of bone marrow depression)
  • an irregular heartbeat caused by a condition called A-V block
  • systemic lupus erythematosus, also called SLE
  • hepatic porphyria, a disturbance in the production of porphyria, a pigment important for liver function and blood formation.

If you are not sure whether any of the above conditions apply to you, ask your doctor.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

If you are not sure whether you should start taking this medicine, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, preservatives or dyes. Your doctor will want to know if you are prone to allergies.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • heart problems
  • glaucoma
  • prostate problems or if you cannot retain your urine
  • liver or kidney problems
  • problems with your blood in the past that were caused by medicines you were taking
  • a mental disorder such as depression or schizophrenia.

Tell your doctor if you are of Asian descent, particularly if you are Chinese or Thai. Your doctor may want to do a genetic test before you take this medicine for the first time.

The risk of serious skin reactions in patients of Han Chinese or Thai origin associated with carbamazepine or chemically related compounds may be predicted by testing a blood sample of these patients.

Your doctor should be able to advise if a blood test is necessary before taking Carbamazepine Sandoz.

Tell your doctor if you are pregnant or intend to become pregnant. You may need to change your medication. Your doctor will discuss with you the potential risk of taking Carbamazepine Sandoz during pregnancy since it may cause harm or abnormalities in your baby during pregnancy and soon after birth. Risk of neurodevelopmental disorders (how the brain functions leading to difficulties in social, emotional and mental function) cannot be excluded among children born to women with epilepsy treated with carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. But, if you have epilepsy, it is very important to control your fits while you are pregnant. Your doctor can help you decide whether or not you should take Carbamazepine Sandoz in this case.

Tell your doctor if you are breastfeeding or plan to breast-feed. This medicine passes into breast milk but it is unlikely to affect your baby. With the advice of your doctor you may breast-feed provided that you watch your baby for any signs of an unwanted side effect. If your baby develops a skin rash, becomes very sleepy or has other unusual symptoms, do not breast-feed again until you speak to your doctor.

If you have not told your doctor about any of the above, tell him/ her before you start taking Carbamazepine Sandoz.

Taking other medicines

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

Some medicines and Carbamazepine Sandoz may interfere with each other. These include:

  • MAOI medicines. This medicine must not be taken together with a MAOI or within 14 days of taking a MAOI.
  • other medicines used to treat depression such as fluvoxamine, nefazodone, paroxetine, bupropion, citalopram, tricyclic antidepressants and trazodone
  • other medicines used to treat seizures including oxcarbazepine, levetiracetam, valproic acid, brivaracetam, lamotrigine, topiramate and phenytoin
  • some medicines used to treat mental disorders such as clozapine, haloperidol, thioridazine, lithium, olanzapine, risperidone, quetiapine and ziprasidone
  • some medicines used to treat heart problems or high cholesterol
  • some medicines used to help you sleep or calm you down
  • some pain relievers such as paracetamol, dextro-propoxyphene, tramadol and ibuprofen
  • warfarin, a medicine used to prevent blood clots
  • some diuretics (fluid tablets), which are medicines used to reduce water retention and high blood pressure
  • some antibiotics and antifungal medicines used to treat infections, such as erythromycin, clarithromycin, doxycycline, itraconazole, ketoconazole, fluconazole, voriconazole and rifampicin
  • corticosteroids such as prednisolone and dexamethasone
  • St John's wort, an ingredient in many medicines that you can buy without a prescription from a pharmacy, health food shop or supermarket
  • antihistamines such as loratadine and terfenadine, which are medicines used to prevent or relieve the symptoms of allergies such as hay fever
  • isoniazid, a medicine used to prevent and treat tuberculosis
  • acetazolamide, a medicine used to reduce fluid retention and to treat glaucoma and some types of seizures
  • cimetidine and omeprazole, medicines used to treat stomach or duodenal ulcers
  • ticlopidine, a medicine used to prevent blood clotting
  • theophylline and aminophylline, medicines used to treat asthma
  • some medicines used to prevent rejection of organ transplants and to treat severe rheumatoid arthritis and some skin diseases, such as cyclosporin and everolimus
  • some medicines used to treat cancer, such as cisplatin, doxorubicin and imatinib
  • methadone, a medicine used to control severe pain and to treat heroin addiction
  • metoclopramide, a medicine used to treat nausea and vomiting
  • isotretinoin, a medicine used to treat acne
  • danazol, a medicine used to treat endometriosis
  • a vitamin called nicotinamide
  • muscle relaxants such as dantrolene and oxybutynin
  • medicines used to treat HIV such as indinavir, ritonavir and saquinavir
  • levothyroxine, a medicine used to treat underactive thyroids
  • praziquantel, a medicine used to treat worm infections of the blood
  • medicines containing oestrogen and progesterone, including hormone replacement therapy and hormonal contraceptives.

The above medicines may be affected by Carbamazepine Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Tell your doctor if you are using hormonal contraceptives (e.g. birth control pills or injections). If you begin taking this medicine while you are using hormonal contraceptives, they may not work as well as they should.

Unplanned pregnancies can happen. Your doctor can suggest another form of birth control (non-hormonal) while you are taking Carbamazepine Sandoz.

Tell your doctor immediately if you notice irregular vaginal bleeding or spotting.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Carbamazepine Sandoz

Follow all directions given to you by your doctor or pharmacist carefully. These directions may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much Carbamazepine Sandoz you need to take each day. This may depend on your age, your medical condition and whether or not you are taking other medicines.

Your doctor will usually start your treatment with a low dose and then slowly increase it to the lowest amount needed to control your condition. Some people will need higher doses than other people will.

How to take it

Swallow the tablets with a full glass of water.

When to take it

Take your medicine during or after a meal. This helps to prevent stomach upset.

Carbamazepine Sandoz is usually taken in 2 or 3 doses during the day. But your doctor may tell you to take it more or less often, depending on your situation.

If you forget to take it

If your next dose is not due for more than 2 or 3 hours, take the missed dose as soon as you remember. Then take your next dose at the usual time and continue on with your normal schedule.

If your next dose is due within 2 or 3 hours, skip the missed dose. Take your next dose at the usual time and continue on with your normal schedule.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Do not stop taking Carbamazepine Sandoz or lower the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. Stopping your medicine suddenly or lowering the dose may cause unwanted side effects or make your condition worse. If you are taking this medicine to treat epilepsy, you could develop seizures (fits). Your doctor will usually reduce the dose slowly before you can stop taking it completely.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Carbamazepine Sandoz. Do this even if there are no signs of discomfort or poisoning.

Keep the telephone numbers for these places handy.

Some of the symptoms of an overdose may include agitation, disorientation, fainting, vomiting, difficulty breathing, fast and irregular heartbeat, blurred vision, shakiness and slurred speech. If you are taking the controlled release (CR) tablets, it may take longer for you to notice these effects.

While you are taking Carbamazepine Sandoz

Things you must do

If you become pregnant while taking this medicine, tell your doctor immediately. Your doctor can discuss with you the risks of taking it while you are pregnant.

Be sure to keep all of your doctor's appointments so that your progress can be checked. To help prevent unwanted side effects from happening, your doctor may want to do some tests before you start taking Carbamazepine Sandoz and from time to time during the course of your treatment.

Contact your doctor immediately if at any time you have thoughts of harming or killing yourself. A number of people being treated with antiepileptics have had such thoughts or behaviour.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Before having any surgery or emergency treatment, tell the doctor or dentist in charge that you are taking this medicine. This medicine may interfere with some of the medicines used during surgery.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Carbamazepine Sandoz.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Things you must not do

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Do not use Carbamazepine Sandoz to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or they have the same condition as you do.

Things to be careful of

Avoid drinking grapefruit juice while you are being treated with this medicine. Grapefruit juice may interact with Carbamazepine Sandoz and affect how your body uses this medicine.

Be careful driving or operating machinery until you know how Carbamazepine Sandoz affects you. Children should be careful when riding bicycles or climbing trees. This medicine may cause dizziness, drowsiness, blurred vision, double vision or lack of muscle coordination in some people, especially when you first start to use it or when the dose is increased.

Be careful when drinking alcohol while you are taking this medicine. The combination could make you more sleepy, dizzy or light-headed than usual. Your doctor may suggest you avoid alcohol while you are being treated with Carbamazepine Sandoz.

When outdoors, wear protective clothing and use at least a 15+ sunscreen. Do not use a sunlamp or tanning bed or booth. This medicine may cause your skin to be much more sensitive to sunlight than it normally is. Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn. If your skin does appear to be burning, tell your doctor.

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • dizziness or light-headedness
  • tiredness or drowsiness
  • eye pain
  • weakness, unsteadiness when walking
  • headache
  • restlessness, agitation or confusion
  • difficulty in speaking or slurred speech
  • numbness or tingling in hands or feet
  • muscle pain or cramps
  • nausea (feeling sick) or vomiting, loss of appetite
  • weight gain
  • stomach pain or discomfort
  • diarrhoea
  • constipation
  • dry mouth
  • swollen, red, sore tongue
  • mouth ulcers or cold sores
  • change in sense of taste
  • blurred or double vision, swollen runny eyes, difficulty seeing
  • ringing or buzzing in the ears or other changes in hearing
  • frequent need to urinate (pass water)
  • sweating
  • hair loss
  • acne
  • change in skin colour
  • excessive hairiness, especially in women
  • sexual disturbances such as impotence
  • breast enlargement in men
  • unusual secretion of breast milk
  • loss of muscle coordination.

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

  • signs of allergy such as swelling of the face, lips, tongue, eyelids, throat, mouth or other parts of the body; wheezing or troubled breathing; difficulty swallowing, itching, hives, chest discomfort or tightness, loss of consciousness
  • skin rash, redness, blisters or peeling skin, accompanied by fever, chills, headache, cough, body aches
  • sudden increase in body temperature, accompanied by sweating, fast heart beat and muscle stiffness, altered consciousness, high blood pressure, excessive salivation
  • constant "flu-like" symptoms (chills, fever, sore throat, swollen glands, aching joints, lack of energy)
  • unusual bleeding or bruising under the skin, nosebleeds
  • shortness of breath and dizziness when exercising
  • frequent infections or fever
  • severe chills, sore throat, swollen glands or mouth ulcers
  • persistent nausea or vomiting, loss of appetite and feeling generally unwell, which may be accompanied by pain in the abdomen, fever, itching, a yellow colour to skin or eyes, dark coloured urine or light coloured bowel motions
  • diarrhoea, abdominal pain and fever
  • severe upper stomach pain, often with loss of appetite and vomiting
  • more frequent or more severe seizures (fits)
  • sudden onset of uncontrollable muscle spasms affecting the eyes, head, neck and body
  • trembling, uncontrolled body movements
  • lethargy, confusion
  • depression, aggressive behaviour, recurrence of a previous mental illness, hallucinations (seeing or hearing things that are not there)
  • swelling of the feet and legs or weight increase due to fluid build-up
  • change in behaviour, weakness
  • change in heartbeat (fast, slow, irregular), sometimes with fainting or chest pain
  • passing less urine than normal which may be accompanied by lack of energy, vomiting, headache and confusion
  • blood in the urine
  • symptoms of sunburn such as redness, itching, swelling or blistering that may happen more quickly than normal
  • red blotchy rash mainly on the face which may be accompanied by fatigue, fever, nausea, loss of appetite
  • swelling and redness along a vein or nerve, which is extremely tender when touched
  • signs that blood clots may have formed, such as sudden severe headache, sudden loss of coordination or vision, pain in the calves, thighs or chest
  • severe headache accompanied by stiff neck, muscle spasms and extreme sensitivity to bright light
  • a fall due to dizziness, drowsiness, decrease in blood pressure or confusion.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people. Some of these side effects (for example, changes in sodium levels, thyroid function, structure of bones, cholesterol level or blood pressure) can only be found when your doctor does tests from time to time to check your progress.

After taking Carbamazepine Sandoz

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store the medicine in a cool dry place.
  • Do not store Carbamazepine Sandoz or any other medicine in the bathroom or near a sink.
  • Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines. Carbamazepine Sandoz will keep well if it is cool and dry.

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.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Carbamazepine Sandoz comes in two types of tablets:

Carbamazepine Sandoz 100mg - White round flat tablets with bevelled edges. One side bears the imprint "GEIGY", the other "B/W" and a score.

Carbamazepine Sandoz 200mg - White round flat tablets with bevelled edges. One side bears the imprint "CG", the other "G/K" and a score.

Available in blisters of 100 tablets.

Ingredients

Active ingredients:

  • Carbamazepine Sandoz 100mg - 100mg carbamazepine
  • Carbamazepine Sandoz 200mg - 200mg carbamazepine.

Inactive ingredients:

  • cellulose-microcrystalline
  • carmellose sodium
  • silica-colloidal anhydrous
  • magnesium stearate.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Australia
Tel: 1 800 671 203
Website: www.novartis.com.au

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park NSW 2113
Australia
Tel: 1800 634 500

This leaflet was revised in June 2023

Australian Register Number(s)

100mg tablets: AUST R 78217 (blisters)

200mg tablets: AUST R 78211 (blisters)

Internal code:

(car060623c) based on PI (car060623i)

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Carbamazepine Sandoz

Active ingredient

Carbamazepine

Schedule

S4

 

1 Name of Medicine

Carbamazepine.

2 Qualitative and Quantitative Composition

Carbamazepine Sandoz tablets contain 100 mg or 200 mg of carbamazepine.
Carbamazepine is a white or yellowish-white almost odourless crystalline powder, tasteless or with a slightly bitter taste; melting point: 189 to 193°C. The powder is slightly soluble in water and ether; soluble 1 in 10 of alcohol and 1 in 10 of chloroform; soluble in acetone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Carbamazepine tablets 100 mg.

White round flat tablets with bevelled edges. One side bears the imprint "GEIGY", the other "B/W" and a score.

Carbamazepine tablets 200 mg.

White round flat tablets with bevelled edges. One side bears the imprint "CG", the other "G/K" and a score.

4 Clinical Particulars

4.1 Therapeutic Indications

Epilepsy.

Complex or simple partial seizures (with or without loss of consciousness), with or without secondary generalisation.
Generalised tonic/ clonic seizures.
Mixed seizure patterns incorporating the above.
Carbamazepine Sandoz is suitable for monotherapy and combination therapy. Carbamazepine Sandoz is usually not effective in absence seizures, atonic seizures and myoclonic seizures and should not be used for status epilepticus (see Section 4.4 Special Warnings and Precautions for Use).

Trigeminal neuralgia.

For relief of pain in idiopathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis; and in idiopathic glossopharyngeal neuralgia. (Carbamazepine Sandoz is not a simple analgesic and is not intended for trivial facial pain or headache.)

Mania and bipolar affective disorders.

Treatment of mania and maintenance treatment of bipolar affective disorders to prevent or attenuate recurrence.

4.2 Dose and Method of Administration

Dosage.

Epilepsy. Wherever possible, Carbamazepine Sandoz should be prescribed as monotherapy. Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is obtained (see Section 5.2 Pharmacokinetic Properties, Absorption, Plasma concentrations). After obtaining adequate seizure control dosage may be reduced very gradually to the minimum effect level.
Determination of plasma concentrations may help in establishing the optimum dosage (see Section 5.2 Pharmacokinetic Properties, Absorption, Plasma concentrations).
When Carbamazepine Sandoz is added to existing anticonvulsant therapy, this should be done gradually while maintaining, or if necessary adjusting, the dosage of the other anticonvulsant(s) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Adults and children over 15 years.

Initially 100 to 200 mg once or twice daily. Slowly raise the dosage until an optimum response is obtained, generally at 400 mg 2 or 3 times daily. In some patients, 1600 mg or even 2000 mg daily may be required in rare instances.

Children aged 6-15 years.

Children 6 to 12 years should commence treatment with 100 mg daily in 2 divided doses increasing by 100 mg/day in 3 to 4 divided doses at weekly intervals until optimal control is obtained. Dosage should generally not exceed 1000 mg daily. The initial dose for children 13 to 15 years is as in adults.
The recommended maintenance doses are:
6-10 years: 400-600 mg daily;
11-15 years: 600-1000 mg daily.
Daily dose should generally not exceed 1000 mg.
Trigeminal neuralgia. The recommended initial dose is 200 to 400 mg daily in 2 divided doses increasing by 200 mg each day in divided doses until pain relief is obtained. This is usually achieved with doses up to 800 mg daily. Larger doses of tablets should be given as 3 to 4 divided doses. The maximum dose should not exceed 1200 mg daily. As soon as the pain is well controlled, gradually reduce the dosage to the minimal effective level. Because trigeminal neuralgia is characterised by periods of remission, attempts should be made to reduce or discontinue the use of carbamazepine at intervals of not more than 3 months.

Children aged less than 6 years.

Limited data are available concerning the safety and efficacy in children less than 6 years old. In children aged 5 years or less, a starting dose of 20 to 60 mg daily has been recommended. This dose can be increased by up to 60 mg/day, every 3 to 7 days, (steady state is usually obtained in less than 3 days) until optimal control is obtained. Divided doses are recommended in order to minimise serum fluctuations following administration. The maximum dose is not well defined, but probably 600 mg/day. Monitoring of serum levels is recommended, especially during the initial stages of therapy.
Mania and maintenance treatment of bipolar affective disorder. The dosage range is 400-1600 mg daily. When used alone in mania the starting dose of carbamazepine should be 200-400 mg daily in 2 divided doses. Dosage should be increased to 800-1000 mg during the first week by daily increments of 200 mg and up to 1600 mg if no response is found after a second week. Due to the differing pharmacokinetic profiles of the various dosage forms of carbamazepine and the need for rapid dose titration, conventional tablets or liquid may be the preferred dose forms for initiating treatment of mania.
For maintenance treatment, carbamazepine is commenced at a dosage of 200-400 mg daily in 2 divided doses. Dosage should be increased weekly by increments of 100 mg. Due to autoinduction, concentrations may fall after 2 to 3 weeks and dosage increases may be necessary after this time. The same plasma level range as for anticonvulsant therapy is considered adequate (4-12 microgram/mL; 17-50 micromol/L). However, dose increases should be titrated against the appearance of side effects.

Method of administration.

Carbamazepine Sandoz tablets may be taken during or after meals with a little liquid.

Dose adjustment.

Pregnancy.

Women of childbearing age under treatment with Carbamazepine Sandoz should be counselled to inform their medical practitioner immediately if pregnancy is suspected (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Elderly.

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Carbamazepine Sandoz should be selected with caution in elderly patients.

4.3 Contraindications

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or to any other component of the formulation.
Atrioventricular block.
Systemic lupus erythematosus.
History of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
History of bone marrow depression.
Because it is structurally related to tricyclic antidepressants, the use of Carbamazepine Sandoz is contraindicated in combination with monoamine oxidase inhibitors (MAOIs). Before administering Carbamazepine Sandoz, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.
Hepatic failure (as metabolism occurs in the liver, it is recommended that carbamazepine not be given to patients with significant hepatic dysfunction).

4.4 Special Warnings and Precautions for Use

Carbamazepine Sandoz should be given only under medical supervision.
It should be prescribed only after a critical benefit/ risk appraisal and under close monitoring in patients with a history of cardiac, hepatic or renal damage, adverse haematological reactions to other drugs or interrupted courses of therapy with carbamazepine.

Serious dermatological reactions.

Serious dermatological reactions, including toxic epidermal necrolysis (TEN; also known as Lyell's syndrome) and Stevens-Johnson syndrome (SJS), have been reported very rarely with carbamazepine. Patients with serious dermatological reactions may require hospitalisation, as these conditions may be life threatening and may be fatal. Most of the SJS/TEN cases appear in the first few months of treatment with carbamazepine. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell's syndrome/ TEN) appear, Carbamazepine Sandoz should be withdrawn at once and alternative therapy should be considered.

Pharmacogenomics.

There is growing evidence of the role of different HLA alleles in predisposing patients to immune mediated adverse reactions.

Association with HLA-A*3101.

Human leukocyte antigen (HLA)-A*3101 may be a risk factor for the development of hypersensitivity syndrome and cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash. Retrospective genome wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.
Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with carbamazepine. The use of carbamazepine should be avoided in patients who are found to be positive for HLA-A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current carbamazepine users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.

Association with HLA-B*1502.

Retrospective studies in patients of Han Chinese and Thai origin found a strong correlation between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients of the human leucocyte antigen (HLA)-B*1502 allele. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher prevalence of the HLA-B*1502 allele in the population. The prevalence of carriers of this allele in Asian populations is above 15% in the Philippines, Thailand, Hong Kong and Malaysia, around 10% in Taiwan, around 4% in North China, around 2 to 4% in South Asia including Indians, and less than 1% in Japan and Korea. The prevalence of the HLA-B*1502 allele is negligible in Caucasian, African, indigenous peoples of the Americas, and Hispanic populations sampled.
Testing for the prevalence of HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Carbamazepine Sandoz. If testing for the presence of the HLA-B*1502 allele should be performed, high resolution 'HLA-B*1502 genotyping' is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.
The use of carbamazepine should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low. Screening is generally not recommended for any current Carbamazepine Sandoz users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA-B*1502 status.
The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects has been shown to decrease the incidence of carbamazepine induced SJS/TEN.

Limitation of genetic screening.

Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with Carbamazepine Sandoz will not develop SJS/TEN and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients positive for HLA-A*3101 and treated with carbamazepine will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Other dermatologic reactions.

Mild skin reactions (e.g. isolated macular or maculopapular exanthemata) can also occur and are mostly transient and not hazardous, and they usually disappear within a few days or weeks, either during the course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close surveillance with consideration given to immediately withdrawing the medication should the reaction worsen with continued use.
The HLA-A*3101 allele has been found to be associated with less severe adverse cutaneous reactions from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption). However, the HLA-B*1502 allele has not been found to predict the risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption).

Hypersensitivity.

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been reported with Carbamazepine Sandoz. If a patient develops these reactions after treatment with Carbamazepine Sandoz, the drug must be discontinued, and an alternative treatment started.
Carbamazepine may trigger hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), a delayed multiorgan hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon) (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal).
Cross-hypersensitivity can occur between carbamazepine and aromatic antiepileptic drugs (e.g. phenytoin, primidone and phenobarbital) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In general, if signs and symptoms suggest hypersensitivity reaction, carbamazepine should be withdrawn immediately.

Seizures.

Carbamazepine Sandoz should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all of these conditions, Carbamazepine Sandoz may exacerbate seizures. In case of exacerbation of seizures, Carbamazepine Sandoz should be discontinued.

Hyponatremia.

Hyponatremia is known to occur with carbamazepine. In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium lowering medicinal products (e.g. diuretics, medicinal products associated with inappropriate ADH secretion), serum sodium levels should be measured prior to initiating carbamazepine therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients.

Hypothyroidism.

Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction requiring an increase in dose of thyroid replacement therapy in patients with hypothyroidism. Hence thyroid function monitoring is suggested to adjust the dosage of thyroid replacement therapy.

Haematological effects.

Aplastic anaemia and agranulocytosis (in some cases fatal) have been reported in association with the use of carbamazepine. However, due to the very low incidence of these conditions, meaningful risk estimates for carbamazepine are difficult to obtain. The overall risk in the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and 2 persons per million per year for aplastic anaemia.
Although reports of transient or persistent reductions in platelet count or white cell count are not uncommon in association with the use of carbamazepine, data are not available to estimate accurately their incidence or outcome. Nevertheless, the vast majority of leucopenia cases have not progressed to aplastic anaemia or agranulocytosis. Nonetheless, complete blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained before treatment as a baseline and periodically thereafter.
If during treatment definitely low or decreased white blood cell or platelet counts are observed, the patient and the complete blood count should be monitored closely. Carbamazepine Sandoz should be discontinued if any evidence of significant bone marrow depression appears.
Because the onset of potentially serious blood dyscrasias may be rapid, patients should be made aware of early toxic signs and symptoms of a potential haematological problem, as well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult the physician immediately.

Anticholinergic effects.

Carbamazepine has shown mild anticholinergic activity. Patients with increased intraocular pressure, urinary retention or prostatism should, therefore, be observed closely during therapy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Ophthalmological effects.

Carbamazepine therapy has been associated with punctate cortical lens opacities and conjunctivitis, although a direct causal relationship has not been established. Baseline and periodic ophthalmological examinations are recommended.

Psychiatric effects.

The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

Suicidal behaviour and ideation.

Antiepileptic drugs (AED), including carbamazepine, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED 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 AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% Cl: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. Based on the subgroup analysis, the adjusted relative risks (estimated odds ratios) of suicidal behaviour or ideation was 0.65 (95% CI: 0.08, 4.42) for carbamazepine compared 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 AED treated patients was 0.43%, 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 AEDs was observed as early as one week after starting drug treatment with AEDs 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 AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs 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 AEDs.
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 carbamazepine or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs 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 AEDs 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 healthcare providers.

Pregnancy and females of reproductive potential.

Carbamazepine may be associated with fetal harm when administered to a pregnant woman (see Section 4.6 Fertility, Pregnancy and Lactation). Carbamazepine Sandoz should be used during pregnancy only if the potential benefit justifies the potential risks.
Adequate counselling should be made available to all pregnant women and women of childbearing potential, regarding the risks associated with pregnancy due to potential teratogenic risk to the fetus (see Section 4.6 Fertility, Pregnancy and Lactation).
Women of childbearing potential should use effective contraception during treatment with carbamazepine and for 2 weeks after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation, Contraception).

Monitoring of plasma concentrations.

Although correlations between dosage and plasma concentrations of carbamazepine, and between plasma concentrations and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma concentrations may be useful in the following circumstances: dramatic increase in seizure frequency, verification of patient compliance; during pregnancy; when treating children or adolescents; in suspected absorption disorders; in suspected toxicity when more than one drug is being used (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dose reduction and withdrawal effects.

Abrupt dose reduction or withdrawal may precipitate convulsions or even status epilepticus, therefore carbamazepine should be withdrawn gradually. If treatment with Carbamazepine Sandoz has to be withdrawn abruptly in a patient with epilepsy, the changeover to the new antiepileptic compound should be made under cover of a suitable drug (e.g. intravenous diazepam or intravenous phenytoin).

Falls.

Carbamazepine treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state, sedation (see Section 4.8 Adverse Effects (Undesirable Effects)) which may lead to falls and, consequently fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete risk assessment of fall should be considered recurrently for patients on long-term carbamazepine treatment.

Use in hepatic impairment.

Baseline and periodic evaluations of hepatic function, particularly in patients with a history of liver disease and in elderly patients, must be performed during treatment with Carbamazepine Sandoz. The drug should be withdrawn immediately in cases of aggravated liver dysfunction or active liver disease.

Use in renal impairment.

Baseline and periodic complete urinalysis and BUN determinations are recommended.

Use in the elderly.

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Carbamazepine Sandoz should be selected with caution in elderly patients.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Dosage, Epilepsy; Section 4.4 Special Warnings and Precautions for Use, Monitoring of plasma concentrations; Section 4.9 Overdose; Section 5.1 Pharmacodynamic Properties, Antiepileptic agent.

Effects on laboratory tests.

Interference with serological testing.

Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.
Carbamazepine and the 10, 11-epoxide metabolite may result in false positive tricyclic antidepressant concentration in fluorescence polarized immunoassay method.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalysing the formation of the active metabolite, carbamazepine-10, 11-epoxide. Coadministration of inhibitors of CYP3A4 may result in an increased plasma concentration of carbamazepine which could induce adverse effects. The dose of Carbamazepine Sandoz may have to be adjusted.
Coadministration of CYP3A4 inducers might increase the rate of Carbamazepine Sandoz metabolism, thus leading to a decrease in carbamazepine plasma concentration and a potential decrease in the therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels. The dose of Carbamazepine Sandoz may have to be adjusted.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver and may, therefore, reduce plasma concentrations of comedications mainly metabolised by CYP3A4 by induction of their metabolism (see Section 4.4 Special Warnings and Precautions for Use).
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10, 11-transdiol derivative from carbamazepine-10, 11-epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10, 11-epoxide plasma concentrations.

Agents that may raise carbamazepine plasma concentrations.

Since high plasma concentrations of carbamazepine and/or carbamazepine-10, 11-epoxide may result in adverse effects (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma concentrations monitored when used concomitantly with the substances described below.

Analgesics, anti-inflammatory drugs.

Dextropropoxyphene, ibuprofen.

Androgens.

Danazol.

Antibiotics.

Macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin.

Antidepressants.

Possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone.

Antiepileptics.

Vigabatrin.

Antifungals.

Azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole).

Antihistamines.

Loratadine, terfenadine.

Antipsychotics.

Olanzapine, quetiapine.

Antituberculosis.

Isoniazid.

Antivirals.

Protease inhibitors for HIV treatment (e.g. ritonavir).

Carbonic anhydrase inhibitors.

Acetazolamide.

Cardiovascular drugs.

Diltiazem, verapamil.

Gastrointestinal drugs.

Possibly cimetidine, omeprazole.

Muscle relaxants.

Oxybutynin, dantrolene.

Platelet aggregation inhibitors.

Ticlopidine.

Other interactions.

Grapefruit juice, nicotinamide (in adults, only in high dosage).

Agents that may raise the active metabolite carbamazepine-10, 11-epoxide plasma levels.

Since raised plasma carbamazepine-10, 11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Carbamazepine Sandoz should be adjusted accordingly and/or plasma levels monitored when used concomitantly with the substances described: quetiapine, valproic acid, valnoctamide, valpromide and primidone.

Agents that may decrease Carbamazepine Sandoz plasma concentrations.

The dose of carbamazepine consequently may have to be adjusted when used concomitantly with the substances described below.

Antiepileptics.

Oxcarbazepine, phenobarbital, phenytoin, primidone, progabide, and although the data is partly contradictory, possibly also clonazepam, valproic acid or valpromide, brivaracetam.

Antineoplastics.

Cisplatin or doxorubicin.

Antituberculosis.

Rifampicin.

Bronchodilators or antiasthma drugs.

Theophylline, aminophylline.

Dermatological drugs.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10, 11-epoxide. Carbamazepine plasma concentrations should be monitored.

Other interactions.

Herbal preparations containing St John's wort (Hypericum perforatum).

Effect of Carbamazepine Sandoz on plasma concentrations of concomitant drugs.

Due to induction of the hepatic mono-oxygenase enzyme system, carbamazepine may lower the plasma concentration and/or diminish or even abolish the activity of certain drugs that are metabolised by this system. The dosage of the following drugs may have to be adjusted to clinical requirements.

Analgesics, anti-inflammatory agents.

Buprenorphine, methadone, paracetamol (long-term administration of carbamazepine and paracetamol may be associated with hepatotoxicity), tramadol.

Antibiotics.

Doxycycline, rifabutin.

Anticoagulants.

Oral anticoagulants (warfarin, phenprocoumon, dicoumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants.

Bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics.

Aprepitant.

Antiepileptics.

Clobazam, clonazepam, ethosuximide, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid. Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine, and mephenytoin plasma levels have been reported in rare instances to increase.

Antifungals.

Itraconazole, voriconazole.

Antihelmintics.

Praziquantel, albendazole.

Antineoplastics.

Imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotics.

Clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.

Antivirals.

Protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).

Anxiolytics.

Alprazolam, midazolam.

Bronchodilators or antiasthma drugs.

Theophylline.

Contraceptives.

Hormonal contraceptives (alternative contraceptive methods should be considered).

Cardiovascular drugs.

Calcium channel blockers (dihydropyridine group), e.g. felodipine, digoxin, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids.

Corticosteroids (e.g. prednisolone, dexamethasone).

Drugs used in erectile dysfunction.

Tadalafil.

Immunosuppressants.

Cyclosporin, everolimus, tacrolimus, sirolimus.

Thyroid agents.

Levothyroxine.

Other drug interactions.

Products containing oestrogens and/or progesterones.

Combinations that require specific consideration.

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine induced toxicity.
Concurrent use of carbamazepine and isoniazid has been reported to increase isoniazid induced hepatotoxicity.
Combined use of carbamazepine and lithium or metoclopramide on one hand and carbamazepine and neuroleptics (haloperidol, thioridazine) on the other may lead to an increase in neurological adverse effects (with the latter combination even in the presence of therapeutic plasma level concentrations).
The causative role of carbamazepine in inducing or contributing to the development of a serotonin syndrome during concomitant use with selective serotonin reuptake inhibitors is unclear. (Symptoms of serotonin syndrome include, e.g. hyperthermia, tremor, convulsions, sweating, muscle contractions and changes in mental state, including confusion, irritability and extreme agitation.)
Concurrent medication with Carbamazepine Sandoz and some diuretics (hydrochlorothiazide, frusemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonise the effects of nondepolarising muscle relaxants (e.g. pancuronium). Their dosage may need to be raised and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.
Carbamazepine Sandoz, like other psychoactive drugs, may reduce alcohol tolerance. It is, therefore, advisable for the patient to abstain from alcohol.
Carbamazepine Sandoz should not be administered with MAO inhibitors (see Section 4.3 Contraindications).
Concurrent use of carbamazepine with hormonal contraceptives may render this type of contraceptive ineffective (see Section 4.6 Fertility, Pregnancy and Lactation, Contraception).
Concomitant use of carbamazepine with direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of direct acting oral anti-coagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is necessary, close monitoring of signs and symptoms of thrombosis is recommended.

4.6 Fertility, Pregnancy and Lactation

Contraception.

Women of childbearing potential should use effective contraception during treatment with Carbamazepine Sandoz and for 2 weeks after the last dose. Breakthrough bleeding has been reported in women taking carbamazepine while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by carbamazepine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Women of childbearing potential should be advised to consider using alternative forms of birth control while taking carbamazepine. Due to enzyme induction, carbamazepine may cause failure of the therapeutic effect of any drugs containing oestrogen and/or progesterone (e.g. failure of contraception) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effects on fertility.

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis (see Section 5.3 Preclinical Safety Data, Carcinogenicity).
(Category D)
Australian 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. Accompanying texts should be consulted for further details.
In animals (mice, rats, rabbits), oral administration of carbamazepine during organogenesis led to increased embryonic mortality at daily doses which caused maternal toxicity (above 200 mg/kg/day i.e. 10 to 20 times the usual human dosage, or about 1.5 times the maximum recommended clinical dose on a surface area basis). In rats, there was also some indication of abortion at 300 mg/kg/day. Near term rat foetuses showed growth retardation at maternally toxic doses. In mice, oral administration of carbamazepine at doses of 40 to 240 mg/kg/day (less than the maximum recommended clinical dose on a surface area basis) caused defects (mainly dilatation of cerebral ventricles) in 4.7% of exposed foetuses compared with 1.3% of controls. In rats, a small number of congenital abnormalities occurred following oral administration of carbamazepine at doses of 250 and 650 mg/kg (respectively, 2 and 4 times the maximum recommended clinical dose on a surface area basis).
The risk of a mother with epilepsy giving birth to a baby with an abnormality is about three times that of the general population. Some of this risk is due to the anticonvulsant drugs taken. Although carbamazepine has been known to produce malformations in one animal species (the rat), the significance of this in humans is not known. Mothers taking more than one anticonvulsant drug might have a higher risk of having a baby with a malformation than mothers taking one drug. Overall, the risk of having an abnormal child as a result of medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy.
Review of a cohort of 1457 women exposed to carbamazepine not combined with valproate revealed a one percent incidence of spina bifida. A smaller cohort of 50 women on carbamazepine monotherapy produced two babies with spina bifida. Other congenital anomalies, such as craniofacial defects, cardiovascular malformations and anomalies involving various body systems (e.g. fingernail hypoplasia and developmental disorder) have been reported. There is evidence suggestive of an increased risk of malformations in humans when carbamazepine has been used in combination with other anticonvulsant drugs. The risk of malformation following exposure to carbamazepine as polytherapy may vary depending on the specific drugs used and may be higher in polytherapy combinations that include valproate. Monotherapy is recommended wherever possible. Patients should be counselled regarding the possibility of an increased risk of malformations and specialist prenatal diagnosis including detailed midtrimester ultrasound should be offered. Minimum effective doses should be given and monitoring of plasma levels is recommended. The plasma concentration could be maintained in the lower side of the therapeutic range provided seizure control is maintained (see Section 5.2 Pharmacokinetic Properties, Absorption, Plasma concentrations).
If pregnancy occurs in a woman receiving Carbamazepine Sandoz, or if the question of initiating treatment with Carbamazepine Sandoz arises during pregnancy, the drug's expected benefits must be carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.
Neurodevelopmental disorders have been reported among children born to women with epilepsy treated with carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Studies related to the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are contradictory and a risk cannot be excluded.
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the offspring of treated epileptic women. Folic acid supplementation has, therefore, been recommended before and during pregnancy. Folic acid supplementation (5 mg) should be commenced four weeks prior to and continued for twelve weeks after conception.

In the neonate.

In order to prevent bleeding disorders in the offspring, it has been recommended that vitamin K1 be given to the mother during the last weeks of pregnancy as well as to the neonate.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal carbamazepine use. These reactions may represent a neonatal withdrawal syndrome.
Carbamazepine passes into human milk (about 25 to 60% of plasma concentrations). The benefits of breastfeeding should be weighed against the possibility of adverse effects occurring in the infant. Mothers taking Carbamazepine Sandoz may breastfeed their infants, provided the infant is observed for possible adverse effects (e.g. excessive somnolence, allergic skin reaction). There have been some reports of cholestatic hepatitis in neonates exposed to carbamazepine during antenatal and/or during breastfeeding. Therefore breastfed infants of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.

4.7 Effects on Ability to Drive and Use Machines

The patient's ability to react may be impaired by the medical condition resulting in seizures and adverse reactions including dizziness, drowsiness, ataxia, diplopia, impaired accommodation and blurred vision have been reported with Carbamazepine Sandoz, especially at the start of treatment or in association with dose adjustments. Patients should, therefore, exercise due caution when driving a vehicle or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Particularly at the start of treatment with Carbamazepine Sandoz, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse effects occur very commonly or commonly, e.g. CNS adverse effects (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions. Such reactions can be minimised by starting with a low dose.
The dose related adverse effects usually abate within a few days, either spontaneously or after a dosage reduction. The occurrence of CNS adverse effects may be a manifestation of relative overdosage or significant fluctuation in concentration of the drug in plasma. In such cases it is advisable to monitor the plasma concentrations and possibly to lower the daily dosage and/or divide it into 3 or 4 fractional doses.
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).

Adverse drug reactions from clinical trials with carbamazepine.

Blood and lymphatic system disorders.

Very common: leucopenia.
Common: eosinophilia, thrombocytopenia.
Rare: leucocytosis, lymphadenopathy.
Very rare: agranulocytosis/ aplastic anaemia (with fatal outcome in some cases), pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia.

Immune system disorders.

Rare: a delayed multi-organ hypersensitivity disorder with fever, skin rashes, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leucopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts), occurring in various combinations. Other organs may also be affected (e.g. lungs, kidneys, pancreas, myocardium, colon).
Very rare: anaphylactic reactions, angioedema, hypogammaglobulinaemia.

Endocrine disorders.

Common: oedema, fluid retention, weight increase, hyponatraemia and blood osmolality decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confusional state, neurological disorders.
Very rare: galactorrhoea; gynaecomastia.

Metabolism and nutrition disorders.

Rare: folate deficiency, decreased appetite.
Very rare: porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria nonacute (porphyria cutanea tarda).

Psychiatric disorders.

Rare: hallucinations (visual or auditory), depression, aggression, agitation, anorexia, restlessness, confusional state.
Very rare: activation of psychosis.

Nervous system disorders.

Very common: ataxia, dizziness, somnolence.
Common: diplopia, headache, increases in seizure frequency in patients with atypical absences.
Uncommon: abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics), nystagmus.
Rare: orofacial dyskinesia, choreoathetosis, eye movement disorder, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesiae, paresis. There have been some reports of paralysis and other symptoms of cerebral arterial insufficiency, but no conclusive relationship to the administration of carbamazepine could be established.
Very rare: neuroleptic malignant syndrome (the causative role of carbamazepine in inducing or contributing to the development of neuroleptic malignant syndrome, especially in conjunction with neuroleptics, is unclear), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders.

Common: accommodation disorders (e.g. blurred vision).
Very rare: lenticular opacities (see Section 4.4 Special Warnings and Precautions for Use), conjunctivitis.

Ear and labyrinth disorders.

Very rare: hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

Cardiac disorders.

Rare: cardiac conduction disorders.
Very rare: arrhythmia, Stokes-Adams attacks and syncope associated with A-V block, cardiac failure, aggravation of symptoms of coronary insufficiency.

Vascular disorders.

Rare: hypertension or hypotension.
Very rare: circulatory collapse, thromboembolism (e.g. pulmonary embolism), thrombophlebitis.

Respiratory, thoracic and mediastinal disorders.

Very rare: pulmonary hypersensitivity characterised by fever, dyspnoea, pneumonitis or pneumonia.

Gastrointestinal disorders.

Very common: vomiting, nausea.
Common: dry mouth.
Uncommon: diarrhoea or constipation.
Rare: abdominal pain.
Very rare: pancreatitis, glossitis, stomatitis.

Hepatobiliary disorders.

Rare: cholestatic hepatitis, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice.
Very rare: hepatic failure, granulomatous liver disease.

Skin and subcutaneous tissue disorders.

Very common: urticaria which may be severe, dermatitis allergic.
Uncommon: dermatitis exfoliative and erythroderma.
Rare: systemic lupus erythematosus, pruritus.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, erythema nodosum, pigmentation disorder, purpura, acne, hyperhidrosis, alopecia, hirsutism.

Musculoskeletal, connective tissue and bone disorders.

Rare: muscular weakness.
Very rare: bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol) leading to osteomalacia/ osteoporosis, arthralgia, myalgia, muscle spasms.

Renal and urinary disorders.

Very rare: tubulointerstitial nephritis and renal failure, as well as signs of renal impairment (e.g. albuminuria, haematuria, oliguria and increased blood urea/ azotaemia), urinary retention, urinary frequency.

Reproductive system.

Very rare: sexual dysfunction/ erectile dysfunction, abnormal spermatogenesis (with decreased sperm count and/or motility).

General disorders and administration site conditions.

Very common: fatigue.

Investigations.

Very common: gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant.
Common: blood alkaline phosphatase increased.
Uncommon: transaminases increased.
Very rare: intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased. Thyroid function test abnormal: decreased L-thyroxin (free thyroxine, thyroxine, triiodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased.

Adverse drug reactions from spontaneous reports (frequency not known).

The following adverse drug reactions have been derived from postmarketing experience with carbamazepine via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Infections and infestations.

Reactivation of human herpes virus 6 infection.

Blood and lymphatic system disorders.

Bone marrow failure.

Injury, poisoning and procedural complications.

Fall (associated with carbamazepine treatment induced ataxia, dizziness, somnolence, hypotension, confusional state, sedation) (see Section 4.4 Special Warnings and Precautions for Use).

Nervous system disorders.

Sedation, memory impairment.

Gastrointestinal disorders.

Colitis.

Musculoskeletal and connective tissue disorders.

Fracture.

Immune system disorders.

Drug rash with eosinophilia and systemic symptoms (DRESS).

Skin and subcutaneous tissue disorders.

Acute generalised exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Investigations.

Bone density decreased.

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

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

Signs and symptoms.

The presenting signs and symptoms of overdosage develop within 1 to 3 hours of ingestion and usually involve the central nervous, cardiovascular, respiratory systems, and the adverse drug reactions mentioned (see Section 4.8 Adverse Effects (Undesirable Effects)). Relapse and aggravation of symptoms on the 2nd and 3rd day after overdose may occur. This is thought to be due to delayed absorption, possibly due to production of a gastric mass of tablets. In the case of the CR tablet, there is the theoretical possibility that this may be accentuated. However, there is limited clinical experience to support this.

Central nervous system.

CNS depression: disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma, blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyper-reflexia, later hyporeflexia, convulsions (especially in small children), psychomotor disturbances, myoclonus, hypothermia, mydriasis.

Respiratory system.

Respiratory depression, pulmonary oedema.

Cardiovascular system.

Tachycardia, hypotension, at times hypertension, conduction disturbance with widening of QRS complex, syncope in association with cardiac arrest.

Gastrointestinal system.

Vomiting, delayed gastric emptying, reduced bowel motility.

Musculoskeletal system.

Rhabdomyolysis.

Renal function.

Retention of urine, oliguria or anuria, fluid retention, water intoxication due to an ADH-like effect of carbamazepine.

Laboratory findings.

Hyponatraemia (see Section 4.9 Overdose, Management), leucocytosis, leucopenia, hypokalaemia, metabolic acidosis, hyperglycaemia, glycosuria, acetonuria, increased muscle creatine phosphokinase.

Management.

There is no specific antidote. Management should be guided initially by the patient's clinical condition. All patients suspected of serious overdose should be admitted to hospital and the plasma carbamazepine concentration measured to confirm carbamazepine poisoning and to ascertain the size of the overdose.

Administration of activated charcoal.

If the patient's level of consciousness is impaired, or the patient has an impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Intubation may be necessary to protect the airway. Supportive medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.
Hyponatraemia is not usually a problem in acute overdosage. However, in chronic intoxication it may be managed by fluid restriction and slow and careful intravenous infusion of NaCl 0.9%. These measures may be useful in preventing brain damage.

Special recommendations.

Hypotension.

Intravenous fluid replacement. If the patient fails to respond, consider intravenous dopamine or dobutamine.

Disturbances of cardiac rhythm.

There are no data regarding drug treatment of carbamazepine induced arrhythmias. These should, therefore, be handled according to the circumstances in each patient.

Convulsions.

Initially administer a benzodiazepine (e.g. diazepam) if seizures occur. If seizures recur, another anticonvulsant, e.g. phenobarbitone (with caution because of increased respiratory depression), may be considered.
Charcoal haemoperfusion has been recommended. Forced diuresis, haemodialysis and peritoneal dialysis have been reported to not be effective.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic groups: antiepileptic, neurotropic, and psychotropic agent.
ATC code: N03AF01.

Antiepileptic agent.

Carbamazepine as an antiepileptic agent has been shown to be effective in the treatment of partial seizures (simple and complex) with and without secondary generalisation, generalised tonic/ clonic seizures and combinations of these seizure types.
In some clinical studies carbamazepine, given as monotherapy to patients with epilepsy including children and adolescents, has been reported to exert a mild psychotropic action, including a beneficial effect on attentiveness and cognitive performance and on symptoms of anxiety and depression, as well as a decrease in irritability and aggressiveness. Other studies have not confirmed these findings.

Neurotropic agent.

As a neurotropic agent carbamazepine is clinically effective in relieving paroxysmal attacks of pain in idiopathic trigeminal neuralgia.

Psychotropic agent.

As a psychotropic agent, carbamazepine has shown clinical efficacy as treatment for mania as well as for the maintenance treatment of bipolar affective disorders, when given either as monotherapy or in combination with neuroleptics, antidepressants or lithium.

Mechanism of action.

The mechanism of action of carbamazepine has been partially elucidated. Carbamazepine stabilises hyperexcited nerve membranes, inhibits repetitive neuronal discharges and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing of sodium dependent action potentials in depolarised neurons via use and voltage dependent blockade of sodium channels may be its main mechanism of action.
Whereas reduction of glutamate release and stabilisation of neuronal membranes may account mainly for the antiepileptic effects, it is speculated that the depressant effect on dopamine and noradrenaline turnover could be responsible for the antimanic properties of carbamazepine.
Carbamazepine possesses anticholinergic and antidiuretic activity and may suppress ventricular automaticity through its membrane depressant effect.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Absorption from the gastrointestinal tract is relatively slow yet almost complete from the tablet formulation.

Plasma concentrations.

When taken as a single oral dose, the tablet yields a peak concentration of unchanged carbamazepine within 4 to 24 hours (majority within 12 hours). An earlier peak is obtained when administered as an oral suspension. During one study, the peak following 400 mg in tablet form was approximately 4.5 microgram/mL. Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon autoinduction by carbamazepine and heteroinduction by other enzyme inducing drugs, as well as on pretreatment status, dosage and duration of treatment. The therapeutic range at steady state is 4 to 12 microgram/mL (or 17 to 50 micromol/L) carbamazepine. The main metabolite, carbamazepine-10, 11-epoxide, possesses anticonvulsant activity and reaches concentrations approximately 30% of those of carbamazepine.

Bioavailability.

Absolute bioavailability could not be determined, as an intravenous formulation was not developed. Nevertheless, it appears that systemic availability of the tablet approaches 100% and is unaffected by food.

Serum protein binding.

70 to 80%. The concentration of unchanged substance in saliva and CSF reflects the nonprotein bound fraction present in plasma.

Distribution.

The concentration of unchanged drug in the CSF and saliva is approximately 20 to 30% of that attained in plasma. Milk concentration ranges from 25 to 60% of the plasma concentration. Carbamazepine readily crosses the placenta. The apparent volume of distribution was found to be 0.8 to 1.9 L/kg.

Metabolism.

Carbamazepine is metabolised in the liver via the epoxide-diol pathway, the main metabolite (carbamazepine-10, 11-epoxide) being pharmacologically active. Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of carbamazepine-10, 11-epoxide. Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10, 11-transdiol derivative from carbamazepine-10, 11-epoxide. Carbamazepine is capable of inducing its own metabolism by the hepatic monooxygenase system.

Elimination.

The elimination half-life of unchanged carbamazepine following a single oral dose averaged 36 hours whereas, after repeated administration which leads to hepatic enzyme induction, it averaged 16 to 24 hours, depending on the duration of treatment. In patients receiving concomitant treatment with other liver enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9 to 10 hours have been found. The mean elimination half-life of the 10, 11-epoxide metabolite in the plasma is about 6 hours following single oral doses of the epoxide itself.

Excretion.

Following a single 400 mg dose, 72% was excreted in the urine mainly in the form epoxidated, hydroxylated and conjugated metabolites. Some 28% of the dose was excreted in the faeces.

Special populations.

Pharmacokinetics were not altered in the elderly. There are no data on patients with impaired hepatic or renal function.

5.3 Preclinical Safety Data

Genotoxicity.

Bacterial and mammalian mutagenicity studies yielded negative results.

Carcinogenicity.

In rats treated with oral carbamazepine at doses of 25, 75 and 250 mg/kg/day for 2 years, the incidence of hepatocellular tumours was dose-dependently increased in females, and aspermatogenesis and testicular atrophy were observed at all doses (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility). This dose range is 0.2 to 2 times the maximum recommended clinical dose of 1200 mg/day, on a surface area basis. The significance of the carcinogenicity findings relative to the use of carbamazepine in humans is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Carbamazepine Sandoz tablets contain the following inactive ingredients: microcrystalline cellulose, carmellose sodium, colloidal anhydrous silica and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture.

6.5 Nature and Contents of Container

Blister packs of 100 and 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

Chemical structure.


5H-dibenzo[b,f]azepine-5-carboxamide.
C15H12N2O.
MW: 236.3

CAS number.

298-46-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes