1.3.1.1 Summary of Product Characteristics

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[Nationally completed name] 200 mg prolonged release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged release tablet contains 200 mg of carbamazepine

Excipients with known effect: Each prolonged release tablet contains 0.220 mg of macrogolglycerol hydroxystearate and 0.204 mmol (4.68 mg) of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged release tablet.

Beige-orange, oval, slightly bi-convex coated tablet, one side debossed with “H/C”, the other with “C/G”, both sides are scored. The tablet can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Epilepsy:

 Complex or simple partial seizures with or without secondary generalization  Generalized tonic-clonic seizures (grand mal). [nationally completed name] is suitable for both monotherapy and combination therapy.

4.2 Posology and method of administration

PosologyIn elderly patients dosage should be determined with caution due to a possibly modified pharmacokinetic and an increased risk of occurrence of interactions with other drugs (see section 4.5).

Before deciding to initiate treatment, patients of Han Chinese and Thai origin should whenever possible be screened for HLA-B*1502 as this allele strongly predicts the risk of severe

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Treatment of each individual should be initiated with a low daily dosage, slowly to be increased until an optimal effective maintenance dosage is obtained.

It may be required to determine the plasma levels for the determination of the optimal dose (see section 5.2).

The following dosage schedule only provides guidelines, which have to be adjusted to the patient’s reaction. In general, one must try to obtain an optimal response at the lowest dose possible.

The duration of treatment depends on the severity and the progress of the disease. When switching from another therapy to [nationally completed name], the dose of the other anti- epileptic should be reduced gradually.

Adults and adolescents above 15 years of age Initially, 100-200 mg twice daily; then the dosage is slowly raised until – generally at 400 mg twice daily – an optimum response is obtained. The recommended maximum dose is 1200 mg per day.

Children of 5-15 years of age Treatment may be initiated with 100 mg twice daily, increased at weekly intervals by 100 mg, until – generally at 200 mg twice daily – an optimal response is obtained. The recommended maximum dose in children from 5 to 6 years old is 35 mg/kg/day. The recommended maximum dose in children from 6 until 15 years old is 1000 mg per day.

Children until 4 years of age For children until 4 years of age [nationally completed name] is not suitable, because these tablets (or halved tablets) should not be chewed. Moreover it should be noticed that the lowest dose possible for [nationally completed name], is 100 mg. This dosage is too high for children below the age of 4 years.

Method of administration The [nationally completed name] tablets should be swallowed, either whole or- if half tablets are prescribed- only half a tablet, unchewed during or after meals with a little liquid. Thanks to slow, controlled release of carbamazepine, they can as a rule be prescribed in a twice-daily dosage.

Switching from regular Carbamazepine tablets to [nationally completed name] tablets Clinical experience has shown that in some patients the dosage in the form of [nationally completed name] tablets - expressed as the number of milligrams - may need to be increased compared to conventional Carbamazepine tablets.

4.3 Contraindications  Known hypersensitivity to the active substance or structurally related drugs (e.g. tricyclic antidepressants) or any of the excipients listed in section 6.1Patients with atrioventricular block

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 Patients with a history of bone-marrow depression  Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda)  Because carbamazepine is structurally related to tricyclic antidepressants, concomitant use of [nationally completed name] is not recommended (see section 4.5)  The use of carbamazepine is not recommended in combination with monoamine-oxidase inhibitors (MAOIs) (see section 4.5).

4.4 Special warnings and precautions for use Carbamazepine should be given only under medical supervision.

Carbamazepine 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.

It is recommended that treatment with a MAO-inhibitor be withdrawn at least 2 weeks before starting carbamazepine therapy.

Haematological effects A transient or persistent mild leucopenia and/ or thrombocytopenia are seen occasionally to frequently. These effects are, however, transient or clinically not relevant in the large majority of cases. Furthermore, a very rare serious persistent leucopenia may occur that can develop into an agranulocytosis.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. These values should also be periodically monitored during treatment.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the complete blood count should be closely monitored. The treatment with carbamazepine should be discontinued if any evidence of significant bone-marrow depression appears.

Patients should be made aware of potential haematological complications, 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 his physician immediately.

Cutaneous reactions Serious and sometimes fatal cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1-6 per 10 000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher.

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There is growing evidence of the role of different HLA alleles in predisposing patients to immune- mediated adverse reactions (see section 4.2).

These reactions may require hospitalization and be life-threatening. Patients who receive carbamazepine should be informed by the prescribing physician about this possible side effect and monitored closely.

Most of the SJS and TEN cases appear in the first few months of treatment with carbamazepine. If symptoms appear (e.g. progressive skin rash often with blisters or mucosal lesions), the treatment with carbamazepine should be withdrawn at once and alternative treatment considered.

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of carbamazepine, carbamazepine must not be re-started in this patient at any time.

HLA-B*1502 allele - in Han Chinese, Thai and other Asian populations HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as Stevens-Johnsonsyndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 2-12% in Han Chinese and about 8% in Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine (see section 4.2). If these individuals test positive, carbamazepine should not be started unless there is no other therapeutic option. Tested patients who are found to be negative for HLA-B*1502 have a low risk of SJS, although the reactions may still rarely occur.

There are some data that suggest an increased risk of serious carbamazepine-associated TEN/SJS in other Asian populations. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia and recently allel frequencies of resp. 2% and 6% are mentioned in Korea and India), testing genetically at risk populations for the presence of HLA- B*1502 may be considered.

The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese (< 1%).

The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest. Since a person carried two copies of each chromosome, a person has chances to inherit the allele. As a result, meaning that the percentage of patients who carry a copy of the allele on at least one of their two copies of the chromosomes (i.e., the “carrier frequency”) is nearly twice as high as the allele frequency. Since even carrying an allele on only one of the two copies of the chromosome may increase a patient’s risk of an adverse drug reaction. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.

HLA-A*3101 allele - European descent and Japanese populations

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There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash (see section 4.8) in people of European descent and the Japanese. The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLAA* 3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population.

The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.

If patients of European descent or Japanese origin are known to be positive for HLAA* 3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.

Hypersensitivity Carbamazepine may trigger (systemic) hypersensitivity reactions, including a delayed multi-organ hypersensitivity disorder in one or more organs (known as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)), in which fever, rash, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of the 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). The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome, including maculopapular rash.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine.

Cross-hypersensitivity can occur between carbamazepine and aromatic antiepilepics such as phenytoin, primidone and phenobarbital.

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, carbamazepine should be withdrawn immediately.

Seizures

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Carbamazepine is usually not effective in absences (petit mal). Carbamazepine should be used with caution in patients with mixed seizures which includes absences, either typical or atypical. There are indications that in patients with atypical absences and who are treated with carbamazepine the frequency of generalized seizures may increase. In the event of exacerbation of seizures, carbamazepine should be discontinued.

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

Renal function Baseline and periodic complete urinalysis and BUN determinations are recommended.

Hyponatremia Hyponatremia is known to occur with carbamazepine. In elderly patients, 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. If hyponatraemia is observed, water restriction is an important counter-measurement.

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.

Anticholinergic effects Carbamazepine has shown mild anticholinergic activity. Patients with increased intraocular pressure, urine retention or sensitivity to obstipation should therefore be closely observed during therapy (see section 4.8).

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

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Carbamazepine.

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Therefore, patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Endocrinological effects Due to enzyme induction, carbamazepine reduces the effect of oestrogen and/or progesterone containing drugs. The reliability of oral contraceptives is decreased by concomitant administration of carbamazepine. During concomitant use of carbamazepine and oral contraceptives breakthrough bleedings have been reported.

Monitoring of plasma levels Although correlations between dosage and plasma levels of carbamazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations: 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).

Withdrawal of treatment Abrupt withdrawal of carbamazepine may precipitate sudden seizures. Therefore the treatment should be gradually withdrawn. If treatment with carbamazepine has to be withdrawn abruptly, the patient should receive another anti-epileptic drug. In the change-over phase the patient should be protected against convulsions with a suitable drug until the new drug reaches therapeutic levels.

Falls Carbamazepine treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusional state and sedation (see section 4.8). These adverse events may increase the risk on falls.

Oral anticoagulants  In case of concomitant use of carbamazepine with coumarines (warfarin, phenprocoumon, dicoumarol and acenocoumarol) the coumarin dose should be increased and after withdrawal of the carbamazepine-therapy the dose should be reduces again (see section 4.5).  When concomitant use of carbamazepine with direct acting oral anticoagulants (rivaroxaban, dabigatran, apixaban and edoxaban) is considered necessary, adequate control on signs and symptoms of thrombosis is recommended (see section 4.5).

Other Phytotherapeutic agents that contain St. John’s wort (Hypericum perforatum) should not be used during treatment with carbamazepine, since this may lead to decreased plasma levels and reduced activity of carbamazepine (see section 4.5).

Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. That is to say essentially “sodium free”.

This medicinal product contains macrogolglycerol hydroxystearate (castor oil polyoxyl hydrogenated). This may cause stomach upset and diarrhea.

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4.5 Interaction with other medicinal products and other forms of interaction

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine-10,11-epoxide. Co-administration of inhibitors of CYP3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration of CYP3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the carbamazepine serum level and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver (see section 5.2). It may affect plasma concentrations of co-medications mainly metabolised by CYP3A4. Consequently, it may decrease the plasma concentrations of co-medications or increase the plasma concentrations of their (active) metabolites.

Agents that may raise carbamazepine plasma levels Inhibition of the metabolism of carbamazepine may lead to raised plasma carbamazepine levels, which may result in adverse reactions like drowsiness, headache, ataxia, diplopia and nystagmus. In case of concomitant use with the substances described below, the plasma levels of carbamazepine should be monitored and the dosage of carbamazepine should be possibly reduced. The interaction effect on plasma concentrations of carbamazepine and the mechanism of interaction is presented after each drug, if known. Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen. Androgens: danazol. Antibiotics: macrolide antibiotics (e.g. erythromycin, clarithromycin), ciprofloxacin. Antidepressants: possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine (carbamazepine approx. 50% increased). Antiepileptics: vigabatrin. Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anti- convulsants may be recommended in patients treated with itraconazole or voriconazole. Antihistamines: loratadine, terfenadine. Antipsychotics: olanzapine. Antituberculosis: isoniazid. Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir). Carbonic anhydrase inhibitors: acetazolamide. Calcium antagonists: diltiazem, verapamil Gastrointestinal drugs: possibly cimetidine, omeprazole. Muscle relaxants: oxybutynin, dantrolene. Other interactions: grapefruit juice, nicotinamide (in high dosage).

Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels 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. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11-

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Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below: The interaction effect on plasma concentrations of carbamazepine-10,11-epoxide is presented after each drug, if known. Antiepileptics: progabide (1.3-fold increase) valproic acid, valnoctamide (5-fold increase), valpromide and primidone Antipsychotics: loxapine, quetiapine.

Agents that may decrease carbamazepine plasma levels The dose of carbamazepine may have to be adjusted when used concomitantly with the substances described below. Antineoplastics: cisplatin or doxorubicin. Antituberculosis: rifampicin. Bronchodilatators or anti-asthma drugs: theophylline. Antiepileptics: mesuximide, phensuximide, ethosuximide, oxcarbazepine, phenytoin and, although the data are partly contradictory, possibly also clonazepam. Other interactions: herbal preparations containing St John's wort (Hypericum perforatum). Concurrent use of St. John’s wort (Hypericum perforatum) may lead to a decrease in serum carbamazepine due to the induction of (hepatic) enzymes by St. John’s wort. Phytotherapeutic agents that contain St. John’s wort should therefore not be used in combination with carbamazepine. The inductive effect may continue for at least two weeks after stopping treatment with St. John’s wort. When a patient is already using St. John’s wort, the level of the anti-epileptic medication should be determined and the use of St. John’s wort discontinued. The level of the anti-epileptic medication may increase after treatment with St. John’s wort has been withdrawn. It may be necessary to adjust the dosage of the anti-epileptic medication.

Effect of carbamazepine on plasma levels of concomitant agents Carbamazepine may lower the plasma level, or diminish - or even abolish - the activity of certain drugs. The dosage of the following drugs may have to be adjusted (the interaction effect on plasma concentrations of concomitant medication and the mechanism of interaction is presented after each drug, if known). Analgesics: buprenorphine (no data; induction of CYP3A4), methadone, paracetamol, phenazone, tramadol. Long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity. Antihelmintics: praziquantel, albendazol. Antibiotics: rifabutin, decrease in half-life of doxycycline. Contraceptives: decreased effect of oral contraceptives. If necessary, alternative contraceptive methods should be considered. Antidepressants: tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine), bupropion, citalopram, mianserin (approx. 50% decreased, induction of CYP3A4),

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Other drug interactions: products containing oestrogens and/or progesterones.

Combinations that require specific consideration

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

Combined use of carbamazepine and lithium or metoclopramide on the one hand, and carbamazepine and neuroleptics (haloperidol, thioridazine) on the other, may lead to increased neurological adverse reactions (with the latter combination even in the presence of ‘therapeutic plasma levels’).

Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.

Carbamazepine may antagonize the effects of non-depolarizing 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.

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

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Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the patient to abstain from alcohol. Oral anticoagulants Concomitant use of carbamazepine with coumarines (warfarin, phenprocoumon, dicoumarol and acenocoumarol) may lead to a shorter half-life of coumarines. A dose adjustment could be necessary (see section 4.4).

Concomitant use may lead to reduced plasma concentrations of direct acting oral anti-coagulants (rivaroxaban, dabigatran, apixaban and edoxaban), with an increased risk of thrombosis (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy There is evidence from clinical observations that carbamazepine could be harmful to the fetus. Newborn infants of mothers who take anti-epileptic medication are known to be more prone to developmental disorders. Furthermore, in connection with the use of carbamazepine during pregnancy, there is a higher incidence of reports of spinal malformations (spina bifida, estimated risk 0.5-1%) and other congenital anomalies (e.g. orofacial disorders, cardiac disorders and other system disorders). It is known that newborn infants from mothers who use antiepileptics show more often developmental disorders than other newborn infants.

Based on data from several pregnancy registries and meta-analyses the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, was 2-3 times increased among mothers exposed to carbamazepine monotherapy in the first trimester.

In general, it is not advisable to discontinue an effective anticonvulsive treatment during pregnancy, as withdrawal of treatment can be harmful to both mother and fetus. It is therefore preferable to give monotherapy during pregnancy as far as possible. The risk that harmful effects occur in the offspring seems to be higher in combination with antiepileptics and seems to be may be higher in polytherapy combinations that include valproate. The risk of harmful effects is higher in case of higher doses and therefore the lowest effective doses of carbamazepine should be given and plasma levels should be monitored. It is recommended to maintain a plasma level in the lower side of the therapeutic range from 4 to 12 micrograms/mL, if this way seizure control is maintained. Some anti-epileptics may cause folic acid deficiency. Folic acid supplementation at dosages that are usually used for pregnant women is strongly recommended. To prevent bleeding disorders in the offspring due to possible vitamin K1 deficiency as a result of maternal use of carbamazepine, administration of vitamin K to the mother during the last weeks of pregnancy may be considered. For the newborn, parenteral administration of vitamin K directly post-partum is recommended.

Breast-feeding Carbamazepine and its epoxide-metabolite pass into the breast milk in low concentrations. The benefits of breast-feeding should be weighed against the small possibility of adverse effects occurring in the infant. Mothers taking carbamazepine may breast-feed their infants, provided the infant is observed for possible adverse reactions (e.g. excessive somnolence, difficulty with drinking,

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Fertility There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Women of child-bearing potential and contraceptive measures Due to enzyme induction, carbamazepine may result in a failure of the therapeutic effect of oral contraceptive drugs containing oestrogen and/or progesterone. Women of child bearing potential should be advised to use alternative contraceptive methods while on treatment with carbamazepine.

4.7 Effects on ability to drive and use machines The patient’s ability to react may be impaired due to seizures and adverse reactions including dizziness and somnolence, ataxia, diplopia, impaired accommodation and blurred vision, especially at the start of treatment or in connection with dose adjustments; Patients should therefore exercise due caution when driving a vehicle or operating machinery.

4.8 Undesirable effects At the start of treatment about one-third of the the patients suffers from side effects, Particularly in elderly patients or at higher plasma levels (8-10 mg/ml) side effects occur more frequently with regard to the CNS (dizziness with nystagmus, blurred vision, diplopia, fatigue, headache, ataxia, dysarthria and slurred speech, dystonia, chorea, myoclonia, tremor and psychosis) gastrointestinal disturbances (nausea and vomiting), as well as allergic disorders.

The adverse reactions that occur at the start of treatment can abate by dosage reduction or spontaneously (7-14 days) during treatment. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is recommended to monitor plasma levels and adapt the dosage, if necessary.

Frequency of side effects: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations Rare: aseptic meningitis. Not known: reactivation of Human herpesvirus 6 infection*.

Blood and lymphatic system disorders Very common: a persistent or fluctuating leucopenia. See for persistent or progressive leucopenia under section 4.4. Common: eosinophilia, thrombocytopenia. Rare: leucocytosis, lymphadenopathy. Very rare: agranulocytosis, aplastic anaemia, pure red cell aplasia, megaloblastic anaemia, reticulocytosis, haemolytic anaemia, pseudolymphoma.

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Not known: pancytopenia, anaemia, bone marrow failure.

Immune system disorders Very Rare: hypogammaglobulinaemia, angio-oedema Not known: drug-induced rash with eosinophilia and systemic symptoms (DRESS syndrome)

Endocrine disorders Very rare: galactorrhoea, gynecomastia. hirsutism, abnormal thyroid function tests: decreased L- thyroxine (FT4, T4, T3) and increased TSH, usually without clinical symptoms.

Metabolism and nutrition disorders Common: fluid retention, hyponatraemia and reduced plasma osmolality due to an antidiuretic hormone (ADH)-like effect, leading in isolated cases to water intoxication accompanied by lethargy, vomiting, headache, mental confusion or neurological abnormalities. Rare: decreased appetite, folate deficiency.

Psychiatric disorders Rare: hallucinations (visual or auditory) depression, restlessness, aggressive behavior, agitation, confusion. Very rare: activation of psychosis.

Nervous system disorders Very common: dizziness, ataxia, somnolence. Common: headache. Uncommon: abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus. Rare: dyskinesia, speech disorders (e.g. dysarthria, slurred speech), choreoathetosis, peripheral neuropathy, paraesthesia, paretic symptom, neuromalignant syndrome. Not known: sedation, memory impairment

Eye disorders Common: diplopia, accommodation disorders (e.g. blurred vision). Rare: oculomotor distubances. Very rare: lens opacities, conjunctivitis, intraocular pressure increased.

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: bradycardia, arrhythmia, atrioventricular block with syncope, congestive heart failure, aggravation of coronary artery disease.

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

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Respiratory, thoracic and mediastinal disorders Very rare: pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or pneumonia.

Gastrointestinal disorders Gastrointestinal disturbances occur in particular at the start of treatment; in case these adverse reactions continue for a long period, one should bear in mind the possibility of an intoxication.

Very common: nausea, vomiting Common: dry mouth. Uncommon: diarrhoea, constipation. Rare: abdominal pain. Very rare: stomach disorders, glossitis, stomatitis, pancreatitis, taste disturbances. Not known: colitis.

Hepatobiliary disorders Rare: jaundice, cholestatic, hepatocellular or mixed forms of hepatitis, cholestasis (vanishing bile duct syndrome). Very rare: granulomatous hepatitis, hepatic failure. Not known: ductopenia.

Skin and subcutaneous tissue disorders Very common: allergic skin reactions, urticaria which may be severe. Uncommon: exfoliative dermatitis. Rare: Lupus erythematosus-like syndrome, pruritus. Very rare: Stevens-Johnson syndrome*,** toxic epidermal necrolysis (TEN or Lyell syndrome)* *, photosensitivity reaction, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss. Not known: Acute generalized exanthemateous pustulosis (AGEP), lichenoid keratosis onychomadesis

Musculoskeletal and connective tissue disorders Rare: muscular weakness. Very rare: arthralgia, muscle pain, muscle spasms.Disturbances in bone metabolism (decrease in plasma calcium and 25-OH-cholecalciferol), leading to osteomalacia/osteoporosis.

Renal and urinary disorders Very rare: tubulo interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria, and blood urea increased/azotaemia), urinary frequency, urinary retention.

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

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Congenital, familial and genetic disorders Very rare: Acute intermittent porphyria ( General disorders and administration site conditions Very common: Fatigue. Common: Oedema. Rare: A delayed multi-organ hypersensitivity disorder with fever, exanthema, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leucopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests, occurring in various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas, myocardium, colon). Very rare: Anaphylactic reaction, aseptic meningitis with myoclonus and peripheral eosinophilia, angioedema.

Investigations Very common: Elevated gamma-GT (due to hepatic enzyme induction). Common: Weight increase, elevated alkaline phosphatase. Uncommon: elevated transaminases. Very rare: Elevated levels of cholesterol, including HDL-cholesterol and triglycerides.

Injury, poisoning and procedural complications Not known: Falls (see section 4.4).

* in the context of DRESS **In some Asian countries also reported as rare. See also section 4.4.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Carbamazepine. The mechanism by which Carbamazepine affects bone metabolism has not been identified.

There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients, these reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among individuals of Han Chinese, Thai and some other Asian ancestry (see sections 4.2 and 4.4 for further information).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 via the national reporting system in Appendix V.

4.9 Overdose

Symptoms

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Metabolism and nutrition disorders Hyponatraemia, possibly metabolic acidosis, possibly hyperglycaemia, water intoxication due to an ADH-like effect of carbamazepine.

Psychiatric disorders Disorientation, agitation, hallucination

Nervous system disorders CNS depression, somnolence, depressed level of consciousness, coma, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, initially hyperreflexia, later hyporeflexia, convulsions, psychomotor disturbances, myoclonus.

Eye disorders Blurred vision, mydriasis.

Cardiac disorders Tachycardia, conduction disturbance with widening of QRS complex; syncope in association with cardiac arrest.

Vascular disorders Hypotension, at times hypertension

Respiratory thoracic and mediastinal disorders Respiratory depression, pulmonary oedema.

Gastrointestinal disorders Vomiting, delayed gastric emptying, reduced bowel motility.

Renal and urinary disorders Retention of urine, oliguria or anuria, fluid retention.

General disorders and administration site conditions Hypothermia

Musculoskeletal system There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.

Investigations Increased muscle creatinine phosphokinase.

Treatment There is no specific antidote.

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Treatment should initially be guided by the patient’s clinical condition; admission to hospital may be necessary. Measurement of the plasma level is desirable to confirm carbamazepine poisoning and may be helpful to ascertain the size of the overdose.

Absorption inhibiting therapy can exist of repeated administration of activated charcoal in combination with an osmotic laxative, if necessary. In case of severe carbamazepine-intoxication there is a risk on decrease of the peristalsis of the colon to ileas due to anticholinergic characteristics of carbamazepine. Repeated administration could lead to complications in such situations. When peristalsis is recovered a dose activated charcoal may be administered. In cases of potential severe intoxications and within 1 hour of intake gastric lavage may be considered. Total intestinal lavage may be considered in case of preparations with regulated release (provided that peristalsis is well and no other contraindications exist). Further treatment is supportive and symptomatic: inclusion in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance, treatment of hypotension with fluid and vasopressors, treatment of convulsions with benzodiazepines. . Special recommendations Activated charcoal haemoperfusion may be considered. Haemodialysis is the effective treatment method with carbamazepines overdose. High-flux haemodialysis could be considered. Relapse and aggravation of symptomatology on the 2nd and 3rd day after overdose, due to delayed absorption, should be anticipated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, Carboxamide derivatives, ATC code: N03A F01

Carbamazepine is effective in simple and complex partial seizures (with or without secondary generalization) and in generalized tonic-clonic seizures.

[nationally completed name] is suitable for both monotherapy and combination therapy.Carbamazepine is clinically effective in trigeminal neuralgia; in alcohol-withdrawal syndrome it raises the lowered convulsion threshold and has a beneficial effect on prevention of withdrawal symptoms; in diabetes insipidus centralis carbamazepine reduces the urinary volume and relieves the feeling of thirst.

As a psychotropic agent carbamazepine proved to have clinical efficacy in the treatment of mania as well as for manic-depressive bipolar affective disorders, when given either as monotherapy or in combination with neuroleptics or lithium.

The mechanism of action of carbamazepine, the active substance of [nationally completed name], has only been partially elucidated. The action of carbamazepine is probably based on blockade of voltage-

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The prevalence of SJS has very strongly increased in carriers of the HLA-B*1502 allele. The prevalence of carriers of this allele is 10-15% in patients of South-East Asian origin (southern China, Taiwan) and 1-4% of the population of South and East Asia.

Based on animal studies it is suggested that carbamazepine has a slightly stronger action than the active metabolite carbamazepine-10,11-epoxide.

5.2 Pharmacokinetic properties

Absorption When [nationally completed name] tablets are administered repeatedly, they yield about 25% lower peak concentrations of active substance in plasma than the conventional tablets; the peaks are attained within 24 hours. Because of these lower peak concentrations a stable daily profile of carbamazepine concentration in plasma is achieved. There is not a significant decrease in Cmin compared to other oral dosage forms. The bioavailability of [nationally completed name] tablets is about 15% lower than that of the other oral dosage forms (100%). Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage form of carbamazepine. Steady-state plasma concentrations of carbamazepine are attained within about 1-2 weeks, depending individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as well as on pretreatment status, dosage, and duration of treatment.

Distribution Carbamazepine is bound to serum proteins to the extent of 70-80%. The concentration of unchanged substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20- 30%). Concentrations in breast milk were found to be equivalent to 25-60% of the corresponding plasma levels.

Carbamazepine crosses the placental barrier. Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.5 l/kg.

Biotransformation Carbamazepine is metabolized in the liver, where the epoxide-diol pathway is the most important one, yielding the 10,11-transdiol derivative and its glucuronide as the main metabolites. Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of the pharmacologically active carbamazepine-10,11-epoxide from carbamazepine. Human microsomal epoxide hydrolase has

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Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver (see section 4.5).

Elimination The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose, whereas after repeated administration it averages only 16-24 hours (auto-induction of the hepatic mono-oxydase system), depending on the duration of the medication. In patients receiving concomitant treatment with other liver-enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half- life values averaging 9-10 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. After administration of a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and 1% as the pharmacologically active 10,11-epoxide metabolite.

9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the epoxide-diol pathway. Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Special patient populations The steady-state plasma concentrations of carbamazepine considered as “therapeutic range” vary considerably interindividually: for the majority of patients a range between 4-12 µg/ml corresponding to 17-50 µmol/L has been reported. Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite) amounts about 30% of carbamazepine levels.

Paediatric population Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in mg/kg) than adults.

Elderly (65 years and older) There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared to young adults.

Patients with impaired hepatic or renal function No data are available on patients with impaired hepatic or renal function.

5.3 Preclinical safety data

Carcinogenicity In rats treated with carbamazepine for 2 years, the incidence of occurrence of hepatocellular tumours in females and benign testicular tumours in mans was found to be increased. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

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Genotoxicity Carbamazepine was not found to be genotoxic in various standard bacterial and mammalian mutagenicity studies.

Reproductive toxicity In male rats testic atrophy, a decrease of the total amount of sperm cells and an increase of the amount of deformed sperm cells, was seen. This resulted in decreased fertility in one study in rats, but not in some other studies in rats. The cumulative evidence from various animal studies in mice, rats and rabbits indicates that carbamazepine has no or only minor teratogenic potential at doses relevant to man. Carbamazepine was teratogenic in high doses in rats and mice. Furthermore carbamazepine causes growth retardation in foetus of rats and mice.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Microcrystalline cellulose Croscarmellose sodium Polyacrylate dispersion 30% Ethylcellulose aqueous dispersion Talc Silica, colloidal anhydrous Magnesium stearate

Film coating: Hypromellose Talc Macrogolglycerol hydroxystearate Titanium dioxide (E 171) Iron oxide yellow (E 172) Iron oxide red (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

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Do not store above 25 °C. Store in the original package.

6.5 Nature and contents of container

The tablets are packed in colourless, transparent or white opaque ALU/PVC/PE/PVDC blisters and inserted in a carton. Pack sizes: 30, 50, 60, 100 and 200 prolonged relase tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY} Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

{MM/YYYY} [To be completed nationally]