Source: Υπουργείο Υγείας (CY) Revision Year: 2016 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or any other component of the formulation.
Patients with atrioventricular block, a history of bone marrow depression or a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
The use of Storilat is contraindicated in combination with monoamine oxidase inhibitors (MAOIs) (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Agranulocytosis and aplastic anaemia have been associated with Storilat; however, due to the very low incidence of these conditions, meaningful risk estimates for Storilat 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 2.0 persons per million per year for aplastic anaemia.
Decreased platelet or white blood cell counts occur occasionally to frequently in association with the use of Storilat. Nonetheless, complete pre-treatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline, and periodically thereafter.
Patients and their relatives should be made aware of early toxic signs and symptoms indicative 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 his physician immediately.
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 (see Section 4.8 Undesirable Effects). However, treatment with Storilat should be discontinued if the patient develops leucopenia which is severe, progressive or accompanied by clinical manifestations, e.g. fever or sore throat. Storilat should also be discontinued if any evidence of significant bone marrow depression appears.
Liver function tests should also be performed before commencing treatment and periodically thereafter, 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 The drug should be withdrawn immediately in cases of aggravated liver dysfunction or acute liver disease.
Some liver function tests in patients receiving carbamazepine may be found to be abnormal, particularly gamma glutamyl transferase. This is probably due to hepatic enzyme induction. Enzyme induction may also produce modest elevations in alkaline phosphatase. These enhancements of hepatic metabolising capacity are not an indication for the withdrawal of carbamazepine.
Severe hepatic reactions to carbamazepine occur very rarely. The development of signs and symptoms of liver dysfunction or active liver disease should be urgently evaluated and treatment with Storilat suspended pending the outcome of the evaluation.
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also 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.
Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.
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 Storilat. Patients with serious dermatological reactions may require hospitalization, 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 Storilat. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. If signs and symptoms suggestive of severe skin reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Storilat should be withdrawn at once and alternative therapy should be considered.
Serious and sometimes fatal cutaneous reactions, including toxic epidermal necrolysis (TEN: also known as Lyell’s syndrome) 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.
There is a growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions (see section 4.2).
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-Johnson syndrome (SJS) when treated with carbamazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and 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 for SJS, although the reactions may still very 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), 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 and Koreans (<1%).
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. HLA-A*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 of 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%.
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine treatment.
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine may be considered if the benefits are thought to exceed risks.
Mild skin reactions e.g. isolated macular or maculopapular exanthemata, are mostly transient and not hazardous, and they usually disappear within a few days or weeks, either during the continued 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 drug should the reaction worsen with continued use.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or non-serious rash (maculopapular eruption).
Storilat may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), reactivation of HHV6 associated with DRESS, a delayed multi-organ hypersensitivity disorder with 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 Undesirable Effects.
In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Storilat should be withdrawn immediately.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that 25-30% of these patients may experience hypersensitivity reactions with oxacarbamazepine.
Cross-hypersensitivity can occur between carbamazepine and phenytoin.
Storilat should be used with caution in patients with mixed seizures which include absences, either typical or atypical. In all these conditions, Storilat may exacerbate seizures. In case of exacerbation of seizures, Storilat should be discontinued.
An increase in seizure frequency may occur during switchover from an oral formulation to suppositories.
Abrupt withdrawal of Storilat may precipitate seizures therefore carbamazepine withdrawal should be gradual. If treatment with Sorilat has to be withdrawn abruptly in a patient with epilepsy, the changeover to another anti-epileptic drug should if necessary be effected under the cover of a suitable drug
Breakthrough bleeding has been reported in women taking Storilat while using hormonal contraceptives. The reliability of hormonal contraceptives may be adversely affected by Stand women of childbearing potential should be advised to consider using alternative forms of birth control while taking Storilat.
Patients taking Storilat and requiring hormonal contraception should receive a preparation containing not less than 50µg oestrogen or use of some alternative non-hormonal method of contraception should be considered.
Although correlations between dosages 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 conditions: 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 4.5 Interaction with other Medicaments and other forms of Interaction).
Storilat 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 Storilat.
Baseline and periodic complete urinalysis and BUN determinations are recommended.
Storilat has shown mild anticholinergic activity; patients with increased intraocular pressure should therefore be warned and advised regarding possible hazards.
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
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. If hyponatraemia is observed, water restriction is an important counter-measurement if clinically indicated.
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.
Storilat has shown mild anticholinergic activity; patients with increased intraocular pressure and urinary retention should therefore be closely observed during therapy (see section 4.8).
The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can induce adverse reactions (increase of carbamazepine or carbamazepine-10,11 epoxide plasma concentrations respectively). The dosage of Storilat should be adjusted accordingly and/or the plasma levels monitored.
Co-administration of CYP3A4 inducers with carbamazepine may decrease carbamazepine plasma concentrations and its therapeutic effect, while discontinuation of a CYP3A4 inducer may increase carbamazepine plasma concentrations. The dosage of Storilat 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 co-medications mainly metabolized by CYP3A4 by induction of their metabolism. See section 4.5 Interactions.
Female patients of childbearing potential should be warned that the concurrent use of Storilat with hormonal contraceptives may render this type of contraceptive ineffective (see sections 4.5 Interactions and 4.6 Pregnancy and lactation). Alternative non-hormonal forms of contraception are recommended when using Storilat.
Cytochrome P450 3A4 (CYP 3A4) is the main enzyme catalysing formation of the active metabolite carbamazepine 10, 11-epoxide. Co-administration of inhibitors of CYP 3A4 may result in increased carbamazepine plasma concentrations which could induce adverse reactions. Co-administration of CYP 3A4 inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in carbamazepine serum level and therapeutic effect.
Similarly, discontinuation of a CYP34A 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, and may therefore reduce plasma concentrations of comedications mainly metabolised by CYP3A4 by induction of their metabolism.
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 epoxide plasma concentrations.
The use of Storilat is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before administering Storilat MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits (see contraindications).
Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Storilat should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Analgesics, anti-inflammatory drugs: dextropropoxyphene.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g. erythromycin, clarithromycin), ciprofloxacine.
Antidepressants: fluoxetine, fluvoxamine, paroxetine, trazodone.
Antiepileptics: vigabatrin.
Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihistamines: loratadine.
Antipsychotics: olanzapine.
Antituberculosis: isoniazid.
Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular drugs: diltiazem, verapamil.
Gastrointestinal drugs: possibly cimetidine, omeprazole.
Other interactions: grapefruit juice, nicotinamide (only in high dosage).
Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Storilat should be adjusted accordingly and/or the plasma levels monitored when used concomitantly with the substances described below:
Quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
The dose of Storilat may have to be adjusted when used concomitantly with the substances described below:
Antiepileptics: oxcarbazepine, phenobarbital, phenytoin (to avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.
Antineoplastics: cisplatin or doxorubicin.
Antituberculosis: rifampicin.
Bronchodilatators or anti-asthma drugs: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Other interactions: herbal preparations containing St John’s wort (Hypericum perforatum).
Carbamazepine may lower the plasma level, diminish or even abolish the activity of certain drugs. The dosage of the following drugs may have to be adjusted to clinical requirement:
Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g. warfarin and acenocoumarol).
Antidepressants: bupropion, citalopram, mianserin, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).
Antiemetics: aprepitant
Antiepileptics: clobazam, clonazepam, ethosuximide, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment. There have been rare reports of an increase in plasma mephenytoin levels.
Antifungals: itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated with voriconazole or itraconazole.
Antihelmintics: albendazole.
Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, aripiprazole, paliperidone.
Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam.
Bronchodilatators or anti-asthma 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: ciclosporin, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Other drug interactions: products containing oestrogens and/or progesterones.
Plasma phenytoin levels have been reported both to be raised and to be lowered by carbamazepine, and plasma mephenytoin levels have been reported in rare instances to increase.
Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced toxicity.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
The combination of lithium and carbamazepine may cause enhanced neurotoxicity in spite of lithium plasma concentrations being within the therapeutic range. Combined use of carbamazepine with metoclopramide or major tranquillisers, e.g. haloperidol, thioridazine, may also result in an increase in neurological side-effects.
Because it (carbamazepine) is structurally related to tricyclic anti-depressants, the use of Storilat is not recommended in combination with monoamine oxidase inhibitors (MAOIs); before administering Storilat, MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical situation permits.
Concomitant medication with Storilat and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatraemia.
Carbamazepine may antagonise the effects of non-depolarising muscle relaxants (e.g. pancuronium); their dosage should be raised and patients monitored closely for a more rapid recovery from neuromuscular blockade than expected.
Storilat, like other psychoactive drugs, may reduce alcohol tolerance; it is therefore advisable for the patient to abstain from alcohol.
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.
Offspring of epileptic mothers with untreated epilepsy are known to be more prone to developmental disorders, including malformations. Developmental disorders and malformations, including spina bifida, and also other congenital anomalies e.g. craniofacial defects such as clept lip/palate, cardiovascular malformations, hypospadias and anomalies involving various body systems, have been reported in association with the use of Storilat. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening. Based on data in a North American pregnancy registry, the rate of major congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic importance, diagnosed within 12 weeks of birth was 3.0% (95% CI 2.1 to 4.2%) among mothers exposed to carbamazepine monotherapy in the first trimester and 1.1% (95% CI 0.35 to 2.5%) among pregnant women not taking any antiepileptic drug (relative risk 2.7, 95% CI 1.1 to 7.0).
Taking these data into consideration:
Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate 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.
In order to prevent bleeding disorders in the offspring, it has also 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 Storilat and other concomitant antiepileptic drug use. A few cases of neonatal vomiting, diarrhoea and/or decreased feeding have also been reported in association with maternal Storilat use. These reactions may represent a neonatal withdrawal syndrome.
Due to enzyme induction, Storilat 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 Storilat.
Carbamazepine passes into the breast milk (about 25-60% of the plasma concentrations). The benefits of breast-feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers taking Storilat may breast-feed their infants, provided the infant is observed for possible adverse reactions (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 breast feeding. Therefore breast-fed infants of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.
There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.
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 reported with Storilat, 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.
Particularly at the start of treatment with Storilat, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting), as well as allergic skin reactions.
The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor the plasma levels and divide the daily dosage into smaller (i.e. 3-4) 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
| Blood and lymphatic system disorders | |
| Very common: | Leucopenia |
| Common: | Thrombocytopenia, eosinophilia |
| Rare: | Leucocytosis, lymphadenopathy |
| Very rare: | Agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, reticulocytosis and possibly haemolytic anaemia. |
| Immune system disorders | |
| Rare: | A delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepato-splenomegaly, 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. liver, lungs, kidneys, pancreas, myocardium, colon). |
| Very rare: | anaphylactic reaction, oedema angioedema, hypogammaglobulinaemia. |
| Not known**: | Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). |
| Infections and infestations | |
| Not known**: | reactivation of Human herpesvirus 6 infection |
| Endocrine disorders | |
| Common: | Oedema, fluid retention, weight increase, hyponatraemia and blood osmolarity 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 non-acute (porphyria cutanea tarda) |
| Psychiatric disorders | |
| Rare: | hallucinations (visual or auditory), depression, anorexia, restlessness, aggregation, agitation, confusional state |
| Very rare: | activation of psychosis |
| Nervous system disorders | |
| Very common: | dizziness, ataxia, somnolence |
| Common: | headache, diplopia |
| Uncommon: | abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus |
| Rare: | dyskinesia, eye movement disturbances, speech disorders (e.g. dysarthria or slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, , and paresis |
| Very rare: | neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia |
| Eye disorders | |
| Common: | accommodation disorders (e.g. blurred vision) |
| Very rare: | lenticular opacities, 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, atrioventricular block with syncope, bradycardia, cardiac failure congestive, coronary artery disease aggravated |
| Respiratory, thoracic and mediastinal disorders | |
| Very rare: | pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or pneumonia |
| Gastro-intestinal disorders | |
| Very common: | nausea, vomiting |
| Common: | dry mouth, with suppositories rectal irritation may occur |
| Uncommon: | diarrhoea, constipation |
| Rare: | abdominal pain |
| Very rare: | glossitis, stomatitis, pancreatitis |
| Not known**: | colitis |
| Hepatobiliary disorders | |
| Rare: | hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice |
| Very rare: | granulomatous hepatitis. Hepatic failure |
| Skin and subcutaneous tissue disorders | |
| Very common: | dermatitus allergic urticaria which may be severe |
| Uncommon: | exfoliative dermatitis |
| Rare: | systemic lupus erythematosus, pruritus |
| Very rare: | Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme and nodosum, alterations in skin pigmentation, purpura, acne, hyperhydrosis, hair loss, hirsutism |
| Not Known**: | acute Generalized Exanthematous Pustulosis (AGEP)**, lichenoid keratosis, onychomadesis |
| 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, muscle pain, muscle spasms |
| Not Known**: | fracture |
| Renal and urinary disorders | |
| Very rare: | interstitial nephritis, renal failure, renal impairment (e.g. albuminuria, haematuria, oliguria and blood urea/azotaemia), urinary frequency, urinary retention |
| Reproductive system | |
| Very rare: | sexual disturbances/erecticle dysfunction spermatogenesis abnormal (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, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased |
| Not known**: | bone density decreased |
* In some Asian countries also reported as rare. See also section 4.4 Special warnings and precautions for use.
** Additional adverse drug reactions from spontaneous reports (frequency not known)
The following adverse drug reactions have been derived from post-marketing experience with Storilat 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 categorized 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.
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Storilat. The mechanism by which Storilat 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 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: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy.phs.
None known.
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