Carbalex 300 mg retard
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Carbalex 300 mg retard (Carbalex 300 mg retard) Carbalex 600 mg retard (Carbalex 600 mg retard)
Composition:
Active substance: carbamazepine;
1 tablet of Carbalex 300 mg retard contains 300 mg of carbamazepine;
1 tablet of Carbalex 600 mg retard contains 600 mg of carbamazepine;
Excipients: ammonio methacrylate copolymer (type A), methacrylate copolymer dispersion, colloidal anhydrous silicon dioxide, magnesium stearate, talc, sodium starch glycolate (type A), microcrystalline cellulose.
Pharmaceutical form. Prolonged-release tablets.
Main physicochemical properties: Carbalex 300 mg retard – white or almost white, round tablets with two dividing lines on one side of the tablet;
Carbalex 600 mg retard – white or almost white, elongated tablets with one line on both sides.
Pharmacotherapeutic group.
Antiepileptic agents. Carbamazepine. ATC code N03A F01.
Pharmacological Properties
Pharmacodynamics.
As an anticonvulsant, carbamazepine is effective against focal (partial) seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, as well as combinations of these seizure types.
In clinical studies, when carbamazepine was used as monotherapy in patients with epilepsy (especially in children and adolescents), psychotropic effects of the drug were observed, partially manifesting as a beneficial effect on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness. According to some studies, the effect of carbamazepine on cognitive function and psychomotor performance was dose-dependent and either questionable or negative. In other studies, a positive effect of the drug on parameters related to attention, learning ability, and memory was observed.
As a neuromodulating agent, carbamazepine is effective in certain neurological disorders. For example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. In addition, carbamazepine is used to alleviate neuropathic pain in various conditions, including spinal cord syringomyelia, post-traumatic paresthesias, and postherpetic neuralgia. In alcohol withdrawal syndrome, carbamazepine increases the seizure threshold (which is reduced in this condition) and reduces the severity of clinical symptoms such as excitability, tremor, and gait disturbances. In patients with central diabetes insipidus, carbamazepine reduces diuresis and thirst.
It has been confirmed that as a psychotropic agent, carbamazepine is effective in: treatment of acute manic states; maintenance therapy of bipolar affective (manic-depressive) disorders (both as monotherapy and in combination with neuroleptics, antidepressants, or lithium salts); schizoaffective psychoses; manic psychoses, where it is used in combination with neuroleptics; and also in acute polymorphic schizophrenia (rapid cycling episodes). The mechanism of action of carbamazepine—the active ingredient in Karbalex 300 mg retard and Karbalex 600 mg retard—is only partially understood. Carbamazepine stabilizes membranes of hyperexcited nerve fibers, inhibits repetitive neuronal firing, and reduces synaptic transmission of excitatory impulses. It has been established that the main mechanism of action is prevention of repetitive sodium-dependent action potentials in depolarized neurons by blocking sodium channels. The anticonvulsant effect of the drug is primarily due to reduced glutamate release and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.
Pharmacokinetics.
After oral administration, carbamazepine is almost completely absorbed from the gastrointestinal tract. Cmax is reached within 12 hours after a single dose. Plasma protein binding is 70–80%. In cerebrospinal fluid and saliva, concentrations proportional to the unbound fraction of the active substance (20–30%) are achieved. Carbamazepine penetrates into breast milk (25–60% of plasma levels) and crosses the placental barrier. The apparent volume of distribution is 0.8–1.9 L/kg. After a single dose, T1/2 is 25–65 hours; with prolonged administration, T1/2 decreases to 8–29 hours (due to enzyme induction of metabolism). In patients taking enzyme inducers of the mono-oxygenase system (phenytoin, phenobarbital), T1/2 is 8–10 hours. Carbamazepine is metabolized in the liver and primarily excreted by the kidneys. The prolonged action of the tablets is independent of food intake. If desired, the tablets can be dissolved in liquid (water, tea, orange juice, milk) without risk of losing the drug's effect. Grapefruit juice, by inhibiting the activity of CYP450-3A4 enzymes in the stomach and liver, significantly increases the bioavailability of carbamazepine.
The onset of anticonvulsant effect varies from several hours to several days (sometimes up to 1 month).
Clinical characteristics.
Indications.
- Epilepsy and complex or simple partial seizures (with or without loss of consciousness), with or without secondary generalization; generalized tonic-clonic seizures. Mixed forms of seizures.
Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release may be used both as monotherapy and in combination therapy.
- Acute manic states and maintenance therapy of bipolar affective disorders, for prevention of relapses or reduction of clinical manifestations of exacerbation.
- Alcohol withdrawal syndrome.
- Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia.
- Diabetic neuropathy with pain syndrome.
- Central diabetes insipidus. Neurohormonal polyuria and polydipsia.
Contraindications.
- Known hypersensitivity to carbamazepine or to chemically related medicinal products (e.g., tricyclic antidepressants) or to any other component of the medicinal product;
- Atrioventricular block;
- History of bone marrow depression;
- History of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
- Acute hepatic failure;
- Concomitant use with monoamine oxidase inhibitors (MAO inhibitors).
Interaction with other medicinal products and other forms of interaction.
The efficacy of medicinal products such as oral anticoagulants (coumarin derivatives), quinidine, hormonal contraceptives, certain antibiotics (doxycycline), which are associated with induction of hepatic enzymes, may be reduced.
Grapefruit juice, which significantly increases absorption of carbamazepine, should be avoided. Carbamazepine intake affects laboratory parameters of thyroid function (thyroid hormone levels).
Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite carbamazepine-10,11-epoxide. Concomitant use of CYP3A4 inhibitors may increase plasma concentrations of carbamazepine, which in turn may lead to adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, leading to potential reduction in plasma carbamazepine concentration and diminished therapeutic effect. Conversely, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma carbamazepine levels.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II hepatic enzymes, and therefore may reduce plasma concentrations of other drugs primarily metabolized by CYP3A4 by inducing their metabolism.
Human microsomal epoxide hydrolase is the enzyme responsible for converting carbamazepine-10,11-epoxide into 10,11-trans-dihydrodiol derivatives. Concomitant administration of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.
Contraindicated combinations.
Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release are contraindicated for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); administration of an MAO inhibitor must be discontinued at least two weeks prior to initiation of treatment (or earlier if clinically justified).
Carbamazepine is contraindicated in combination with voriconazole due to potential loss of voriconazole efficacy caused by induction of hepatic enzymes.
Medicinal products that may increase carbamazepine plasma levels.
Since increased plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels of Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release are required when co-administered with the following medicinal products.
Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g., erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin).
Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptics: stiripentol, vigabatrin.
Antifungal agents: azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole) — concomitant use is contraindicated! Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Antihistamines: loratadine, terfenadine.
Antipsychotics: olanzapine, loxapine, quetiapine.
Antituberculosis agents: isoniazid.
Antiemetics and anti-nausea agents: aprepitant.
Antiviral agents: HIV protease inhibitors (e.g., ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular agents: diltiazem, verapamil.
Gastrointestinal agents: cimetidine, omeprazole.
Muscle relaxants: oxybutynin, dantrolene.
Antiplatelet agents: ticlopidine.
Other substances: niacin, grapefruit juice, nicotinamide (when administered in high doses to adults).
Medicinal products that may increase plasma levels of the active metabolite carbamazepine-10,11-epoxide.
Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels of Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release are required when co-administered with the following medicinal products: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.
Medicinal products that may decrease carbamazepine plasma levels.
Dosage adjustment of Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release may be required when co-administered with the following medicinal products.
Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended to adjust phenytoin plasma concentration to 13 µg/mL prior to starting carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).
Antineoplastic agents: cisplatin or doxorubicin.
Antituberculosis agents: rifampicin.
Bronchodilators or anti-asthmatic agents: theophylline, aminophylline.
Dermatological agents: isotretinoin.
Herbal products: preparations containing St. John’s wort (Hypericum perforatum).
Interaction with other substances: mefloquine may exhibit antagonistic properties towards the antiepileptic effect of Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release. Therefore, dosage adjustment of these agents may be necessary.
Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma concentrations of carbamazepine should be monitored.
Effect of Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release on plasma levels of concomitantly administered medicinal products.
Carbamazepine may reduce plasma levels of certain medicinal products and diminish or nullify their effects. Carbamazepine is a potent inducer of hepatic CYP3A4 and is also known to induce CYP1A2, 2B6, 2C9/19, and thus may reduce plasma concentrations of concomitantly administered drugs primarily metabolized by CYP1A2, 2B6, 2C9/19, and 3A4 through induction of their metabolism. Dosage adjustment of the following medicinal products may be required according to clinical needs.
Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long-term use of carbamazepine with paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone (antipyrine), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, rivaroxaban, dabigatran, apixaban, edoxaban, dicoumarol, and acenocoumarol).
Antidepressants: mianserin, sertraline, bupropion, citalopram, nefazodone, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine). Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release are contraindicated for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); administration of an MAO inhibitor must be discontinued at least two weeks prior to initiation of treatment (or earlier if clinically justified).
Antiepileptic agents: methsuximide, phensuximide, clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increases and decreases in plasma phenytoin levels have been reported with carbamazepine, as well as isolated cases of increased plasma mefenytoin levels.
Antifungal agents: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Antihelminthic agents: praziquantel, albendazole.
Antineoplastic agents: imatinib, temsirolimus, lapatinib, sirolimus, cyclophosphamide.
Neuroleptic agents: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antiviral agents: protease inhibitors for HIV treatment (e.g., indinavir, ritonavir, saquinavir).
Antiemetics and anti-nausea agents: aprepitant.
Anxiolytics: alprazolam, midazolam.
Bronchodilators or anti-asthmatic agents: theophylline.
Contraceptives: hormonal contraceptives (e.g., oral contraceptives and levonorgestrel subdermal implant). Cases of breakthrough bleeding and unintended pregnancy have been reported. Alternative contraceptive methods should be considered.
Cardiovascular agents: calcium channel blockers (dihydropyridine group), e.g., felodipine, digoxin, isradipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: corticosteroids (e.g., prednisolone, dexamethasone).
Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Opioids: buprenorphine.
Agents for erectile dysfunction: tadalafil.
Other agents: products containing estrogens and/or progestogens (alternative contraceptive methods should be considered); buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.
Combinations requiring special consideration.
Concomitant use of carbamazepine and levetiracetam may lead to increased carbamazepine toxicity.
Concomitant use of carbamazepine and isoniazid may lead to enhanced hepatotoxicity of isoniazid.
Concomitant use of carbamazepine with lithium or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may lead to increased neurological adverse effects (in the case of the latter combination, even at therapeutic plasma levels).
Combined therapy with Carbalex 300 mg prolonged-release and Carbalex 600 mg prolonged-release and certain diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium, vecuronium, rocuronium, cisatracurium). Increased doses of these agents may be required, and patients require close monitoring due to the possibility of unexpectedly rapid termination of neuromuscular blockade.
Carbamazepine, like other psychotropic agents, may reduce tolerance to alcohol; patients are advised to abstain from alcohol consumption.
Concomitant use of carbamazepine with direct oral anticoagulants (rivaroxaban, dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of direct oral anticoagulants, increasing the risk of thrombosis. Therefore, if concomitant use is necessary, more careful monitoring for signs and symptoms of thrombosis is recommended.
Effect on serological testing.
Carbamazepine may yield false-positive results in HPLC (high-performance liquid chromatography) assays for perphenazine concentration.
Carbamazepine and carbamazepine-10,11-epoxide may yield false-positive results in immunoassays using fluorescence polarization techniques for determination of tricyclic antidepressant concentrations.
Special precautions for use.
Carbalex 300 mg retard and Carbalex 600 mg retard should be prescribed only under medical supervision, only after benefit/risk assessment, and with careful monitoring of patients with cardiac, hepatic, or renal disorders, hematological adverse reactions to other drugs in history, and patients who have previously discontinued treatment with Carbalex 300 mg retard or Carbalex 600 mg retard.
It is recommended to perform a general urine analysis and determine blood urea nitrogen levels at the beginning and periodically during therapy.
Carbalex 300 mg retard and Carbalex 600 mg retard exhibit mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised about potential risk factors.
One should bear in mind the possible activation of latent psychoses, and in elderly patients, the possible development of confusion and anxious agitation.
The drug is generally ineffective in petit mal (absence) seizures and myoclonic seizures. Some cases indicate that seizure exacerbation may occur in patients with atypical absences.
Prior to initiating therapy, blood tests and liver function tests should be performed.
During treatment, the following parameters should be monitored:
- Blood counts – weekly during the first month, then monthly;
- Liver function – every 3–4 months if values are within normal limits, and at shorter intervals if abnormalities are detected.
If signs of hematopoietic disorders, progressive or symptomatic leukopenia, allergic skin reactions, or significant deterioration in liver function occur, treatment with Carbalex retard should be discontinued.
Regular monitoring and cautious dosing are necessary for patients with cardiovascular diseases, hepatic and/or renal dysfunction, liver disease, and patients with glaucoma.
Women of childbearing potential. Carbamazepine may harm the fetus if used during pregnancy. Prenatal exposure to carbamazepine increases the risk of serious congenital malformations and other adverse outcomes (see section "Use during pregnancy or breastfeeding").
Unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks, carbamazepine should not be used in women of childbearing potential.
Women must be fully informed about the potential risk to the fetus if they take carbamazepine during pregnancy.
Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing age.
Women of childbearing potential must use effective contraception during treatment and for two weeks after discontinuation of therapy. Due to enzyme induction, carbamazepine may reduce the therapeutic effect of hormonal contraceptives; therefore, women of childbearing potential should consult their physician regarding the use of other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").
Women planning pregnancy should discuss with their physician switching to alternative treatment before conception and discontinuation of contraception (see section "Use during pregnancy or breastfeeding").
Women should be advised to seek immediate medical advice if they become pregnant or suspect they may be pregnant while taking carbamazepine.
Hematological effects. Agranulocytosis and aplastic anemia have been associated with the use of the drug; however, due to the extremely low incidence of these conditions, it is difficult to assess the significant risk of using Carbalex 300 mg retard and Carbalex 600 mg retard. The overall risk in untreated individuals is 4.7 cases per 1,000,000 per year for agranulocytosis and 2 cases per 1,000,000 per year for aplastic anemia.
Transient or persistent reduction in platelet or white blood cell counts has been observed periodically or frequently with the use of Carbalex 300 mg retard and Carbalex 600 mg retard. However, most of these cases have been confirmed as transient and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, including platelet count (reticulocyte count and hemoglobin level), should be performed before initiating therapy and periodically during treatment.
If white blood cell or platelet counts decrease significantly during therapy, careful monitoring of the patient is required, and regular complete blood counts should be performed. Treatment with Carbalex 300 mg retard and Carbalex 600 mg retard must be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical symptoms such as fever or sore throat. Carbalex 300 mg retard and Carbalex 600 mg retard should be discontinued if signs of bone marrow suppression occur.
Patients should be informed about early signs of toxicity and symptoms of possible hematological disorders, as well as dermatological and hepatic reactions. Patients should be warned that if reactions such as fever, angina, skin rashes, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura occur, they should seek immediate medical advice.
Hyponatremia may occur as a result of carbamazepine treatment. In many cases, hyponatremia is likely due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of SIADH is dose-dependent. Elderly patients and patients receiving diuretics are at higher risk of developing hyponatremia.
Signs and symptoms of hyponatremia include headache, new onset of seizures or increased seizure frequency, decreased concentration, memory impairment, confusion, weakness, and unsteadiness of gait, which may lead to falls.
Serious dermatological reactions. Serious dermatological reactions, including toxic epidermal necrolysis (TEN, or Lyell's syndrome) and Stevens-Johnson syndrome (SJS), occur very rarely with the use of Carbalex 300 mg retard and Carbalex 600 mg retard. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of SJS/TEN occur within the first few months of treatment with Carbalex 300 mg retard and Carbalex 600 mg retard. If symptoms of serious dermatological reactions (such as SJS, Lyell's syndrome/TEN) develop, treatment with Carbalex 300 mg retard and Carbalex 600 mg retard should be immediately discontinued and alternative therapy initiated. If a patient develops SJS/TEN during carbamazepine treatment, carbamazepine must never be re-administered to this patient. These reactions occurred at a frequency of 1 to 6 cases per 10,000 individuals newly using carbamazepine in countries with predominantly European populations, but the risk is estimated to be approximately 10 times higher in some Asian countries.
There is increasing evidence of the role of various HLA alleles in patient susceptibility to immune-mediated adverse reactions.
HLA-B*1502 allele in Chinese, Thai, and other Asian populations. HLA-B*1502 has been shown to be strongly associated with the risk of severe skin reactions known as Stevens-Johnson syndrome (SJS) in individuals of Chinese and Thai origin during carbamazepine treatment. The prevalence of HLA-B*1502 is approximately 10% in the Chinese and Thai populations. Whenever possible, individuals of Chinese or Thai origin should be tested for the HLA-B*1502 allele before initiating carbamazepine treatment (see section "Dosage and administration"). If the test result is positive, carbamazepine should not be initiated. Patients who test negative for HLA-B*1502 have a low risk of developing SJS. There is some evidence suggesting an increased risk of carbamazepine-related TEN/SJS in other Asian populations. Due to the prevalence of this allele in other Asian populations (e.g., over 15% in the Philippines and Malaysia), genetic testing for HLA-B*1502 in patients at risk may be advisable. The prevalence of the HLA-B*1502 allele is low (<1%) in individuals of European origin, Africans, Latin Americans, as well as Japanese and Koreans.
HLA-A*3101 allele in Europeans and Japanese.
There is some evidence that HLA-A*3101 is associated with an increased risk of skin adverse reactions caused by carbamazepine, including SJS, TEN, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash (see section "Adverse reactions"), in individuals of European origin and Japanese.
The prevalence of the HLA-A*3101 allele varies significantly among ethnic groups: from 2 to 5% in European populations and about 10% in Japanese.
Additionally, it is estimated that Native Americans (Indians), Arabs, Chinese (Han ethnicity), and Koreans have a similar prevalence of the HLA-A*3101 allele, which is less common among African Americans, Thais, and Taiwanese.
The presence of the HLA-A*3101 allele increases the risk of carbamazepine-induced skin reactions (mostly less severe) from 5.0% in the general population to 26.0% among individuals of European origin, while its absence reduces the risk from 5.0% to 3.8%.
There is insufficient data to recommend HLA-A*3101 testing before initiating carbamazepine treatment.
If patients of European or Japanese origin are known to carry the HLA-A*3101 allele, the benefit should be carefully weighed against the risks before initiating carbamazepine treatment.
Other dermatological reactions. Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may occur. These usually resolve within a few days or weeks, either with continued dosing or after dose reduction. However, since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored so that drug administration can be immediately discontinued if the reaction worsens.
The presence of the HLA-A*3101 allele in patients is associated with less severe adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular rashes).
However, the presence of HLA-B*1502 has not been established as an indicator of risk for the aforementioned skin reactions.
Hypersensitivity. Carbalex 300 mg retard and Carbalex 600 mg retard may provoke hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed-type hypersensitivity reactions with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (including destruction and disappearance of intrahepatic bile ducts), which may manifest in various combinations. Other organs may also be affected (lungs, kidneys, pancreas, myocardium, colon).
Carbamazepine may cause eosinophilia and systemic symptoms, also known as multiorgan hypersensitivity. Some of these events have been fatal or life-threatening. DRESS is typically, although not exclusively, accompanied by fever, rash, and/or lymphadenopathy associated with involvement of other organ systems such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, which sometimes resembles acute viral infection. Eosinophilia is often present. This disorder may present variably, and other organ systems not mentioned here may be affected. It is important to note that early signs of hypersensitivity (e.g., fever, lymphadenopathy) may be present even if rash is not evident. If such signs and symptoms are present, the patient's condition should be immediately evaluated. Carbalex retard should be discontinued if an alternative etiology for these signs and symptoms cannot be established.
Patients with hypersensitivity reactions to carbamazepine should be informed that approximately 25–30% of them may also have hypersensitivity reactions to oxcarbazepine.
Cross-hypersensitivity may occur with the use of carbamazepine and phenytoin.
In general, if symptoms of hypersensitivity occur, treatment with Carbalex 300 mg retard and Carbalex 600 mg retard should be immediately discontinued.
Seizures. Carbalex 300 mg retard and Carbalex 600 mg retard should be used with caution in patients with mixed seizure types, including absences (typical or atypical). Under these circumstances, the drug may provoke seizures. If seizures are provoked, treatment with Carbalex 300 mg retard and Carbalex 600 mg retard should be immediately discontinued.
Increased seizure frequency may occur during transition from oral formulations to suppositories.
Liver function. Liver function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. If liver function abnormalities worsen or during active liver disease, the drug should be immediately discontinued.
Carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, hemochromatosis).
Acute attacks have been reported in patients taking carbamazepine.
Some laboratory parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT). This is likely due to induction of liver enzymes. Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such increased hepatic metabolic activity is not an indication for discontinuation of carbamazepine.
Severe reactions due to carbamazepine use are very rare. If symptoms of liver dysfunction or active liver disease occur, the patient should be urgently evaluated, and treatment with Carbalex 300 mg retard and Carbalex 600 mg retard should be suspended until test results are obtained.
Kidney function. Kidney function assessment and blood urea nitrogen measurement are recommended at the beginning and periodically during therapy.
Hyponatremia. Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal impairment associated with low sodium levels, or in patients receiving concomitant treatment with drugs that lower sodium levels (such as diuretics, drugs associated with inadequate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, measurements should be taken every 2 weeks, then monthly for the first 3 months of treatment or as clinically necessary. This is particularly important for elderly patients. Water intake should be limited in such cases.
Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations, necessitating an increase in thyroid hormone replacement dose for patients with hypothyroidism.
Anticholinergic effects. Carbalex 300 mg retard and Carbalex 600 mg retard exhibit moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure should be closely monitored during therapy.
Psychiatric effects. The possibility of activation of latent psychosis, and in elderly patients, confusion or agitation, should be considered.
Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behavior with carbamazepine use. Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to seek medical advice if signs of suicidal thoughts or behavior occur.
Endocrine effects. Due to hepatic enzyme induction, carbamazepine may reduce the therapeutic effect of estrogen and/or progesterone-containing drugs. This may lead to reduced contraceptive efficacy, symptom recurrence, or breakthrough bleeding or spotting. Women taking carbamazepine who require hormonal contraception should receive a preparation containing at least 50 mcg of estrogen, or alternative non-hormonal contraceptive methods should be considered for such patients.
Plasma level monitoring. Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma drug levels may be advisable in the following cases: sudden increase in seizure frequency, verification of patient adherence to prescribed therapy, during pregnancy, in the treatment of children and adolescents; when malabsorption is suspected, in suspected toxicity, and when more than one drug is used.
Dose reduction and discontinuation. Abrupt discontinuation of Carbalex 300 mg retard and Carbalex 600 mg retard may provoke seizures. If abrupt discontinuation is necessary in patients with epilepsy, transition to a new antiepileptic drug should occur while continuing appropriate therapy (e.g., intravenous or rectal diazepam, or intravenous phenytoin).
Dose reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be tapered gradually over 6 months. If immediate discontinuation is necessary, transition to a new antiepileptic drug in patients with epilepsy should be carried out while continuing appropriate therapy.
Switching from tablets to retard tablets. Clinical experience indicates that in some patients, switching to retard tablets may necessitate an increase in drug dosage.
Due to drug interactions and different pharmacokinetics of antiepileptic drugs, doses of Carbalex 300 mg retard and Carbalex 600 mg retard in elderly patients should be carefully adjusted.
Falls. Carbamazepine treatment has been associated with ataxia, dizziness, somnolence, hypotension, confusion, and sedation (see section "Adverse reactions"), which may lead to falls and, consequently, fractures or other injuries. In conditions, diseases, or with medications that may exacerbate these effects, the risk of falls should be periodically evaluated in patients receiving long-term carbamazepine treatment.
Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free."
Use during pregnancy or breastfeeding.
Pregnancy.
General risk associated with antiepileptic medicinal products (AEDs).
All women of childbearing age receiving antiepileptic therapy, and especially women planning pregnancy and pregnant women, should be informed about the potential risk to the fetus from both seizures and antiepileptic treatment.
Abrupt discontinuation of AED treatment should be avoided, as it may lead to seizures, which may have serious consequences for the woman and the unborn child.
If possible, monotherapy is preferred for the treatment of epilepsy during pregnancy, as treatment with multiple AEDs is associated with a higher risk of congenital malformations.
Risks associated with carbamazepine.
Carbamazepine crosses the placental barrier. Prenatal exposure to carbamazepine increases the risk of congenital malformations and other adverse outcomes. The impact of carbamazepine during pregnancy causes serious malformations 2–3 times more frequently than in the general population, where the frequency of these malformations is 2–3%. Such malformations as fetal neural tube defects, craniofacial defects including cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various fetal organ systems have been reported. Specialized antenatal monitoring for these malformations is recommended. Neurodevelopmental disorders have been reported in children born to women with epilepsy who used carbamazepine alone or in combination with other AEDs during pregnancy. Study results regarding the risk of neurodevelopmental disorders in children exposed in utero to carbamazepine are conflicting, and the risk cannot be excluded.
Unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks, carbamazepine should not be used during pregnancy. Women must be fully informed and understand the risks of taking carbamazepine during pregnancy.
There is evidence that the risk of malformations with carbamazepine use is dose-dependent. If, after careful benefit/risk assessment and consideration of alternative treatments, the decision is made to treat with carbamazepine, monotherapy and the lowest effective dose should be used, and plasma carbamazepine levels should be monitored. Plasma concentrations can be maintained in the lower part of the therapeutic range of 4 to 12 mcg/mL, provided seizure control is maintained.
It has been reported that some AEDs, such as carbamazepine, reduce serum folate levels. Folate deficiency in mothers with epilepsy increases the risk of fetal congenital malformations. Folic acid is recommended before and during pregnancy. To prevent coagulation disorders in the child, vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns.
If a woman plans to become pregnant, all efforts should be made before conception and discontinuation of contraception to switch to appropriate alternative treatment. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to re-evaluate the treatment method and consider alternative options.
Women of childbearing potential. Carbamazepine should not be used in women of childbearing potential, except when the benefit/risk ratio of carbamazepine use outweighs alternative treatment options. Women must be fully informed and understand the potential risk to the fetus if carbamazepine is taken during pregnancy, so pregnancy planning is essential. Before initiating carbamazepine therapy, the possibility of performing a pregnancy test should be considered in women of childbearing age.
Women of childbearing potential must use effective contraception during and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may reduce the therapeutic effect of hormonal contraceptives (see section "Interaction with other medicinal products and other forms of interaction"), so women of childbearing potential should consult their physician regarding the use of other effective contraceptive methods. At least one effective method of contraception (e.g., intrauterine) or two additional forms of contraception, including a barrier method, should be used. Individual circumstances should be evaluated when choosing a contraceptive method, involving the patient in the discussion.
Newborns. To prevent coagulation disorders in newborns, vitamin K1 is recommended for the mother during the last weeks of pregnancy and for the newborn.
There have been several reports of seizures and/or respiratory depression in newborns associated with maternal use of Carbalex 300 mg retard, Carbalex 600 mg retard, and other anticonvulsant drugs. Several cases of vomiting, diarrhea, and/or decreased appetite in newborns associated with maternal use of Carbalex retard have been reported.
Breastfeeding. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding should be carefully weighed against the remote possibility of adverse effects in the infant. Women receiving Carbalex 300 mg retard and Carbalex 600 mg retard may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).
Cases of cholestatic hepatitis in newborns whose mothers received carbamazepine before and/or during breastfeeding have been reported. Therefore, infants breastfed by mothers receiving carbamazepine should be closely monitored for adverse effects on the hepatobiliary system.
Fertility. Very rare cases of impaired fertility in men and/or abnormalities in spermatogenesis parameters have been reported.
Ability to affect reaction speed when driving or operating machinery.
The patient's ability to react may be impaired due to the medical condition causing seizures and adverse reactions caused by carbamazepine, including dizziness, somnolence, ataxia, diplopia, accommodation disorders, and blurred vision, especially during the initial stages of treatment, dose adjustment, higher dosing, or concomitant alcohol consumption. Therefore, patients should exercise caution when driving or operating machinery.
Method of Administration and Dosage
The drug can be taken during, after, or between meals with a small amount of liquid. Tablets may be divided into parts without losing their prolonged-release effect; they can also be dissolved in various beverages (in 1 glass of water, tea, orange juice, or milk), except those containing grapefruit juice.
Before starting therapy, patients of Chinese or Thai origin should be tested for HLA-B*1502, as this allele is strongly predictive of the risk of developing severe Stevens-Johnson syndrome associated with carbamazepine (for information on genetic testing and skin reactions, see section "Special Warnings and Precautions for Use").
Epilepsy
If possible, Carbalex 300 mg retard and Carbalex 600 mg retard should be prescribed as monotherapy.
Treatment should be initiated with a low daily dose, which should then be gradually increased until optimal effect is achieved.
Determining plasma levels of the active substance may be helpful in selecting the optimal dose. Therapeutic plasma concentrations of carbamazepine typically range from 4–12 µg/mL (17–50 µmol/L).
When adding Carbalex 300 mg retard or Carbalex 600 mg retard to already prescribed antiepileptic drugs, the dose should be gradually increased without changing the dose of the currently used antiepileptic agent, or adjusted as needed.
Children aged 5 to 10 years – 150–300 mg twice daily (15–20 mg/kg/day).
Adults and children aged 10 years and older. Therapy should begin at a dose of 150 mg twice daily, gradually increasing the dose until optimal effect is achieved. Generally, the average therapeutic dose is 600 mg/day, which should usually be taken in the evening if prescribed once daily by the physician.
Some patients may require a carbamazepine dose up to 1600 mg or even 2000 mg per day.
Acute manic states and maintenance therapy in bipolar affective disorders
Dosages may range from 300 to 1500 mg/day. Therapy is usually conducted at a dose of 400–600 mg/day in 2–3 divided doses.
For treatment of acute manic states, the dose should be increased rapidly, whereas gradual dose escalation in small increments is optimal and recommended for prevention of bipolar disorders.
Alcohol withdrawal syndrome
The average daily dose is 600 mg. In some cases, a dose of 1200 mg/day should be used during the first days of treatment.
In severe cases of alcohol withdrawal, treatment should begin with a combination of carbamazepine and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations above. After the acute phase has resolved, Carbalex 300 mg retard and Carbalex 600 mg retard may be continued as monotherapy.
Trigeminal neuralgia
Initial dose is 300 mg/day. It should be gradually increased until pain symptoms disappear. The average daily dose is 600 mg.
Painful diabetic neuropathy
The average daily dose is 600 mg, which can be administered once daily or divided into two 300 mg doses – morning and evening.
Central diabetes insipidus. Neurohormonal polyuria and polydipsia.
The average dose for adults is 300 mg 2–3 times daily. For children, the dose should be reduced according to age and body weight.
Children
Due to faster elimination of carbamazepine, children may require higher doses per kilogram of body weight compared to adults. Carbalex 300 mg retard and Carbalex 600 mg retard may be administered to children aged 5 years and older under medical supervision and prescription. These formulations should be prescribed to children with particular caution, only after careful evaluation by the physician of the benefit-risk ratio regarding complications, and preferably as monotherapy.
Overdose
Acute toxicity
Lowest lethal dose: adults – 3.2 g (a 24-year-old woman died from cardiac arrest, and a 24-year-old man died from pneumonia and hypoxic encephalopathy); children – 4 g (a 14-year-old girl died from cardiac arrest), 1.6 g (a 3-year-old girl died from aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice – 1100 to 3750; rats – 3850 to 4025; rabbits – 1500 to 2680; guinea pigs – 920.
Symptoms. Initial signs and symptoms appear within 1–3 hours. Symptoms and complaints occurring in overdose typically reflect involvement of the central nervous, cardiovascular, and respiratory systems.
Central nervous system: CNS depression; confusion, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (early), hyporeflexia (later); seizures, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: respiratory depression, pulmonary edema.
Cardiovascular system: tachycardia, arterial hypotension, occasionally arterial hypertension, conduction disturbances with widening of the QRS complex; cardiac arrest associated with loss of consciousness.
Gastrointestinal tract: nausea, vomiting, delayed gastric emptying, reduced colonic motility.
Urinary system: urinary retention, oliguria or anuria; fluid retention; dilutional hyponatremia caused by carbamazepine’s antidiuretic hormone-like effect.
Laboratory findings: hyponatremia, possible metabolic acidosis, hyperglycemia, elevated creatine phosphokinase muscle fraction. Leukocytosis, leukopenia, glycosuria, and acetonuria have occasionally been observed in overdose. Electroencephalogram may show arrhythmia.
Combined poisoning. When taken concomitantly with alcohol, tricyclic antidepressants, or barbiturates, symptoms of acute carbamazepine poisoning may be intensified or altered.
Treatment. There is no specific antidote. Initial treatment should be based on the patient’s clinical condition; hospitalization is indicated. Plasma carbamazepine concentration should be measured to confirm poisoning and assess the degree of overdose.
Gastric evacuation, gastric lavage, activated charcoal, and laxatives should be administered. Late gastric evacuation may lead to delayed absorption and recurrence of intoxication symptoms during recovery. Even more than 4 hours after ingestion, repeated gastric lavage should be performed, especially if the patient has also consumed alcohol.
In case of respiratory depression, keep airways open; endotracheal intubation, mechanical ventilation, and oxygen administration are indicated if necessary.
For hypotension or shock, plasma expanders should be administered. If blood pressure does not respond to volume expansion, vasopressor agents should be considered.
Symptomatic and supportive treatment should be provided in an intensive care unit, with continuous cardiac monitoring and careful correction of electrolyte imbalances.
Special recommendations. In case of arterial hypotension, intravenous dopamine or dobutamine is indicated; for cardiac arrhythmias, treatment should be individualized; for seizures – administration of benzodiazepines (e.g., diazepam) or other anticonvulsants such as phenobarbital (with caution due to increased risk of respiratory depression) or paraldehyde; in case of hyponatremia (water intoxication) – fluid restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution. These measures may help prevent cerebral edema.
Warning: diazepam or barbiturates may exacerbate respiratory depression (especially in children), hypotension, and lead to coma. Barbiturates should not be used if monoamine oxidase inhibitors have also been taken by the patient, either in overdose or during recent therapy (within 1 week).
Hemosorption using charcoal columns is recommended. Forced diuresis, hemodialysis, and peritoneal dialysis have been reported as ineffective. Dialysis is indicated only in severe poisoning associated with renal failure. Blood transfusion is indicated in severe poisoning in young children.
Recurrence of overdose symptoms on the 2nd and 3rd day after ingestion should be anticipated due to delayed absorption of the drug.
Adverse Reactions
Certain types of adverse reactions, such as those affecting the central nervous system (CNS) (dizziness, headache, ataxia, somnolence, general weakness, diplopia), gastrointestinal tract (nausea, vomiting), or allergic skin reactions, may occur at the beginning of treatment with Karbalex 300 mg retard and Karbalex 600 mg retard, particularly when too high an initial dose is administered or when treating elderly patients.
Dose-dependent adverse reactions usually resolve within a few days, either spontaneously or after a temporary reduction in dosage. CNS-related adverse reactions may result from relative overdose or significant fluctuations in plasma concentrations of the active substance. In such cases, monitoring of the active substance plasma levels is recommended.
List of adverse reactions
The following terms are used to assess the frequency of adverse reactions: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).
| MedDRA System Organ Classes |
Frequency |
Adverse Reactions |
| Infections and infestations |
Unknown |
Reactivation of human herpesvirus type 6 infection |
| Blood and lymphatic system disorders |
Very common |
Leukopenia1) |
| Common |
Thrombocytopenia, eosinophilia |
|
| Uncommon |
Leukocytosis, lymphadenopathy, folic acid deficiency |
|
| Rare |
Blood dyscrasias2), such as agranulocytosis, aplastic anemia, pancytopenia and other types of anemia (hemolytic, megaloblastic), non-regenerative anemia, reticulocytosis |
|
| Unknown |
Bone marrow suppression |
|
| Immune system disorders |
Uncommon |
Hypersensitivity reactions3) |
| Rare |
Acute allergic/anaphylactic reaction, angioedema |
|
| Unknown |
DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) |
|
| Endocrine disorders |
Common |
Edema, fluid retention, weight gain, hyponatremia4) |
| Rare |
Galactorrhea, gynecomastia |
|
| Unknown |
Decreased plasma concentrations of folic acid and vitamin B12, increased plasma homocysteine levels |
|
| Metabolism and nutrition disorders |
Rare |
Acute intermittent porphyria, variegate porphyria, late cutaneous porphyria |
| Unknown |
Hyperammonemia |
|
| Psychiatric disorders |
Uncommon |
Hallucinations (visual or auditory), depression, aggression, anorexia, agitation, confusion |
| Rare |
Activation of latent psychoses |
|
| Nervous system disorders |
Very common |
Dizziness, ataxia, somnolence |
| Common |
Headache |
|
| Uncommon |
Involuntary movements such as tremor, dystonia, muscle twitching, tics, nystagmus |
|
| Uncommon |
Movement disorders such as orofacial dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria, slurred speech), choreoathetosis, neuropathy, peripheral paresthesia and paresis |
|
| Rare |
Dysgeusia, neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia |
|
| Unknown |
Sedation, memory impairment, exacerbation of multiple sclerosis |
|
| Eye disorders |
Uncommon |
Transient visual disturbances such as accommodation disorders, diplopia, blurred vision |
| Rare |
Opacification of the lens, conjunctivitis, retinopathy, increased intraocular pressure |
|
| Ear and labyrinth disorders |
Rare |
Disorders of hearing such as tinnitus, hyperacusis, hypoacusis and altered sound perception |
| Cardiac disorders |
Uncommon |
Conduction disorders |
| Rare |
Bradycardia, arrhythmias, atrioventricular block5), heart failure, exacerbation of ischemic heart disease |
|
| Vascular disorders |
Uncommon |
Hypertension, hypotension |
| Rare |
Circulatory collapse, thromboembolism (e.g., pulmonary artery thromboembolism), thrombophlebitis |
|
| Respiratory, thoracic and mediastinal disorders |
Rare |
Lung hypersensitivity reactions6) |
| Gastrointestinal disorders |
Very common |
Nausea and vomiting |
| Common |
Loss of appetite, dry mouth |
|
| Uncommon |
Diarrhea, constipation |
|
| Uncommon |
Abdominal pain |
|
| Rare |
Stomatitis, gingivitis, glossitis, pancreatitis |
|
| Unknown |
Colitis |
|
| Hepatobiliary disorders |
Very common |
Elevated gamma-glutamyltransferase levels7) |
| Common |
Elevated alkaline phosphatase levels |
|
| Uncommon |
Elevated transaminase levels |
|
| Uncommon |
Hepatitis8), jaundice, vanishing bile duct syndrome |
|
| Rare |
Granulomatous hepatitis, liver failure |
|
| Skin and subcutaneous tissue disorders |
Very common |
Allergic dermatitis, urticaria9) |
| Uncommon |
Exfoliative dermatitis, erythroderma |
|
| Uncommon |
Systemic lupus erythematosus, pruritus |
|
| Rare |
Severe skin adverse reactions: Stevens-Johnson syndrome (SJS)10), toxic epidermal necrolysis (TEN, Lyell's syndrome), photosensitivity reaction, exudative polymorphic erythema, nodular erythema, pigment changes, purpura, acne, generalized hyperhidrosis, pustular eruption (AGEP), alopecia, hirsutism |
|
| Unknown |
Lichenoid keratosis, onychomadesis |
|
| Musculoskeletal and connective tissue disorders |
Uncommon |
Muscle weakness |
| Rare |
Disorders of bone metabolism, decreased plasma calcium and 25-hydroxycholecalciferol levels in blood11), arthralgia, myalgia, muscle spasms |
|
| Unknown |
Fractures |
|
| Renal and urinary disorders |
Rare |
Interstitial nephritis, renal failure (albuminuria, proteinuria, hematuria, oliguria and elevated blood urea nitrogen/azotemia), urinary disorders (dysuria, pollakiuria, urinary retention) |
| Reproductive system and breast disorders |
Rare |
Sexual dysfunction such as impotence, decreased libido, male fertility disorder, abnormal spermatogenesis (with reduced number and/or motility of spermatozoa) |
| General disorders and administration site conditions |
Very common |
Fatigue |
| Investigations |
Very common |
Elevated gamma-glutamyltransferase levels7) |
| Common |
Elevated alkaline phosphatase levels |
|
| Uncommon |
Elevated transaminase levels |
|
| Rare |
Hypogammaglobulinemia, elevated serum prolactin levels, thyroid-stimulating hormone level abnormalities, decreased plasma calcium and 25-hydroxycholecalciferol levels in blood, elevated cholesterol and triglyceride levels |
|
| Unknown |
Decreased bone density, decreased folic acid and vitamin B12 levels, elevated homocysteine levels |
|
| Injury |
Unknown |
Fall12) |
- According to published data, benign leukopenia is transient in approximately 10% of cases and persistent in 2% of cases.
- Sometimes life-threatening.
- Delayed hypersensitivity reactions affecting various organ systems, accompanied by fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, joint pain (arthralgia), leukopenia, eosinophilia, hepatosplenomegaly, or abnormal liver function tests, and ductopenia (intrahepatic bile ducts) in various combinations. Other organs may also be affected, such as the lungs, kidneys, pancreas, myocardium, and colon.
- Hyponatremia is associated with decreased blood osmolality due to an antidiuretic hormone (ADH)-like effect and, in rare cases, may lead to water intoxication, manifested by lethargy, vomiting, headache, confusion, and neurological disturbances.
- In rare cases associated with syncope and hypotension or hypertension.
- Accompanied by fever, dyspnea, pneumonitis, or pneumonia (alveolitis).
- Due to induction of hepatic enzymes—usually without clinical significance.
- Cholestatic, hepatocellular, or mixed type.
- Sometimes severe.
- Observed with "rare" frequency in some Asian countries (see section "Special Warnings and Precautions for Use").
- This may lead to osteomalacia/osteoporosis.
- Associated with ataxia, dizziness, somnolence, hypotonia, confusion, and sedation (see section "Special Warnings and Precautions for Use").
Shelf life. 5 years.
Storage conditions. Store in a dry, light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging. 10 tablets per blister, 10 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
G.L. Pharma GmbH.
Manufacturer's address and location of business operations.
Schlossplatz 1, 8502 Lannach, Austria.