Rifampicin and isoniazid tablets
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN and ISONIAZID Tablets
Composition:
Active substances: rifampicin, isoniazid;
One film-coated tablet contains rifampicin 150 mg, isoniazid 75 mg;
Excipients: microcrystalline cellulose, crospovidone, pregelatinized starch, ascorbic acid, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose (Methocel E5 LVP), hypromellose (Methocel E15 LVP), polyethylene glycol 4000, talc, titanium dioxide (E 171), iron oxide red (E 172), simethicone emulsion.
Medicinal form. Film-coated tablets.
Main physico-chemical properties: biconvex, capsule-shaped film-coated tablets of reddish-brown color, with a score on one side and smooth on the other.
Pharmacotherapeutic group.
Combined antituberculosis agents. ATC code J04AM02.
Pharmacological Properties
Pharmacodynamics
In vitro, rifampicin exerts bactericidal activity against a broad spectrum of microorganisms, including Mycobacterium tuberculosis. The mechanism of action of rifampicin involves inhibition of DNA-dependent RNA polymerase, thereby suppressing transcription. In tuberculosis, rifampicin acts bactericidally against both intracellular and extracellular microorganisms. Bacterial resistance may develop as a result of mutations in the target enzyme (RNA polymerase).
Isoniazid has high activity against Mycobacterium tuberculosis. It exerts bactericidal effects in vitro and in vivo against mycobacteria. Its mechanism of action is associated with inhibition of the synthesis of long-chain mycolic acids, which are components of the mycobacterial cell wall. Resistance to isoniazid develops rapidly when it is used as monotherapy for clinical diseases caused by mycobacteria.
Pharmacokinetics
Rifampicin
Absorption
Rifampicin is rapidly absorbed from the gastrointestinal tract. Its bioavailability is 90–95% in adults, but may be lower in children. Concomitant food intake delays absorption and reduces peak plasma concentration (Cmax), but does not reduce the overall bioavailability of rifampicin.
Following a single oral dose of 4 tablets of rifampicin/isoniazid 150 mg/75 mg, the mean (± SD) Cmax of rifampicin was 12232 ng/mL (± 3129), and the corresponding area under the plasma concentration-time curve (AUC) was 89786 ng*h/mL (± 22019). The mean (± SD) tmax of rifampicin was 3.60 (± 0.93) hours.
Distribution
Rifampicin is 60–90% bound to plasma proteins, with a volume of distribution of approximately 0.9 L/kg. The concentration of rifampicin in cerebrospinal fluid is similar to that of unbound rifampicin in plasma. Rifampicin readily crosses the placental barrier.
Metabolism
Rifampicin undergoes hydrolysis and deacetylation to form several metabolites, including the active metabolite deacetyl-rifampicin. Rifampicin induces its own metabolism; following repeated dosing, bioavailability decreases to approximately 70%, and systemic clearance increases.
Elimination
The elimination half-life of rifampicin after a single dose is approximately 3 hours. After repeated doses, this value decreases to about 1–2 hours. Rifampicin and its metabolites are primarily excreted via bile, and rifampicin undergoes enterohepatic recirculation. Approximately 25% of the dose is excreted in urine.
Special Patient Populations
Prolonged elimination half-life of rifampicin has been reported in patients with impaired hepatic function or biliary obstruction.
Isoniazid
Absorption
After oral administration, isoniazid is rapidly absorbed, with bioavailability ≥ 80%, and peak plasma concentrations (Cmax) are reached within 1–2 hours. The rate and extent of absorption are reduced when isoniazid is administered with food. Isoniazid undergoes significant presystemic (first-pass) metabolism in the intestinal wall and liver.
Following a single dose of 4 tablets of rifampicin/isoniazid 150 mg/75 mg, the mean (± SD) Cmax of isoniazid was 4649 ng/mL (± 1713), and the corresponding AUC was 14547 ng*h/mL (± 7408). The mean (± SD) tmax of isoniazid was 0.68 ± 0.55 hours.
Distribution
Isoniazid is distributed throughout the body with a volume of distribution ranging from 0.57 L/kg to 0.76 L/kg. Plasma protein binding is very low (0–10%).
Metabolism
Isoniazid undergoes extensive metabolism in the mucosal cells of the small intestine and in the liver. It is primarily inactivated by acetylation. Acetylated isoniazid (acetylisoniazid) is subsequently hydrolyzed. Acetylation of isoniazid depends on genetically determined metabolic phenotypes known as fast or slow acetylators, which is related to genetic polymorphism in the metabolic enzyme N-acetyltransferase. Different ethnic groups have varying proportions of acetylator phenotypes. Acetylator status is a key determinant of the efficacy of a given dose of isoniazid.
Drug exposure in fast acetylators is approximately half that in slow acetylators when the same dose of isoniazid is administered.
Elimination
Up to 95% of isoniazid is excreted in urine within 24 hours, primarily as inactive metabolites. Less than 10% of the dose is excreted in feces. The main urinary metabolites are N-acetylisoniazid and isonicotinic acid.
Pharmacokinetics in Renal Impairment
Information on the pharmacokinetics of isoniazid and its metabolites in patients with renal impairment is limited. In slow acetylators, the elimination half-life of isoniazid is prolonged and drug exposure is increased. Exposure to (inactive) metabolites of isoniazid is likely increased in both fast and slow acetylators.
Clinical characteristics.
Indications.
Treatment of pulmonary and extrapulmonary tuberculosis in the intensive (initial) and continuation (maintenance) phases of therapy.
Contraindications.
The use of the drug is contraindicated:
- in patients with hypersensitivity to rifampicin, isoniazid, or any of the excipients of the drug;
- in hepatic insufficiency;
- in patients with porphyria;
- during surgical procedures involving general anesthesia;
- when used concomitantly with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir/elbasvir; protease inhibitors boosted with ritonavir; isavuconazole; ledipasvir; lurasidone; midostaurin; ombitasvir/paritaprevir; praziquantel; rilpivirine; sofosbuvir; velpatasvir; voriconazole; voxilaprevir (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions.
Antimicrobial agents and INR (International Normalized Ratio – standard for prothrombin time index determination)
Numerous cases of increased vitamin K antagonist activity have been reported in patients receiving antibacterial agents. Risk factors include severe infectious or inflammatory diseases, age, and the patient's general condition. Under these conditions, it is difficult to distinguish between the infectious pathology and its treatment when an INR imbalance occurs.
Concomitant use of rifampicin with other antibiotics causing vitamin K-dependent coagulopathy, such as cefazolin (or other cephalosporins with an N-methylthiotetrazole side chain), should be avoided, as this may lead to serious coagulation disorders that could be fatal (especially at high doses). If concomitant use is necessary, intensified INR monitoring is recommended.
Enzyme induction
Rifampicin is a potent inducer of metabolic enzymes, including cytochrome P450 (CYP450) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, and UDP-glucuronosyltransferases (UGT). In vitro and in vivo studies have shown that rifampicin also induces transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2). Many medicinal products are substrates for at least one or more of these enzymes and/or transporters. Rifampicin may accelerate the metabolism and thus reduce the activity of certain co-administered drugs, or increase the activity of prodrugs requiring metabolic activation. Therefore, clinically significant interactions with numerous drugs from various classes are likely. Dose adjustments of these drugs may be required at the start or discontinuation of their administration, considering that the inductive effect reaches its maximum after approximately 15 days and persists for 1–2 weeks after stopping rifampicin.
Contraindicated combinations (see section "Contraindications")
Interactions related to rifampicin:
Bictegravir
Very significant reduction in bictegravir concentration, which may lead to loss of efficacy.
Cobicistat
Risk of reduced efficacy of cobicistat due to enhanced metabolism by rifampicin.
Daclatasvir
Reduction in daclatasvir plasma concentration due to enhanced hepatic metabolism by rifampicin.
Dasabuvir
Risk of reduced dasabuvir plasma concentration due to rifampicin.
Delamanid
Reduction in delamanid plasma concentration due to enhanced hepatic metabolism by rifampicin.
Protease inhibitors boosted with ritonavir (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir)
Very significant reduction in protease inhibitor plasma concentration due to enhanced hepatic metabolism by rifampicin.
For the combination (saquinavir + ritonavir): risk of severe hepatocellular toxicity.
Grazoprevir/elbasvir
Risk of reduced plasma concentrations of grazoprevir and elbasvir under the influence of rifampicin, potentially affecting their efficacy.
Isavuconazole
Reduction in isavuconazole plasma concentration due to enhanced hepatic metabolism by rifampicin.
Ledipasvir
Significant reduction in ledipasvir plasma concentration due to enhanced hepatic metabolism by rifampicin.
Lurasidone
Reduction in lurasidone plasma concentration due to enhanced hepatic metabolism by rifampicin.
Midostaurin
Reduction in midostaurin concentration under the influence of rifampicin.
Ombitasvir/paritaprevir
Reduction in plasma concentration during dual therapy due to enhanced hepatic metabolism by rifampicin.
Praziquantel
Very significant reduction in praziquantel plasma concentration, with risk of treatment inefficacy due to enhanced hepatic metabolism by rifampicin.
Rilpivirine
Significant reduction in rilpivirine plasma concentration due to enhanced hepatic metabolism by rifampicin.
Sofosbuvir
Risk of reduced sofosbuvir plasma concentration due to reduced intestinal absorption caused by rifampicin.
Velpatasvir
Reduction in velpatasvir plasma concentration under the influence of rifampicin, potentially affecting efficacy.
Voriconazole
Significant reduction in voriconazole plasma concentration, with risk of loss of efficacy due to enhanced hepatic metabolism by rifampicin.
Voxilaprevir
Reduction in voxilaprevir plasma concentrations under the influence of rifampicin, with risk of loss of efficacy.
Not recommended combinations (see section "Special precautions for use")
Interactions related to isoniazid:
Carbamazepine
Increased plasma concentration of carbamazepine with signs of overdose due to inhibition of its hepatic metabolism.
Disulfiram
Behavioral and coordination disturbances.
Interactions related to rifampicin:
Abiraterone
Significant reduction in abiraterone plasma concentration, with risk of reduced efficacy.
Apixaban, dabigatran, rivaroxaban
Reduction in plasma concentrations of apixaban, dabigatran, or rivaroxaban under the influence of rifampicin, with risk of reduced therapeutic effect.
Apripritant
Very significant reduction in aprapitant concentration.
Apremilast
Reduction in apremilast plasma concentration due to enhanced metabolism by rifampicin.
Atorvastatin, simvastatin
Very significant reduction in atorvastatin or simvastatin plasma concentration due to enhanced hepatic metabolism by rifampicin.
Atovaquone
Reduction in atovaquone plasma concentration by the enzyme inducer.
Bedaquiline
Reduction in bedaquiline plasma concentration due to enhanced metabolism by rifampicin.
- Bosentan*
Risk of reduced bosentan plasma concentration, significant for rifampicin.
Clopidogrel
Strong induction of CYP2C19, leading to both increased plasma concentration of the active metabolite of clopidogrel and enhanced platelet inhibition, which may particularly increase the risk of bleeding. As a precaution, concomitant use of clopidogrel and rifampicin is not recommended.
Cyclophosphamide
Risk of increased plasma concentrations of the active metabolite of cyclophosphamide under the influence of rifampicin, and thus increased toxicity.
Cyproterone used as a hormonal contraceptive
Risk of reduced efficacy of cyproterone. An additional barrier method of contraception (condom) should be used throughout the duration of combination therapy and for one cycle after discontinuation of rifampicin.
Docetaxel
Reduction in concentration of the cytotoxic drug due to enhanced metabolism by rifampicin, with risk of reduced efficacy.
Dolutegravir in integrase inhibitor class resistance
Reduction in dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Dronedarone
Significant reduction in dronedarone concentration due to enhanced metabolism without significant change in the active metabolite.
Estrogen and progestin contraceptives
Reduced contraceptive efficacy due to enhanced hepatic metabolism of the hormonal contraceptive by rifampicin. An additional barrier method of contraception (condom) should be used throughout the period of concomitant use and for one menstrual cycle after discontinuation of rifampicin.
Etoposide
Reduction in etoposide plasma concentration by rifampicin. If combination is necessary, clinical monitoring and possible dose adjustment of etoposide are required during concomitant use and 1–2 weeks after discontinuation of rifampicin.
Fentanyl
Reduction in fentanyl plasma concentration due to enhanced hepatic metabolism by rifampicin. During rifampicin use, another opioid should be preferred.
Fluconazole
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to the azole antifungal agent).
Idelalisib
Reduction in idelalisib plasma concentration due to enhanced hepatic metabolism by rifampicin.
5-alpha-reductase inhibitors (dutasteride, finasteride)
Reduction in plasma concentrations of 5-alpha-reductase inhibitors under the influence of rifampicin. If combination cannot be avoided, careful clinical monitoring is required.
Metabolized tyrosine kinase inhibitors
Reduction in plasma concentration and efficacy of tyrosine kinase inhibitor due to enhanced metabolism by rifampicin.
Ir inotecan
Likely reduction in plasma concentrations of the active metabolite of irinotecan, with risk of inefficacy of cytotoxic therapy.
- Itraconazole*
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to the azole antifungal agent).
- Ivacaftor*
Significant reduction in ivacaftor plasma concentration with risk of loss of efficacy.
- Ketoconazole*
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to the azole antifungal agent).
- Macitentan*
Reduction in macitentan plasma concentration due to enhanced metabolism by rifampicin.
- Mianserin*
Risk of loss of mianserin efficacy.
- Midazolam*
Risk of lack of midazolam effect due to very significant reduction in its plasma concentration due to enhanced hepatic metabolism.
- Naloxegol*
Reduction in naloxegol concentration under the influence of rifampicin.
- Nevirapine*
Reduction in nevirapine plasma concentration due to enhanced hepatic metabolism by rifampicin.
- Nimodipine*
Reduction in calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical monitoring of the patient and possible dose adjustment of the calcium antagonist during and after rifampicin treatment are required.
- Olaparib*
Reduction, possibly very significant, in olaparib plasma concentration due to enhanced hepatic metabolism by rifampicin.
- Oxycodone*
Reduction in oxycodone plasma concentration due to enhanced metabolism by rifampicin. Dose adjustment of oxycodone may be possible.
- Paclitaxel*
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin, with risk of reduced efficacy.
- Posaconazole*
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to the azole antifungal agent).
- Quetiapine*
Very significant reduction in quetiapine plasma concentration due to enhanced hepatic metabolism by the inducer, with risk of inefficacy.
- Quinine*
Risk of loss of quinine efficacy due to enhanced hepatic metabolism by rifampicin.
- Raltegravir*
Reduction in raltegravir concentration under the influence of rifampicin. If combination cannot be avoided, doubling the raltegravir dose may be considered.
- Ranolazine*
Very significant reduction in ranolazine concentration.
- Regorafenib*
Reduction in regorafenib plasma concentration due to enhanced metabolism by rifampicin.
- Rolapitant*
Very significant reduction in rolapitant concentration with risk of loss of efficacy.
- Sertraline*
Risk of inefficacy of antidepressant treatment.
- Tenofovir alafenamide*
Reduction in tenofovir alafenamide plasma concentration due to reduced absorption by rifampicin. Clinical monitoring is required during combination therapy and 1–2 weeks after discontinuation of rifampicin.
- Telithromycin*
Very significant reduction in telithromycin plasma concentration with risk of inefficacy of antimicrobial treatment due to enhanced hepatic metabolism by rifampicin.
- Ticagrelor*
Significant reduction in ticagrelor plasma concentration due to enhanced hepatic metabolism by rifampicin, with risk of reduced therapeutic effect.
- Ulipristal*
Risk of reduced ulipristal effect due to enhanced hepatic metabolism by rifampicin. An alternative drug not affected or minimally affected by rifampicin should be preferred.
- Vemurafenib*
Risk of reduced vemurafenib plasma concentration with reduced efficacy.
- Vinca alkaloids cytotoxics*
Rifampicin reduces plasma concentrations of vinca alkaloids, potentially affecting efficacy.
- Vismodegib*
Risk of reduced vismodegib plasma concentration due to enhanced hepatic metabolism by rifampicin.
- Zidovudine*
Reduction in zidovudine plasma concentration by half due to enhanced metabolism by rifampicin. If combination use cannot be avoided, intensified clinical and biological monitoring is required.
Combinations requiring precautions
Interactions related to isoniazid:
Halogenated volatile anesthetics
Potentiation of hepatotoxic effects of isoniazid with enhanced formation of toxic isoniazid metabolites. In case of planned surgery, as a precaution, isoniazid treatment should be discontinued one week before surgery and resumed only 15 days later.
Glucocorticoids (except hydrocortisone in replacement therapy)
When used concomitantly with prednisolone, reduced isoniazid plasma concentration has been observed. This effect is due to increased hepatic metabolism of isoniazid and reduced glucocorticoid levels. Clinical and biological monitoring is required.
Ketoconazole
Reduction in ketoconazole plasma concentration.
It is recommended to separate the doses of both antimicrobial agents by at least 12 hours. Plasma concentration of ketoconazole should be monitored and the dose adjusted if necessary.
Phenytoin and fosphenytoin
When used concomitantly with isoniazid, phenytoin overdose (reduced metabolism) has been observed. Careful clinical monitoring, determination of phenytoin plasma concentration, and possible dose adjustment during and after isoniazid treatment are required.
Pyrazinamide
When used concomitantly, hepatotoxic effects may be enhanced. Clinical and biological monitoring is required.
Rifampicin
Enhanced hepatotoxic effect of isoniazid (enhanced formation of toxic isoniazid metabolites – see sections "Special precautions for use" and "Adverse reactions"). Clinical and biological monitoring of this combination is required. In case of hepatitis, isoniazid should be discontinued.
Stavudine
Increased risk of peripheral neuropathy due to additive side effects. Regular clinical and biological monitoring, especially at the beginning of treatment, is required.
Interactions related to rifampicin:
Valproic acid and valpromide
Risk of seizures due to enhanced hepatic metabolism of valproate by rifampicin. Clinical and biological monitoring and possible dose adjustment of the anticonvulsant during and after rifampicin treatment are required.
Afatinib
Reduction in afatinib plasma concentration due to enhanced metabolism by rifampicin. Clinical monitoring during combination therapy and 1–2 weeks after its discontinuation is required.
Albendazole
Significant reduction in albendazole and its active metabolite plasma concentrations under the influence of rifampicin, with risk of reduced efficacy. Clinical monitoring of therapeutic response and possible dose adjustment of albendazole during and after rifampicin treatment are required.
Androgens (androstanolone, norethandrolone, testosterone)
Risk of reduced androgen plasma concentration and thus efficacy due to enhanced hepatic metabolism by rifampicin. Clinical and biological monitoring during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Calcium channel antagonists (except nimodipine)
Reduction in calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical observation and possible dose adjustment of the calcium antagonist during and after rifampicin treatment are required.
Class IA antiarrhythmics (disopyramide, hydroquinidine, quinidine)
Reduction in plasma concentration and efficacy of the antiarrhythmic agent (enhanced hepatic metabolism).
Clinical monitoring, ECG, and possibly monitoring of antiarrhythmic plasma concentration are required. Doses of the antiarrhythmic agent should be adjusted during and after rifampicin treatment (due to risk of antiarrhythmic overdose).
Vitamin K antagonists (warfarin, acenocoumarol, fluindione)
Reduced effect of vitamin K antagonist due to enhanced hepatic metabolism by rifampicin. More frequent INR monitoring is required. Dose adjustment of the vitamin K antagonist may be necessary during rifampicin treatment and 8 days after its discontinuation.
Aripiprazole
Reduction in aripiprazole plasma concentration. Clinical observation and possible dose adjustment of aripiprazole during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Bazedoxifene
Reduction in bazedoxifene plasma concentrations under the influence of rifampicin. Monitoring for any signs indicating loss of efficacy (bleeding) is required.
Buspirone
Reduction in buspirone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of buspirone during and after rifampicin treatment are required.
Carbamazepine
Reduction in plasma concentration and efficacy of carbamazepine due to enhanced hepatic metabolism by rifampicin. Clinical monitoring, plasma concentration control, and dose adjustment of carbamazepine during and after rifampicin treatment are required.
Carvedilol
Significant reduction in carvedilol plasma concentration due to enhanced hepatic metabolism by rifampicin. Regular clinical monitoring and dose adjustment of carvedilol during rifampicin treatment are required. After discontinuation of rifampicin, there is a risk of significant increase in carvedilol plasma concentration, requiring dose reduction and careful clinical observation.
Caspo fungin
Reduction in caspofungin plasma concentration. During rifampicin treatment from day 2, maintain a dose of 70 mg daily.
Clarithromycin
Reduction in clarithromycin plasma concentration and risk of reduced efficacy, especially in HIV-infected patients, due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring is required.
Clozapine
Risk of inefficacy of antipsychotic therapy (reduced clozapine plasma concentration due to enhanced hepatic metabolism). Clinical monitoring and possible increase in clozapine dose during rifampicin treatment are required.
Cyproterone used as antiandrogen
Risk of reduced efficacy of cyproterone. Clinical monitoring and possible dose adjustment of cyproterone during and after combination therapy are required.
Dapsone
Increased effect of the hydroxylamine metabolite, responsible for side effects including methemoglobinemia, hemolytic anemia, agranulocytosis, and hemolysis.
Deferasirox
Risk of reduced deferasirox plasma concentration. Serum ferritin should be monitored during and after rifampicin treatment. Dose adjustment of deferasirox is recommended if necessary.
Digoxin
Moderate reduction in digoxin concentration. Clinical monitoring and ECG are required.
Disopyramide
Risk of reduced disopyramide concentration by rifampicin. Clinical monitoring and possible dose adjustment of disopyramide during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Dolutegravir, in absence of integrase inhibitor class resistance
Adjustment of dolutegravir dose to 50 mg twice daily during combination therapy and one week after its discontinuation.
Reduction in dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Efavirenz
Reduction in plasma concentration and efficacy of efavirenz due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring, especially at the beginning of combination therapy, is required.
Enalapril
Reduced effect of enalapril active metabolites. If required by the patient's clinical condition, dose adjustment may be necessary.
Glucocorticoids
Reduction in plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in patients with Addison's disease treated with hydrocortisone and in transplantation cases. Clinical and biological monitoring and dose adjustment of corticosteroids during and after rifampicin treatment are required.
There is a risk of reduced efficacy of hydrocortisone due to enhanced metabolism; consequences are serious if hydrocortisone is used as replacement therapy or in transplantation. Clinical and biological monitoring and dose adjustment of hydrocortisone during combination therapy and after discontinuation of rifampicin are required.
Haloperidol
Risk of reduced haloperidol plasma concentration and therapeutic efficacy due to enhanced hepatic metabolism by rifampicin. Clinical observation and, if necessary, dose adjustment during and after rifampicin treatment are required.
Thyroid hormones (described for phenytoin, rifampicin, carbamazepine)
Risk of clinical hypothyroidism in hypothyroid patients due to enhanced metabolism of T3 and T4 hormones. Monitoring of serum T3 and T4 concentrations and, if necessary, dose adjustment of thyroid hormones during and after rifampicin treatment are required.
Immunosuppressants
Reduction in blood concentration and efficacy of immunosuppressants due to enhanced hepatic metabolism by rifampicin. Dose increase of the immunosuppressant under blood concentration control is recommended, and dose reduction after discontinuation of rifampicin is required.
Isoniazid
Increased hepatotoxicity of isoniazid (enhanced formation of toxic isoniazid metabolites). Clinical and biological monitoring of this combination is required. In case of hepatitis, isoniazid should be discontinued.
Ivabradine
Risk of reduced ivabradine efficacy due to enhanced metabolism by rifampicin. Clinical monitoring and dose adjustment of ivabradine during combination therapy and after discontinuation of rifampicin are required.
Levonorgestrel
When levonorgestrel is used for emergency contraception, significant reduction in levonorgestrel plasma concentration with risk of loss of efficacy is observed. If the enzyme-inducing agent was used within the last 4 weeks, consider using non-hormonal emergency contraception (copper intrauterine device (IUD)). If IUD use is not possible, double the dose of levonorgestrel should be administered.
Linezolid
Risk of reduced linezolid efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible increase in linezolid dose during rifampicin treatment are required.
Maraviroc
In the absence of concomitant use with a potent CYP3A4 inhibitor, reduced maraviroc concentration under the influence of rifampicin is observed. In such cases, maraviroc dose should be increased to 600 mg twice daily.
Metadone
Reduction in methadone plasma concentration with risk of withdrawal syndrome due to enhanced hepatic metabolism. Increase the frequency of methadone administration (2–3 times daily instead of once).
Metronidazole
Reduction in metronidazole plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of metronidazole during and after rifampicin treatment are required.
Mineralocorticoids
Reduction in plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in patients with Addison's disease treated with hydrocortisone and in transplantation cases.
Clinical and biological monitoring and dose adjustment of corticosteroids during and after rifampicin treatment are required.
Montelukast
Risk of reduced montelukast efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of anti-asthmatic agents during and after rifampicin treatment are required.
Morphine
Reduction in plasma concentration and efficacy of morphine and its active metabolite. Clinical monitoring and possible dose adjustment of morphine during and after rifampicin treatment are required.
Nintedanib
Reduction in nintedanib plasma concentration due to reduced absorption by rifampicin. Clinical monitoring during combination use is required.
Paracetamol
Concomitant use of paracetamol and rifampicin may increase the risk of hepatotoxicity.
Pioglitazone
Reduction in glitazone plasma concentration due to enhanced metabolism by rifampicin. Clinical and biological monitoring and dose adjustment of glitazone during and after rifampicin treatment are required.
Non-contraceptive progestins (with or without estrogen)
Reduced efficacy of progestin. Clinical monitoring and possible dose adjustment of hormonal therapy during and after inducer use are required.
Propafenone
Reduction in propafenone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and ECG. Dose adjustment of propafenone during combination therapy and after discontinuation of rifampicin may be necessary.
Terbinafine
Reduction in terbinafine plasma concentration and efficacy due to enhanced hepatic metabolism by rifampicin.
Clinical monitoring is required. Dose adjustment of terbinafine during rifampicin treatment is recommended if necessary.
Theophylline and aminophylline
Reduction in plasma concentration and efficacy of theophylline (enhanced metabolism due to enzyme induction).
Clinical observation is recommended. Dose adjustment of theophylline during and after rifampicin treatment may be necessary.
Tiagabine
Reduction in tiagabine plasma concentration due to enhanced hepatic metabolism. Increase in tiagabine dose may be required when combined with rifampicin.
Vitamin D
Reduction in vitamin D concentration has been observed during rifampicin treatment. Dose adjustment of vitamin D may be necessary.
Zolpidem
Reduction in zolpidem plasma concentration and efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, another hypnotic medicinal product should be used.
Zopiclone
Reduction in zopiclone plasma concentration and efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, another hypnotic medicinal product should be used.
Interactions requiring consideration
Interactions related to rifampicin
Bortezomib
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin, with risk of reduced efficacy.
- Cabazitaxel*
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin, with risk of reduced efficacy.
- Exemestane*
Risk of reduced exemestane efficacy due to enhanced hepatic metabolism by rifampicin.
- Metformin*
Reduction in metformin concentration under the influence of rifampicin.
- Metoprolol, propranolol*
Reduction in plasma concentration and efficacy of beta-blockers (enhanced hepatic metabolism).
- Perampanel*
Significant reduction (up to two-thirds) in perampanel concentration.
- Tamoxifen*
Risk of tamoxifen inefficacy due to enhanced metabolism by rifampicin.
Special precautions for use.
The use of rifampicin and isoniazid may cause liver function impairment.
Isoniazid may cause seizures in cases of overdose (in slow acetylators) or in patients predisposed to seizures. Patients should be carefully monitored and anticonvulsant therapy should be administered if necessary.
Isoniazid may increase blood phenytoin levels and cause signs of toxicity, including nystagmus, ataxia, and confusion (see section "Interaction with other medicinal products and other forms of interaction").
Hepatitis, sometimes severe and fatal, may occur during treatment or even several months after completion of isoniazid therapy. The risk of developing hepatitis depends on the patient's age.
Treatment should be discontinued immediately if signs or symptoms of liver injury occur, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. Continuing treatment may lead to severe liver damage. Careful monitoring is required when administering isoniazid to patients with chronic liver disease or severe renal insufficiency.
Cases of moderate to severe cholestasis have been reported during treatment with rifampicin. Patients should seek immediate medical attention if they experience symptoms such as pruritus, loss of appetite, nausea, vomiting, abdominal pain, jaundice, dark urine, or yellowing of the eyes or skin. If cholestasis is confirmed, the drug should be discontinued.
Serious bullous reactions: Cases of serious bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), sometimes fatal, have been reported during anti-tuberculosis therapy (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of skin reactions and closely monitored. Patients should be advised to seek immediate medical attention if symptoms suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur (progressive rash, often accompanied by blistering and mucosal lesions). The medicinal product should be permanently discontinued if the cause of such manifestations cannot be established.
Severe systemic hypersensitivity reactions, including fatal cases, such as drug reaction with eosinophilia and systemic symptoms (DRESS), have been observed during anti-tuberculosis therapy (see section "Adverse reactions").
It is important to note that early signs of hypersensitivity may occur, such as fever, lymphadenopathy, or laboratory abnormalities (including eosinophilia and liver function abnormalities), even in the absence of skin rash.
If such signs or symptoms occur, patients should be instructed to seek immediate medical advice.
The medicinal product should be discontinued if the cause of the signs and symptoms cannot be determined.
The drug is generally not used in combination with abiraterone, apixaban, atovaquone, apremilast, aprepitant, atorvastatin, bedaquiline, bosentan, certain anticoagulants such as clopidogrel (for vitamin K antagonists, see section "Interaction with other medicinal products and other forms of interaction"), carbamazepine, cyclophosphamide, cyproterone (used as a hormonal contraceptive), dabigatran, disulfiram, docetaxel, dolutegravir (only in cases of integrase inhibitor resistance), dronedarone, etoposide, fentanyl, fluconazole, idelalisib, dutasteride, finasteride, tyrosine kinase inhibitors metabolized by CYP3A4, irinotecan, itraconazole, ivacaftor, ketoconazole, macitentan, mianserin, midazolam, naloxegol, nevirapine, nimodipine, olaparib, oxycodone, paclitaxel, posaconazole, quetiapine, quinine, raltegravir, ranolazine, regorafenib, rivaroxaban, teicoplanin, apitant, ticagrelor, telithromycin, ulipristal, combined hormonal and progestin-only contraceptives, vemurafenib, vinca alkaloid cytotoxics, vismodegib, and zidovudine (see section "Interaction with other medicinal products and other forms of interaction").
Paradoxical reaction
After initial improvement in tuberculosis, symptoms may worsen again. In these patients, clinical or radiological deterioration of existing tuberculosis lesions or development of new lesions has been observed. These reactions typically occur within the first weeks or months of anti-tuberculosis treatment. Cultures are usually negative, and such reactions generally do not indicate treatment failure.
The cause of this paradoxical reaction is not fully understood, but it is likely due to an exaggerated immune response. If a paradoxical reaction is suspected, symptomatic treatment to suppress the excessive immune response should be initiated if necessary. In addition, continuation of standard anti-tuberculosis therapy is recommended.
Patients should seek immediate medical attention if their symptoms worsen. Symptoms are typically related to the affected tissues. Possible general symptoms include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness (see section "Adverse reactions").
Interstitial lung disease (ILD)/pneumonitis
Cases of interstitial lung disease (ILD) or pneumonitis have been reported in patients receiving this medicinal product for tuberculosis treatment. ILD/pneumonitis are life-threatening conditions. A thorough evaluation should be performed in all patients presenting with sudden onset and/or unexplained worsening of pulmonary symptoms (dyspnea with dry cough) and fever to confirm the diagnosis. If ILD/pneumonitis is diagnosed, the drug should be permanently discontinued in cases of severe manifestations (respiratory failure or acute respiratory distress syndrome), and appropriate treatment should be initiated if necessary.
Rifampicin is a potent inducer of drug-metabolizing enzymes and transporters. This may reduce or increase the effects of concomitantly administered drugs, thereby affecting their efficacy and safety (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, patients should not take any other medicinal products without prior consultation with a physician.
Hepatic impairment
The drug should be prescribed to patients with hepatic impairment only when absolutely necessary, with caution, and under close medical supervision.
Regular clinical and biological monitoring is required due to the risk of increased hepatotoxicity with the combination of isoniazid and rifampicin:
- Complete blood count (including platelet count), e.g., on day 8, at the end of month 1, then at longer intervals (once every 2 months),
- Liver function monitoring (transaminases, bilirubin).
Treatment should be discontinued if signs of hepatocellular injury (hepatitis) occur.
Since isoniazid-associated hepatitis occurs more frequently in patients aged 35 years and older, this patient group should have transaminase levels measured at the start of treatment and at least once monthly during therapy.
Other factors that increase the risk of hepatitis include daily alcohol consumption, chronic liver disease, intravenous drug use, and African or Latin American ethnicity in women.
In some cases, hyperbilirubinemia may occur within the first days of treatment due to competition at the cellular level between rifampicin and bilirubin for hepatic excretion. Isolated and mild hyperbilirubinemia is not in itself an indication to discontinue treatment; the decision to discontinue should be based on repeat testing, observed trends, and the patient's clinical status (see section "Adverse reactions").
Discoloration of teeth, urine, sweat, sputum, and tears
Rifampicin may cause yellow, orange, red, or brown discoloration of teeth, urine, sweat, sputum, and tears, which should be explained to the patient. Rifampicin may permanently stain contact lenses.
Peripheral neuropathy
To prevent peripheral neuropathy, regular neurological examinations should be performed, and particular caution should be exercised when prescribing the drug to patients who abuse alcohol.
Pyridoxine (vitamin B6) supplementation prevents or resolves rare cases of drug-induced neuropathy, especially in elderly patients or those with poor nutrition.
Coagulation disorders (see section "Adverse reactions")
Cases of coagulation disorders have been reported during rifampicin use, particularly in combination with cephalosporins (including cefazolin). Appropriate monitoring is required in high-risk patients (those with risk factors leading to vitamin K deficiency or affecting other coagulation mechanisms). Vitamin K supplementation (e.g., in cases of established vitamin K deficiency or hypoprothrombinemia) should be considered if necessary.
Intermittent therapy
Hypersensitivity reactions are frequently, if not exclusively, associated with intermittent (intermittent) administration or repeated discontinuation of rifampicin (see section "Adverse reactions").
Effect on adrenal function
Drug administration may unmask latent adrenal insufficiency controlled by corticosteroid therapy (see section "Adverse reactions"). Therefore, such patients should be monitored, and adrenal cortical function should be assessed at the first sign of doubt.
Effect on laboratory test results
Rifampicin may delay the biliary excretion of contrast agents used in radiographic imaging of the gallbladder.
Microbiological methods for determining plasma concentrations of folic acid and vitamin B12 should not be used during rifampicin therapy.
Rifampicin temporarily competes with bilirubin and bromsulphthalein (BSP). To avoid false-positive results, the BSP test should be performed in the morning before taking rifampicin.
Due to reported cross-reactions causing false-positive urine opiate tests in patients taking rifampicin, particularly with the KIMS (kinetic interaction of microparticles in solution) method, confirmation of results using methods such as gas chromatography/mass spectrometry is recommended.
Use during pregnancy or breastfeeding.
Pregnancy
Rifampicin
Animal studies have shown teratogenic effects in rats and mice at high doses.
Clinical experience with rifampicin use during a limited number of pregnancies has not revealed any specific developmental abnormalities or fetotoxic effects. Although rifampicin crosses the placental barrier and is found in umbilical cord blood, further studies are needed to assess the consequences of exposure during pregnancy. Therefore, rifampicin should be used during pregnancy only if no therapeutic alternative exists.
Isoniazid
Animal studies have not shown teratogenic effects of isoniazid. In the absence of teratogenic effects in animals, a malformative effect in humans is not expected. Substances known to cause developmental abnormalities in humans have shown teratogenic effects in animals in well-conducted studies on two species. Clinical experience with isoniazid use in a limited number of pregnant women has not revealed any specific developmental abnormalities or fetotoxic effects. However, additional studies are needed to assess the consequences of exposure during pregnancy.
Therefore, use of this combination during pregnancy should be considered only when necessary, bearing in mind that effective treatment of active tuberculosis should continue as prescribed during pregnancy. Concomitant administration with pyridoxine is recommended due to the effects of isoniazid.
Use near the end of pregnancy may lead to early bleeding in both mother and newborn. Rifampicin use increases the risk of bleeding. Prophylactic administration of vitamin K1 to the mother during the month preceding delivery and appropriate administration to the newborn after birth are effective. Concomitant use with pyridoxine is recommended.
Lactation
Rifampicin and isoniazid pass into breast milk.
Isoniazid is poorly protein-bound, and its passage into breast milk has been demonstrated, with concentrations equivalent to those in maternal plasma. Due to the potential risk of acetylation defects in the newborn and considering the neurotoxic and hepatotoxic potential of isoniazid, breastfeeding is not recommended.
Fertility
There are no data on the effect of the drug on human fertility.
Ability to affect reaction speed when driving or operating machinery.
Adverse reactions associated with isoniazid use include dizziness, visual disturbances, and psychotic reactions (see section "Adverse reactions"). Patients should be informed of this and advised not to drive, operate machinery, or engage in any activity where these symptoms could endanger themselves or others.
Method of Administration and Dosage
The medicinal product is intended for oral administration.
Adult patients should be given a single daily dose, preferably on an empty stomach, at least 30 minutes before a meal or 2 hours after a meal:
- for patients with body weight less than 50 kg — 3 tablets per day;
- for patients with body weight 50 kg and above — 4 tablets per day.
Renal Impairment
Since dose adjustment may be required for patients with impaired renal function (creatinine clearance ≤ 50 mL/min), it is recommended to use separate formulations of ethambutol and isoniazid.
Hepatic Impairment
Limited data indicate that the pharmacokinetics of isoniazid and rifampicin are altered in patients with hepatic impairment. Therefore, patients with hepatic dysfunction should be closely monitored for signs of toxicity. The medicinal product must not be administered to patients with hepatic insufficiency (see section "Contraindications").
Elderly Patients
No specific dosage regimen is required; however, the presence of hepatic or renal insufficiency should be taken into account. Additional administration of pyridoxine (vitamin B6) may be necessary.
Interruption of Treatment
If treatment with the medicinal product has been interrupted for any reason, including non-adherence to the regimen, the medicinal product must not be used to resume therapy. To resume treatment, ethambutol, isoniazid, pyrazinamide, and rifampicin should be administered separately, as rifampicin must be reintroduced at a lower dose. Refer to official guidelines on resuming antituberculosis therapy.
Children
The medicinal product is not administered to children. Alternative medicinal products with appropriate dosing should be used for this patient group.
Overdose
Symptoms. Cases of overdose have been reported in adults following ingestion of 9 g of rifampicin, and fatal overdoses after ingestion of 14 g of rifampicin.
Symptoms are primarily associated with isoniazid overdose, for which the lethal dose is 200 mg/kg.
Signs and symptoms of overdose typically appear within 30 minutes to 3 hours after ingestion and include nausea, vomiting, dizziness, visual disturbances, hallucinations, skin and urine reddening (due to rifampicin content), hyperbilirubinemia, hepatomegaly, and moderate increases in alkaline phosphatase and transaminases.
In cases of rifampicin overdose, arterial hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest — some with fatal outcomes — have been reported. Facial edema or periorbital swelling have also been observed. The minimal acute lethal or toxic dose has not been precisely established. The minimal lethal dose varies significantly, particularly depending on concomitant conditions (e.g., hepatic insufficiency, alcohol abuse). Seizures, coma, and hypoxia may occur, potentially leading to fatal outcomes.
Typical laboratory findings in overdose include metabolic acidosis, ketonuria, and hyperglycemia.
Treatment. Gastric lavage in a specialized facility is required, along with measures to correct acidosis, cardiopulmonary resuscitation, administration of anticonvulsants, and high-dose pyridoxine. In severe cases, treatment may include hemodialysis.
Adverse Reactions
The frequency of all adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).
Adverse reactions associated with rifampicin and isoniazid use.
Rifampicin and isoniazid are generally well tolerated at recommended doses.
General disorders and administration site reactions
Common: Paradoxical reaction (recurrence or new appearance of tuberculosis symptoms, clinical and radiological signs in a patient who previously showed improvement after appropriate anti-tuberculosis treatment, referred to as a paradoxical reaction). This reaction is diagnosed after excluding poor patient adherence to treatment regimen, treatment resistance, adverse reactions from tuberculosis treatment, and secondary bacterial/fungal infections).
Adverse reactions associated with rifampicin use.
Reactions to rifampicin occurring during continuous or intermittent treatment:
Infections and infestations
Frequency not known: Pseudomembranous colitis, influenza-like syndrome, and bone pain, most commonly occurring between the 3rd and 6th month of treatment. The frequency of this syndrome varies but may occur in up to 50% of patients receiving treatment once weekly at doses of 25 mg/kg or higher.
Blood and lymphatic system disorders
Common: Thrombocytopenia with or without purpura, usually associated with intermittent therapy. This phenomenon is reversible if treatment is discontinued at the first signs of purpura.
Uncommon: Leukopenia.
Frequency not known: Cases of disseminated intravascular coagulation, sometimes fatal, eosinophilia, agranulocytosis, hemolytic anemia, coagulation disorders.
Immune system disorders
Frequency not known: Anaphylactic reactions (urticaria, bronchospasm, angioedema), anaphylactic shock.
Endocrine disorders
Frequency not known: Decompensation of latent or corticosteroid-treated compensated adrenal insufficiency, leading to manifestations of acute adrenal insufficiency (see section "Special precautions").
Metabolism and nutrition disorders
Frequency not known: Loss of appetite.
Psychiatric disorders
Frequency not known: Isolated cases of psychiatric or psychological disorders have been reported.
Nervous system disorders
Common: Headache, dizziness.
Frequency not known: Rifampicin should be discontinued in cases of purpura development, as fatal cerebral hemorrhages have been reported with continued or resumed use.
Eye disorders
Frequency not known: Discoloration of tears. Rifampicin may permanently stain contact lenses.
Vascular disorders
Frequency not known: Shock, vasomotor reactions, vasculitis, hemorrhages.
Respiratory, thoracic and mediastinal disorders
Frequency not known: Dyspnea, respiratory and asthmatic disorders, abnormal sputum discoloration, interstitial lung disease (including pneumonia).
Gastrointestinal disorders
Common: Nausea, vomiting.
Uncommon: Diarrhea.
Frequency not known: Other gastrointestinal disorders such as abdominal pain, flatulence, tooth discoloration (may be irreversible).
Hepatobiliary disorders
Frequency not known: Hepatitis, hyperbilirubinemia, cholestasis (see section "Special precautions").
Liver injury or hepatitis may occur as a hypersensitivity reaction to rifampicin, most commonly within the first month of treatment. Direct hepatotoxic effects of rifampicin may also occur (see section "Special precautions").
Transient hyperbilirubinemia may occur in the first days of treatment (see section "Special precautions").
Skin and subcutaneous tissue disorders
Frequency not known: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions"), skin hypersensitivity reactions, pruritus with or without rash, urticaria, allergic dermatitis, pemphigoid, discoloration of sweat.
Musculoskeletal and connective tissue disorders
Frequency not known: Muscle weakness, myopathy, bone pain.
Renal and urinary disorders
Frequency not known: Acute renal failure, usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia (discoloration of urine). Cortical necrosis has also been reported.
Pregnancy, postpartum and perinatal period
Frequency not known: Postpartum hemorrhage.
Reproductive system and breast disorders
Frequency not known: Menstrual cycle disturbances.
Congenital, familial and genetic disorders
Frequency not known: Porphyria.
General disorders and administration site reactions
Very common: Febrile episodes (fever), chills.
Frequency not known: Edema.
Investigations
Common: Increased blood bilirubin levels, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
Frequency not known: Decreased blood pressure, increased creatinine levels, increased plasma liver enzymes.
Adverse reactions associated with isoniazid use
Reproductive system and breast disorders
Gynecomastia.
Skin and subcutaneous tissue disorders
Drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions"), rash, acne, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome (see section "Special precautions"), exfoliative dermatitis, pemphigus.
Gastrointestinal disorders
Nausea, vomiting, epigastric pain.
Frequency not known: Pancreatitis.
Hepatobiliary disorders
Hepatotoxicity: relatively common elevation of transaminase levels, bilirubinuria, rare acute hepatitis (with or without jaundice), some of which may be severe and occasionally fatal.
Hepatotoxicity is enhanced by interaction with rifampicin due to enzyme induction mechanisms. Other enzyme inducers may have similar effects (e.g., barbiturates).
Vascular disorders
Frequency not known: Vasculitis.
Nervous system disorders
Neurotoxicity (likely due to the active substance itself in connection with pyridoxine deficiency): peripheral neuropathy, manifesting as distal paresthesias, particularly in slow acetylators, malnourished patients, and those suffering from alcoholism.
Seizures.
Psychiatric disorders
Psychiatric disorders resembling neuropsychiatric excitation: hyperactivity, euphoria, insomnia.
In predisposed individuals, particularly when used concomitantly with ethionamide, manic episodes, acute delirium, or depression have been observed.
Anorexia.
Eye disorders
Optic neuritis and optic nerve atrophy.
General disorders and administration site reactions
Fever.
Musculoskeletal and connective tissue disorders
Myalgia, arthralgia.
In special cases: rheumatoid syndrome, algodystrophy (shoulder-hand syndrome), lupus-like syndrome.
Immune system disorders
Many toxic effects are associated with hypersensitivity and/or high-dose use (more than 10 mg/kg).
Hypersensitivity reactions
Rare: Fever, rash, acne, jaundice or hepatitis, lymphadenopathy, eosinophilia, blood dyscrasias.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Protect from light and moisture.
Keep out of reach of children.
Packaging.
28 tablets in a blister. 24 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
LUPIN LIMITED.
Manufacturer's address and location of business activity.
A-28/1, MIDC Industrial Area, Chikhalthana, Aurangabad, Maharashtra 431210, India.