Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN, ISONIAZID, PYRAZINAMIDE AND ETHAMBUTOL HYDROCHLORIDE Tablets

Composition:

Active substances: rifampicin, isoniazid, pyrazinamide, ethambutol hydrochloride;

One film-coated tablet contains: rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg, ethambutol hydrochloride 275 mg;

Excipients: microcrystalline cellulose, crospovidone, pregelatinized starch, ascorbic acid, gelatin, colloidal anhydrous silicon dioxide, magnesium stearate; coating "Wincoat WT-MPAQ-01266P brown"*.

*Composition of coating "Wincoat WT-MPAQ-01266P brown": polyvinyl alcohol, talc, titanium dioxide (E 171), iron oxide red (E 172), soy lecithin, xanthan gum.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets, brown in color, with a score on one side and smooth on the other.

Pharmacotherapeutic group.

Combination antituberculosis agents. ATC code J04AM06.

Pharmacological Properties

Pharmacodynamics

A combined antituberculosis agent whose activity is determined by its constituent components.

Rifampicin — a semi-synthetic broad-spectrum antibiotic, exerts bacteriostatic and, at high doses, bactericidal effects. It is active against M. tuberculosis (both intracellular and extracellular forms) and is a first-line antituberculosis agent. Rifampicin inhibits DNA-dependent RNA polymerase responsible for bacterial genome synthesis.

Isooniazid — an antituberculosis agent, a derivative of isonicotinic acid. Isoniazid exhibits high activity against tuberculous mycobacteria, particularly those undergoing rapid division. Positive treatment outcomes are observed when isoniazid is combined with other antituberculosis agents. Its mechanism of action involves inhibition of mycolic acid synthesis, a component of the bacterial cell wall. The minimal inhibitory concentration (MIC) of isoniazid against M. tuberculosis ranges from 0.05 to 0.025 mg. Resistance to isoniazid develops rapidly when it is used as monotherapy.

Rifampicin and isoniazid are bactericidal antituberculosis agents. They are particularly active against rapidly growing extracellular mycobacteria and also exhibit intracellular bactericidal activity.

Rifampicin is active against slowly and intermittently growing M. tuberculosis.

Rifampicin acts on DNA-dependent RNA polymerase of susceptible strains. It interacts with bacterial RNA polymerase without inhibiting enzymatic systems of the host organism.

Isoniazid is active against rapidly multiplying tubercle bacilli.

The spectrum of antimicrobial activity and the prevalence of acquired resistance of mycobacteria to rifampicin and isoniazid may vary geographically and over time. Therefore, information on local resistance patterns is useful, especially for treating severe infections. These data may only serve as a guide to the likely susceptibility of a bacterial strain to antibiotics.

Ethambutol — a chemotherapeutic agent exerting bacteriostatic activity against mycobacteria resistant to other antituberculosis agents. Its tuberculostatic mechanism of action is associated with inhibition of nucleic acid synthesis in bacterial cells. Ethambutol is active against almost all strains of M. tuberculosis, including M. bovis and M. kansasii.

The antibacterial efficacy of ethambutol varies from bacteriostatic to bactericidal depending on its concentration. Ethambutol exerts bactericidal effects at concentrations of 6–8 mcg/mL and higher, while lower concentrations show bacteriostatic activity.

Ethambutol acts on mycobacteria located extracellularly and intracellularly within macrophages. Intracellular effective concentrations exceed extracellular levels by 7 times.

Available literature provides differing information on its mechanism of action. Mycobacteria rapidly absorb ethambutol when it is added to cultures in the exponential growth phase. Ethambutol disrupts lipid synthesis in mycobacteria both during rapid growth and in dormant organisms, indicating that its mechanism of action is independent of the growth phase. Significant growth inhibition occurs only after 24 hours.

Natural resistance of M. tuberculosis and M. bovis to ethambutol is very rare; acquired resistance develops slowly but is difficult to overcome.

Cross-resistance with other antimycobacterial chemotherapeutic agents is very rare; therefore, ethambutol acts against mycobacteria resistant to other chemotherapeutic agents (e.g., isoniazid, rifampicin, streptomycin, pyrazinamide, etc.).

Ethambutol is also used when mycobacteria are sensitive to other antimycobacterial chemotherapeutic agents or when retreatment is required, which usually indicates resistance issues.

Activity against atypical mycobacteria varies significantly and should always be confirmed by susceptibility testing.

Ethambutol has no activity against other bacteria, viruses, or fungi.

Pyrazinamide — acts against mycobacteria resistant to first- and second-line antituberculosis agents. It exerts bactericidal activity in acidic environments. To express its activity, it is converted into its active form—pyrazinoic acid—by enzymatic action. It penetrates well into tuberculous lesions; its activity is not reduced in the acidic environment of caseous masses. Therefore, it should be administered in cases of caseous lymphadenitis, tuberculomas, and caseous-pneumonic processes. Resistance develops rapidly when pyrazinamide is used alone; therefore, it should be combined with other antituberculosis agents. The in vitro MIC of pyrazinamide is 20 mg/L. Pyrazinamide has no activity against atypical mycobacteria.

Pyrazinamide exerts bactericidal and sterilizing effects against M. tuberculosis within an acidic pH range, M. africanum, and M. microti. It is particularly effective against slowly proliferating intracellular pathogens and exhibits a pronounced post-antibiotic effect. In vitro, pyrazinamide is ineffective against most strains of M. bovis and nontuberculous mycobacteria (e.g., M. kansasii, M. smegmatis, M. avium). Cross-resistance exists with morphazinamide, a derivative of pyrazinamide, but not with other antituberculosis agents.

The exact mechanism of action of pyrazinamide is unknown. Pyrazinamide is converted into pyrazinoic acid, which has antimycobacterial activity. A possible target of pyrazinoic acid is ribosomal protein S1 (RpsA).

Acquired resistance in sensitive pathogens from clinical isolates exceeds 80% and is caused by mutations in the pncA gene or its promoter region. This gene encodes the enzyme pyrazinamidase, which converts pyrazinamide into its active bactericidal form—pyrazinoic acid.

Mutations in the rpsA gene have also been occasionally reported. This gene encodes ribosomal protein S1, the presumed target of pyrazinoic acid. In resistant strains, the primary resistance mechanism remains unknown.

The prevalence of acquired resistance among M. tuberculosis, M. africanum, and the Mycobacterium tuberculosis complex varies locally.

The aforementioned tuberculosis pathogens are generally sensitive to pyrazinamide.

Pharmacokinetics

Rifampicin

Absorption. Absorption in the gastrointestinal tract is rapid and nearly complete. Concomitant food intake reduces rifampicin absorption. Maximum plasma concentrations of approximately 10 mcg/mL are achieved within 2–3 hours after a single 600 mg dose taken on an empty stomach.

Distribution. The apparent volume of distribution is 0.8 L/kg in adults. Plasma protein binding is approximately 80%.

It penetrates well into macrophages.

Tissue diffusion is high in the lungs, liver, and kidneys; moderate in other tissues; and low only in cases of meningitis. Rifampicin readily crosses the placental barrier.

Metabolism. Rifampicin is primarily metabolized to deacetylrifampicin, which has the same antibacterial activity. Rifampicin induces its own metabolism.

Elimination. The plasma half-life depends on the dose: approximately 2.5 hours after a single 300 mg dose, 3–4 hours after a 600 mg dose, and approximately 5 hours after a 900 mg dose. After repeated daily administration over several days, rifampicin bioavailability decreases, and its half-life shortens to 1–2 hours after repeated 600 mg doses. Due to its enzyme-inducing effect on the liver, rifampicin accelerates its own metabolism, resulting in increased systemic clearance after repeated administration. The majority of the drug is excreted in bile; 80% of the excreted amount consists of the metabolite deacetylrifampicin.

Rifampicin is also detected in urine. Between 150 mg and 900 mg (4–18%), depending on the dose, is excreted unchanged in urine.

Excretion in milk is approximately 2 mcg/mL after a 600 mg dose, and in saliva, it averages 0.5 mcg/mL after a 600 mg dose.

Special patient groups. Plasma concentrations in elderly patients are similar to those in younger patients. In renal impairment, the half-life increases only at doses exceeding 600 mg/day. Dose adjustment is not required during dialysis.

In hepatic impairment, plasma concentrations increase and the half-life is prolonged. Dose adjustment may be necessary in cases of severe hepatic dysfunction.

Isoniazid

Maximum isoniazid concentration is reached within 1–2 hours after oral administration. At the 3rd hour, effective plasma concentrations should range from 1 to 2 mcg/mL. Isoniazid diffuses well throughout the body, including the pleura, lungs, sputum, saliva, cerebrospinal, peritoneal, and ascitic fluids. Isoniazid also crosses the placental barrier. Its concentration in milk is identical to that in plasma.

Isoniazid is primarily metabolized via acetylation to acetylisoniazid. This metabolism is genetically determined: "slow acetylators" and "fast acetylators" exist.

Acetylisoniazid is then converted to acetylhydrazine, which exhibits hepatotoxic effects. Acetylhydrazine, in turn, is acetylated to diacetylhydrazine, which is non-toxic. The plasma half-life averages 1 hour in "fast acetylators" and 3 hours in "slow acetylators."

Between 75% and 95% of the administered dose is excreted in urine within 24 hours, primarily as metabolites. Other excretion routes (feces, saliva) are quantitatively insignificant.

Pyrazinamide

Pyrazinamide is readily absorbed from the gastrointestinal tract. Peak plasma concentrations occur approximately 2 hours after oral administration, reaching 33 mcg/mL after 1.5 g and 59 mcg/mL after 3 g.

Serum concentrations then decline, with a plasma half-life of approximately 9–10 hours.

Approximately 30% of the dose is excreted in urine as pyrazinoic acid, and 4% as unchanged pyrazinamide within 24 hours.

Absorption. Pyrazinamide is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Maximum serum concentrations (approximately 33 mcg/mL after 1.5 g and approximately 65 mcg/mL after 3 g) are achieved within 1–3 hours. The minimal inhibitory concentration of pyrazinamide for most wild-type M. tuberculosis strains ranges from 6.25 mcg/mL to 50 mcg/mL at pH 5.5.

Administration of a single daily dose of 1.5 g pyrazinamide achieves more effective serum levels than three 0.5 g doses per day.

Distribution. Pyrazinamide penetrates well into tissues and fluids. Effective concentrations have been detected in the liver, kidneys, lungs, cerebrospinal fluid, peripheral nerve cells, and macrophages.

In vitro, 15% of pyrazinamide binds to alpha-1-acid glycoprotein and 40% is fully bound to plasma albumin. In vivo data are unavailable.

Metabolism. Pyrazinamide is converted to pyrazinoic acid by microsomal deaminase and then hydroxylated to 5-hydroxypyrazinoic acid with the participation of xanthine oxidase. 5-Hydroxypyrazinoic acid and its numerous metabolites are excreted by the kidneys.

Elimination. Approximately 4% of pyrazinamide is excreted unchanged by the kidneys, 36% as pyrazinamide carboxylic acid, and the remainder as metabolites. The half-life is 9–10 hours with normal renal function and approximately 26 hours in chronic renal failure.

Linearity. Serum concentrations of pyrazinamide are directly proportional to the dose in the range of 0.5 to 3 g.

Renal impairment. In patients with renal impairment, pyrazinamide elimination is slower (t1/2 approximately 26 hours), and serum concentrations increase. Reduced elimination of pyrazinoic acid may lead to uric acid retention, increasing the risk of arthralgia.

Pyrazinamide and its metabolites are readily removed by hemodialysis. Between 31.5% and 45% of the administered pyrazinamide is eliminated by hemodialysis.

In contrast, elimination by continuous peritoneal dialysis is moderate, amounting to 10–12%.

Patients on dialysis should take pyrazinamide 4–6 hours before or immediately after dialysis (see sections "Administration and Dosage" and "Special Precautions").

Hepatic impairment. In patients with hepatic insufficiency, clearance is reduced, resulting in prolonged pyrazinamide half-life. AUC values increased threefold, and the half-life of pyrazinoic acid doubled.

Ethambutol hydrochloride

Ethambutol is readily absorbed after oral administration. Food intake does not significantly impair its absorption. After a single 25 mg/kg dose, peak plasma concentrations of up to 5 mcg/mL are reached within 4 hours; after 24 hours, concentrations decrease to less than 1 mcg/mL. The majority of the dose is excreted unchanged in urine, and up to 20% in feces within 48 hours. Between 8% and 15% of the dose appears in urine as inactive metabolites.

Ethambutol readily diffuses into erythrocytes and cerebrospinal fluid during meningeal inflammation. It has also been reported to cross the placenta.

Absorption. After oral administration, ethambutol is rapidly absorbed, with serum concentrations proportional to the administered dose. Peak serum concentrations (approximately 5 mg/L after a 15 mg/kg oral dose) are reached within approximately 2 hours.

After parenteral administration, the absorption phase is absent, and the dose becomes systemically available immediately.

Distribution. Ethambutol is rapidly eliminated from plasma. Depending on concentration, it binds to serum proteins and has good diffusion capacity into various tissues and cells. It distributes well into lung tissue and accumulates in cells such as erythrocytes and macrophages. In erythrocytes, ethambutol remains bound for a prolonged period at 2–4 times the plasma concentration. Erythrocytes are considered a reservoir from which ethambutol is slowly released. Concentrations in macrophages are 7 times higher than in the extracellular space.

In healthy individuals, ethambutol poorly crosses the blood-brain barrier, but literature reports adequate concentrations in the cerebrospinal fluid of patients with tuberculous meningitis.

Ethambutol crosses into the fetal circulation. Cord blood levels are 32% of maternal serum concentrations.

Metabolism and elimination. The biological half-life in patients with healthy kidneys is (2)–4–(6) hours. Within the first few hours after oral administration, ethambutol is practically unmetabolized; only 15% is excreted in urine as inactive metabolites.

After intravenous administration, mean 24-hour urinary excretion values are (50)–70–80% of the dose, with approximately 0.8% excreted in feces within 48 hours. Ethambutol is primarily filtered through glomeruli and minimally secreted by renal tubules. A reduction in creatinine clearance below 100 mL/min is expected to lead to ethambutol accumulation if dosing remains unchanged. Since normal renal function is crucial for elimination, the risk of accumulation increases with the degree of renal impairment, necessitating dose adjustment. Ethambutol is effectively removed by hemodialysis, whereas peritoneal dialysis is less effective.

Clinical characteristics.

Indications.

For the treatment of pulmonary and extrapulmonary tuberculosis during the intensive (initial) phase of therapy.

Contraindications.

The use of the medicinal product is contraindicated:

• in patients with hypersensitivity to rifampicin, isoniazid, pyrazinamide, ethambutol, or any of the excipients;
• in hepatic insufficiency, including severe impairment of liver function (Child–Pugh class C); in acute liver diseases (e.g., hepatitis) and within 6 months after recovery from hepatitis;
• 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");
• in patients with optic neuritis;
• in patients with a history of visual disturbances, except when clinical evaluation determines that the drug may be used.

Interaction with other medicinal products and other types of interactions.

Rifampicin and isoniazid

Antimicrobial agents and INR (International Normalized Ratio — standard for determining prothrombin index)

Numerous cases of increased vitamin K antagonist activity have been reported in patients receiving antibacterial agents. Risk factors include severe infections or inflammatory conditions, advanced age, and poor general condition. Under these circumstances, it is difficult to distinguish the consequences of infectious disease from those of its treatment in the occurrence of INR imbalance.

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 and potentially fatal outcomes (especially when used at high doses). If concomitant use is necessary, intensified monitoring of INR 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 drugs are substrates for at least one or more of these enzymes and/or transporters. Rifampicin may accelerate metabolism and thus reduce the activity of certain co-administered drugs, or increase the activity of prodrugs requiring metabolic activation, and therefore may induce clinically significant interactions with many drugs across various classes. Dose adjustments of these drugs may be required at the initiation or discontinuation of rifampicin therapy to maintain optimal blood concentrations, considering that the induction effect reaches its maximum after approximately 15 days and persists for 1–2 weeks after rifampicin discontinuation.

Contraindicated combinations (see section "Contraindications")

Interactions related to rifampicin

Bictegravir

Very significant reduction in bictegravir concentration, potentially leading to loss of efficacy.

Cobicistat

Risk of reduced cobicistat efficacy due to enhanced metabolism by rifampicin.

Daclatasvir

Reduced plasma concentration of daclatasvir due to enhanced hepatic metabolism by rifampicin.

Dasabuvir

Risk of reduced dasabuvir plasma concentration due to rifampicin.

Delamanid

Reduced plasma concentration of delamanid 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.

Saquinavir + ritonavir combination: 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

Reduced plasma concentration of isavuconazole due to enhanced hepatic metabolism by rifampicin.

Ledipasvir

Significant reduction in plasma concentration of ledipasvir due to enhanced hepatic metabolism by rifampicin.

Lurasidone

Reduced plasma concentration of lurasidone due to enhanced hepatic metabolism by rifampicin.

Midostaurin

Reduced midostaurin concentration under the influence of rifampicin.

Ombitasvir/paritaprevir

Reduced plasma concentration with dual therapy due to enhanced hepatic metabolism by rifampicin.

Praziquantel

Very significant reduction in praziquantel plasma concentration, risking 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 by rifampicin.

Velpatasvir

Reduced plasma concentration of velpatasvir under the influence of rifampicin, potentially affecting efficacy.

Voriconazole

Significant reduction in voriconazole plasma concentration, risking loss of efficacy due to enhanced hepatic metabolism by rifampicin.

Voxilaprevir

Reduced plasma concentrations of voxilaprevir under the influence of rifampicin, risking 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, risking reduced efficacy.

Apixaban, dabigatran, rivaroxaban

Reduced plasma concentrations of apixaban, dabigatran, or rivaroxaban under the influence of rifampicin, risking reduced therapeutic effect.

Apomorphine

Reduced apomorphine plasma concentration due to enhanced metabolism by rifampicin.

Aprepitant

Very significant reduction in aprepitant concentration.

Atorvastatin, simvastatin

Very significant reduction in atorvastatin or simvastatin plasma concentration due to enhanced hepatic metabolism by rifampicin.

Atovaquone

Reduced atovaquone plasma concentration by enzyme inducer.

Bedaquiline

Reduced 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 clopidogrel's active metabolite and enhanced platelet inhibition, thereby increasing bleeding risk. Therefore, concomitant use of clopidogrel and rifampicin is not recommended.

Cyclophosphamide

Risk of increased plasma concentration of cyclophosphamide's active metabolite under the influence of rifampicin, thus increasing its toxicity.

Cyproterone used as hormonal contraceptive

Risk of reduced cyproterone efficacy. 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

Reduced concentration of cytotoxic agent due to enhanced metabolism by rifampicin, risking reduced efficacy.

Dolutegravir, in integrase inhibitor class resistance

Reduced plasma concentration of dolutegravir due to enhanced metabolism by rifampicin.

Dronedarone

Significant reduction in dronedarone concentration due to enhanced metabolism without significant change in active metabolite.

Estrogen- and progestogen-containing contraceptives

Reduced efficacy of hormonal contraceptives due to enhanced hepatic metabolism 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

Reduced etoposide plasma concentration by rifampicin. If combination is necessary, clinical monitoring is required and etoposide dose adjustment may be needed during concomitant use and 1–2 weeks after rifampicin discontinuation.

Fentanyl

Reduced fentanyl plasma concentration due to enhanced hepatic metabolism by rifampicin. During rifampicin use, preference should be given to another opioid.

Fluconazole

Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).

Idelalisib

Reduced idelalisib plasma concentration due to enhanced hepatic metabolism by rifampicin.

5-alpha-reductase inhibitors (dutasteride, finasteride)

Reduced plasma concentrations of 5-alpha-reductase inhibitors under the influence of rifampicin. If combination cannot be avoided, careful clinical monitoring is required.

Tyrosine kinase inhibitors metabolized by CYP3A4

Reduced plasma concentration and efficacy of tyrosine kinase inhibitor due to enhanced metabolism by rifampicin.

Irinotecan

Likely reduction in plasma concentration of irinotecan's active metabolite, risking inefficacy of cytotoxic therapy.

• Itraconazole*

Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).

Ivacaftor

Significant reduction in ivacaftor plasma concentration, risking loss of efficacy.

Ketoconazole

Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).

Macitentan

Reduced 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

Reduced naloxegol concentration under the influence of rifampicin.

• Nevirapine*

Reduced nevirapine plasma concentration due to enhanced hepatic metabolism by rifampicin.

Nimodipine

Reduced calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical monitoring is required and calcium antagonist dose adjustment may be needed during rifampicin therapy and after its discontinuation.

Olaparib

Reduced, possibly very significant, olaparib plasma concentration due to enhanced hepatic metabolism by rifampicin.

Oxycodone

Reduced oxycodone plasma concentration due to enhanced metabolism by rifampicin. Oxycodone dose adjustment may be required.

Paclitaxel

Reduced concentration of cytotoxic agent due to enhanced metabolism by rifampicin, risking reduced efficacy.

Posaconazole

Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption by azole antifungal).

Quetiapine

Very significant reduction in quetiapine plasma concentration due to enhanced hepatic metabolism by enzyme inducer, risking inefficacy.

Quinine

Risk of loss of quinine efficacy due to enhanced hepatic metabolism by rifampicin.

Raltegravir

Reduced raltegravir concentration under the influence of rifampicin. If combination cannot be avoided, doubling the raltegravir dose should be considered.

Ranolazine

Very significant reduction in ranolazine concentration.

Regorafenib

Reduced regorafenib plasma concentration due to enhanced metabolism by rifampicin.

Rolapitant

Very significant reduction in rolapitant concentration, risking loss of efficacy.

Sertraline

Risk of antidepressant treatment inefficacy.

Tenofovir alafenamide

Reduced tenofovir alafenamide plasma concentration due to reduced absorption by rifampicin. Clinical monitoring should be performed during combination therapy and 1–2 weeks after rifampicin discontinuation.

Telithromycin

Very significant reduction in telithromycin plasma concentration, risking antimicrobial treatment inefficacy due to enhanced hepatic metabolism by rifampicin.

• Ticagrelor*

Significant reduction in ticagrelor plasma concentration due to enhanced hepatic metabolism by rifampicin, risking 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 concentration of vinca alkaloids, potentially affecting efficacy.

Vismodegib

Risk of reduced vismodegib plasma concentration due to enhanced hepatic metabolism by rifampicin.

Zidovudine

Reduced 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 caution

Interactions related to isoniazid

Halogenated volatile anesthetics

Potentiation of hepatotoxic effects of isoniazid with enhanced formation of toxic isoniazid metabolites. As a precaution in elective surgery, isoniazid therapy should be discontinued one week before surgery and resumed only 15 days thereafter.

Glucocorticoids (except hydrocortisone in replacement therapy)

When used concomitantly with prednisolone, reduced isoniazid plasma concentration has been observed. The mechanism involves increased hepatic metabolism of isoniazid and reduced glucocorticoid levels. Clinical and biological monitoring is required.

Ketoconazole

Reduced ketoconazole plasma concentration.

It is recommended to separate the doses of both antimicrobial agents by at least 12 hours. Ketoconazole plasma concentration should be monitored and dose adjusted if necessary.

Phenytoin and fosphenytoin

Overdose of phenytoin (reduced metabolism) has been observed when used concomitantly with isoniazid. Careful clinical monitoring, determination of phenytoin plasma concentration, and possible dose adjustment are required during and after isoniazid therapy.

Pyrazinamide

Enhanced hepatotoxic effects may occur when used concomitantly. 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 administration should be discontinued.

Stavudine

Increased risk of peripheral neuropathy due to additive side effects. Regular clinical and biological monitoring is required, especially at the beginning of therapy.

Interactions related to rifampicin

Valproic acid and valpromide

Risk of seizures due to enhanced hepatic metabolism of valproate by rifampicin. Clinical and biological monitoring is required, and possible dose adjustment of the anticonvulsant during and after rifampicin therapy.

Afatinib

Reduced afatinib plasma concentration due to enhanced metabolism by rifampicin. Clinical monitoring is required during combination therapy and 1–2 weeks after its discontinuation.

Albendazole

Significant reduction in albendazole and its active metabolite plasma concentrations under the influence of rifampicin, risking reduced efficacy. Clinical monitoring of therapeutic response is required and albendazole dose adjustment may be needed during and after concomitant use with rifampicin.

Androgens (androstanolone, norethandrolone, testosterone)

Risk of reduced androgen plasma concentration and thus reduced efficacy due to enhanced hepatic metabolism by rifampicin. Clinical and biological monitoring is required during combination therapy and 1–2 weeks after rifampicin discontinuation.

Calcium channel antagonists (except nimodipine)

Reduced calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical observation is required and possible dose adjustment of calcium antagonist during and after rifampicin therapy.

Class IA antiarrhythmics (disopyramide, hydroquinidine, quinidine)

Reduced plasma concentration and efficacy of antiarrhythmic agent (enhanced hepatic metabolism).

Clinical monitoring, ECG, and possibly monitoring of antiarrhythmic plasma concentration are required. Dose adjustments may be needed during and after rifampicin therapy (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 vitamin K antagonist may be needed during rifampicin therapy and 8 days after its discontinuation.

Aripiprazole

Reduced aripiprazole plasma concentration. Clinical observation is required and dose adjustment of aripiprazole may be needed during combination therapy and 1–2 weeks after rifampicin discontinuation.

Bazedoxifene

Reduced bazedoxifene plasma concentrations under the influence of rifampicin. Monitoring for any signs of loss of efficacy (e.g., bleeding) is required.

Buspirone

Reduced buspirone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required and dose adjustment of buspirone may be needed during and after rifampicin therapy.

Carbamazepine

Reduced plasma concentration and efficacy of carbamazepine due to enhanced hepatic metabolism by rifampicin. Clinical monitoring, plasma concentration control, and carbamazepine dose adjustment are required during and after rifampicin therapy.

Carvedilol

Significant reduction in carvedilol plasma concentration due to enhanced hepatic metabolism by rifampicin. Regular clinical monitoring and carvedilol dose adjustment are required during rifampicin therapy. After rifampicin discontinuation, there is a risk of significant increase in carvedilol plasma concentration, requiring dose reduction and careful clinical observation.

Caspofungin

Reduced caspofungin plasma concentration. When treating with rifampicin, starting from day 2, the dose should be maintained at 70 mg daily.

Clarithromycin

Reduced plasma concentration and risk of reduced efficacy of clarithromycin, especially in HIV-infected patients, due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring is required.

Clozapine

Risk of antipsychotic treatment inefficacy (reduced clozapine plasma concentration due to enhanced hepatic metabolism). Clinical monitoring is required and clozapine dose increase may be needed during rifampicin therapy.

Cyproterone used as antiandrogen

Risk of reduced cyproterone efficacy. Clinical monitoring is required and cyproterone dose adjustment may be needed during and after combination therapy.

Dapsone

Increased effect of hydroxylamine metabolite, responsible for adverse 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. Deferasirox dose adjustment is recommended if needed.

Digoxin

Moderate reduction in digoxin concentration. Clinical monitoring and ECG are required.

Disopyramide

Risk of reduced disopyramide concentration by rifampicin. Clinical monitoring is required and disopyramide dose adjustment may be needed during combination therapy and 1–2 weeks after rifampicin discontinuation.

Dolutegravir, in absence of integrase inhibitor class resistance

Adjust dolutegravir dose to 50 mg twice daily during combination therapy and for one week after its discontinuation.

Reduced plasma concentration of dolutegravir due to enhanced metabolism by rifampicin.

Efavirenz

Reduced plasma concentration and efficacy of efavirenz due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring is required, especially at the beginning of combination therapy.

Enalapril

Reduced effect of enalapril's active metabolites. Depending on the patient's clinical status, dose adjustment may be required.

Glucocorticoids

Reduced plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients on hydrocortisone replacement and in transplant recipients. Clinical and biological monitoring and corticosteroid dose adjustment are required during and after rifampicin therapy.

There is a risk of reduced hydrocortisone efficacy due to enhanced metabolism. Consequences are serious when hydrocortisone is used as replacement therapy or in transplantation. Clinical and biological monitoring and hydrocortisone dose adjustment are required during combination therapy and after rifampicin discontinuation.

Haloperidol

Risk of reduced haloperidol plasma concentration and therapeutic efficacy due to enhanced hepatic metabolism by rifampicin. Clinical observation is required and dose adjustment may be needed during and after rifampicin therapy.

Thyroid hormones

Risk of clinical hypothyroidism in hypothyroid patients due to enhanced metabolism of T3 and T4 hormones. Monitoring of serum T3 and T4 concentrations is required and thyroid hormone dose adjustment may be needed during and after rifampicin therapy.

Immunosuppressants

Reduced blood concentration and efficacy of immunosuppressants due to enhanced hepatic metabolism by rifampicin. Increased immunosuppressant dose is recommended with blood concentration monitoring, and dose reduction after rifampicin discontinuation.

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 administration should be discontinued.

Ivabradine

Risk of reduced ivabradine efficacy due to enhanced metabolism by rifampicin. Clinical monitoring and ivabradine dose adjustment are required during combination therapy and after rifampicin discontinuation.

Levonorgestrel

When levonorgestrel is used for emergency contraception, significant reduction in plasma concentration occurs, risking loss of efficacy. If enzyme inducer was used within the last 4 weeks, consider using non-hormonal contraception (copper intrauterine device [IUD]). If IUD use is not possible, double dose of levonorgestrel should be administered.

Linezolid

Risk of reduced linezolid efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required and linezolid dose increase may be needed during rifampicin therapy.

Maraviroc

If not co-administered with a potent CYP3A4 inhibitor, reduced maraviroc concentration occurs under the influence of rifampicin. In such case, maraviroc dose should be increased to 600 mg twice daily.

Methadone

Reduced methadone plasma concentration, risking withdrawal syndrome due to enhanced hepatic metabolism. Methadone dosing frequency should be increased (2–3 times daily instead of once).

Metronidazole

Reduced metronidazole plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required and metronidazole dose adjustment may be needed during and after rifampicin therapy.

Mineralocorticoids

Reduced plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients on hydrocortisone replacement and in transplant recipients.

Clinical and biological monitoring and corticosteroid dose adjustment are required during and after rifampicin therapy.

Montelukast

Risk of reduced montelukast efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required and dose adjustment of anti-asthmatic agents may be needed during and after rifampicin therapy.

Morphine

Reduced plasma concentration and efficacy of morphine and its active metabolite. Clinical monitoring is required and morphine dose adjustment may be needed during and after rifampicin therapy.

Nintedanib

Reduced nintedanib plasma concentration due to reduced absorption by rifampicin. Clinical monitoring is required during combination use.

Paracetamol

Concomitant use of paracetamol and rifampicin increases the risk of hepatotoxicity.

Pioglitazone

Reduced glitazone plasma concentration due to enhanced metabolism by rifampicin. Clinical and biological monitoring and glitazone dose adjustment are required during and after rifampicin therapy.

Non-contraceptive progestins (with or without estrogen)

Reduced progestagen efficacy. Clinical monitoring is required and hormonal treatment dose adjustment may be needed during and after inducer use.

Propafenone

Reduced propafenone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and ECG are required. Propafenone dose adjustment may be needed during combination therapy and after rifampicin discontinuation.

Terbinafine

Reduced plasma concentration and efficacy of terbinafine due to enhanced hepatic metabolism by rifampicin.

Clinical monitoring is required. Terbinafine dose adjustment may be needed during rifampicin therapy.

Theophylline and aminophylline

Reduced plasma concentration and efficacy of theophylline (enhanced metabolism via enzyme induction).

Clinical observation is recommended. Theophylline dose adjustment may be required during and after rifampicin therapy.

Tiagabine

Reduced tiagabine plasma concentration due to enhanced hepatic metabolism. Tiagabine dose increase may be required when combined with rifampicin.

Vitamin D

Reduced vitamin D concentration has been observed during rifampicin therapy. Vitamin D dose adjustment may be necessary.

Zolpidem

Reduced plasma concentration and efficacy of zolpidem due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, use another hypnotic agent.

Zopiclone

Reduced plasma concentration and efficacy of zopiclone due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, use another hypnotic agent.

Interactions to be considered

Interactions related to rifampicin

Bortezomib

Reduced cytotoxic agent concentration due to enhanced metabolism by rifampicin, risking reduced efficacy.

• Cabazitaxel*

Reduced cytotoxic agent concentration due to enhanced metabolism by rifampicin, risking reduced efficacy.

Exemestane

Risk of reduced exemestane efficacy due to enhanced hepatic metabolism by rifampicin.

Metformin

Reduced metformin concentration under the influence of rifampicin.

Metoprolol, propranolol

Reduced plasma concentration and efficacy of beta-blocker (enhanced hepatic metabolism).

Perampanel

Significant reduction (up to two-thirds) in perampanel concentration.

Tamoxifen

Risk of tamoxifen inefficacy due to enhanced metabolism by rifampicin.

Pyrazinamide

Unwanted interaction reactions may occur when combined with the following drugs:

Active substance/group of active substances	Interaction	Recommendations
Analgesics
Acetylsalicylic acid (ASA)	Indirect interaction: doses of ASA ≥ 3000 mg/day promote excretion of uric acid, doses of ASA 75–2000 mg/day inhibit excretion of uric acid, as well as pyrazinamide (see section "Special precautions"), thus potentially enhancing the inhibition of uric acid excretion.	Close monitoring of uric acid levels.
Antidiabetic agents
Antidiabetic agents	Indirect effect on antidiabetic action: pyrazinamide accelerates reduction of blood glucose levels and causes fluctuations in blood glucose levels.	Monitor blood glucose levels.
Immunosuppressants
Cyclosporine	Serum cyclosporine levels ▼, immunosuppressive effect ▼	Close monitoring of serum cyclosporine levels.
Antituberculosis medicinal products
Rifampicin	Rifampicin and pyrazinamide: hepatotoxicity ▲, rifampicin: plasma clearance ▲, AUC ▼.	Liver function tests are recommended before and during treatment (see section "Special precautions"); dose adjustment of rifampicin or pyrazinamide is not required.
Uricosuric agents
Probenecid	Excretion of uric acid ▼, elimination ▼.	Close monitoring of uric acid levels.
Antiviral agents
Zidovudine	Pyrazinamide: serum levels ▼, therapeutic effect ▼	Close monitoring of pyrazinamide serum levels.

Other interactions

Pyrazinamide may antagonize drugs with uricosuric properties, such as ascorbic acid and contrast agents. In such cases, careful monitoring of the patient is recommended. Alcohol consumption should be avoided during pyrazinamide treatment, and caution should be exercised when using potentially hepatotoxic agents concomitantly, as the risk of hepatotoxicity increases in both cases.

Ethambutol hydrochloride

The following medicinal products affect the efficacy of ethambutol: aluminum hydroxide and similar antacids delay and/or reduce ethambutol absorption.

A reduction in the therapeutic effect of ethambutol has been reported with spermine, spermidine, and magnesium.

Other interactions

Patients suffering from alcoholism and receiving disulfiram have an increased risk of visual impairment when treated with ethambutol.

Effect on laboratory tests

At sufficient serum concentrations, ethambutol reacts with phentolamine and may produce false-positive results in the diagnosis of pheochromocytoma.

Special precautions for use.

Rifampicin and isoniazid

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 and even several months after completion of isoniazid therapy. The risk of hepatitis development depends on the patient's age.

Treatment should be discontinued immediately if signs and symptoms of liver injury occur, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. Continuing treatment may lead to severe liver damage. Close monitoring is required in patients with chronic liver disease or severe renal insufficiency.

Cases of moderate to severe cholestasis have been reported during rifampicin therapy. Patients should seek immediate medical attention if symptoms such as pruritus, loss of appetite, nausea, vomiting, abdominal pain, yellowing of the sclera or skin, or darkening of urine occur. If cholestasis is confirmed, the drug should be discontinued.

Serious bullous reactions: Cases of serious bullous reactions, including Stevens-Johnson syndrome (SJS), Lyell’s syndrome (toxic epidermal necrolysis or TEN), sometimes fatal, have been reported during antituberculosis therapy (see section "Adverse reactions"). Patients should be warned about signs and symptoms of skin reactions and closely monitored. Immediate medical attention is required if symptoms of SJS or TEN occur (progressive rash, often accompanied by blistering and mucosal involvement). The treatment should be permanently discontinued if the etiology of such manifestations cannot be established.

Severe systemic hypersensitivity reactions, including fatal cases, such as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been observed during antituberculosis therapy (see section "Adverse reactions").

It is important to note that early signs of hypersensitivity, such as fever, lymphadenopathy, or laboratory abnormalities (including eosinophilia, liver function abnormalities), may occur without apparent skin rash.

Patients should seek immediate medical attention if such signs or symptoms occur.

Treatment with the drug should be discontinued if the cause of these symptoms cannot be established.

The medicinal product should generally not be used in combination with the following agents:

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, dolotegravir (only in cases of integrase inhibitor resistance), dronedarone, etoposide, fentanyl, fluconazole, idelalisib, dutasteride, finasteride, metabolized tyrosine kinase inhibitors, irinotecan, itraconazole, ivacaftor, ketoconazole, macitentan, mianserin, midazolam, naloxegol, nevirapine, nimodipine, olaparib, oxycodone, paclitaxel, posaconazole, quetiapine, quinine, raltegravir, ranolazine, regorafenib, rivaroxaban, rilpivirine, theophylline, apitant, ticagrelor, telithromycin, ulipristal, combined hormonal and progestin-only contraceptives, vemurafenib, vinca alkaloid cytotoxics, vismodegib, zidovudine, rivaroxaban, rolapitant, sertraline, simvastatin, tenofovir alafenamide (see section "Interaction with other medicinal products and other forms of interactions").

Paradoxical reaction

After initial improvement during treatment, tuberculosis symptoms may worsen again. These patients may experience clinical or radiological deterioration of existing tuberculosis lesions or development of new lesions. These reactions typically occur within the first weeks or months of antituberculosis therapy. Cultures are usually negative, and such reactions generally do not indicate treatment inefficacy.

The cause of this paradoxical reaction is unknown, but an exaggerated immune response is a likely explanation. If a paradoxical reaction is suspected, symptomatic treatment to reduce the excessive immune response should be initiated, if necessary. Continued standard antituberculosis therapy is recommended.

Patients should seek immediate medical attention if their condition worsens. Symptoms are usually characteristic of the affected tissues. General symptoms may include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness (see section "Adverse reactions").

Interstitial lung disease (ILD)/pneumonia

Cases of interstitial lung disease or pneumonia have been reported in patients receiving rifampicin and isoniazid for tuberculosis treatment. ILD/pneumonia are life-threatening conditions. A thorough evaluation should be performed in all patients with sudden onset and/or unexplained worsening of pulmonary symptoms (dyspnea with dry cough) and fever to confirm the diagnosis of ILD/pneumonia. If ILD/pneumonia is diagnosed, the drug should be permanently discontinued in cases of severe manifestations (respiratory failure and acute respiratory distress syndrome), and appropriate treatment should be initiated if needed.

Rifampicin is a potent inducer of transporters and enzymes responsible for drug metabolism. This may reduce or increase the effect of concomitantly administered drugs, thereby affecting their efficacy and safety (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, patients are advised not to take any other medicinal products without prior consultation with a physician.

Hepatic function impairment

The drug should be prescribed to patients with hepatic dysfunction only when absolutely necessary, with caution, and under close medical supervision.

Regular clinical and biological monitoring of patients 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 the first month, then at longer intervals (every 2 months), liver function monitoring (transaminases, bilirubin).

Treatment with the drug should be discontinued if signs of hepatocellular injury (hepatitis) occur.

Since hepatitis associated with isoniazid use occurs more frequently in patients over 35 years of age, this patient group should have transaminase levels measured at the beginning of treatment and at least once a month during treatment.

Other factors that increase the risk of hepatitis include daily alcohol consumption, chronic liver disease, intravenous drug use, and being of African or Latin American ethnicity.

In some cases, hyperbilirubinemia may occur in the first days of treatment due to competition at the cellular level between rifampicin and bilirubin for hepatic excretion. Isolated and mild hyperbilirubinemia alone is not an indication for discontinuation of treatment; the decision to discontinue the drug 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 discoloration of teeth, urine, sweat, sputum, and tears to yellow, orange, red, or brown, which should be explained to the patient. Rifampicin may permanently stain contact lenses.

Peripheral neuropathies

To prevent peripheral neuropathies, regular neurological examinations should be performed, and particular caution should be exercised in patients who abuse alcohol.

Pyridoxine (vitamin B6) supplementation prevents or resolves rare cases of drug-induced neuropathy, especially in elderly patients or those who are malnourished.

Coagulation disorders (see section "Adverse reactions")

Cases of coagulation disorders have been reported during rifampicin use, particularly in combination with cephalosporin-class drugs (including cefazolin). Appropriate monitoring is required in patients at risk (patients with risk factors leading to vitamin K deficiency or affecting other coagulation mechanisms). Additional vitamin K supplementation may be necessary (e.g., in cases of established vitamin K deficiency or hypoprothrombinemia).

Intermittent therapy

Hypersensitivity reactions are often, if not exclusively, associated with intermittent (intermittent) administration or repeated discontinuation of rifampicin (see section "Adverse reactions").

Effect on adrenal function

The drug may decompensate latent adrenal insufficiency controlled by corticosteroid therapy (see section "Adverse reactions"). Therefore, monitoring of such patients is recommended, and adrenal cortex function tests should be performed at the slightest suspicion.

Effect on clinical test results

Rifampicin may delay the biliary excretion of contrast agents used for radiographic examination of the gallbladder.

Microbiological methods for determining plasma folate and vitamin B12 concentrations should not be used during rifampicin therapy.

Rifampicin temporarily competes with bilirubin and bromsulphthalein (BSP). To avoid false-positive results, the bromsulphthalein test should be performed in the morning before taking rifampicin.

Since cross-reactions with false-positive urine opiate test results have been reported in patients receiving 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.

Pyrazinamide

Pyrazinamide should be used in patients with gout only in emergency situations.

In patients with impaired renal function (glomerular filtration rate < 30 mL/min), pyrazinamide should be administered three times a week. In such cases, separate formulations of ethambutol, isoniazid, pyrazinamide, and rifampicin are recommended.

Since pyrazinamide accumulation in blood may occur in dialysis patients, its levels should be monitored in such patients.

Difficulties in blood glucose control may occur in patients with diabetes mellitus during pyrazinamide therapy, and serum glucose levels may be unstable.

Tubular reabsorption of uric acid inhibition due to pyrazinamide may lead to hyperuricemia (see section "Adverse reactions"). In rare cases, this effect may result in arthralgia, especially in sensitive patients. Therefore, serum uric acid concentration should be monitored regularly (every 3–4 weeks). In cases of very high serum uric acid levels, treatment with uricosuric agents, such as benzbromarone, may be necessary.

Photosensitization may occur during pyrazinamide therapy (see section "Adverse reactions"), so patients taking pyrazinamide should avoid direct sunlight exposure.

There is an increased risk of hepatotoxic reactions in patients who regularly consume or abuse alcohol.

Liver and kidney function tests should be performed regularly before and during treatment (approximately every 3–4 weeks).

In patients with a history of liver dysfunction or increased susceptibility to liver injury (e.g., alcoholism), appropriate laboratory parameters should be checked once or several times per week, especially during the first few months of treatment. Dose reduction of pyrazinamide may also be required. If dose adjustment is necessary, separate formulations of ethambutol, isoniazid, pyrazinamide, and rifampicin are recommended.

If serum transaminase levels exceed the upper limit of normal by at least three times, consideration should be given to using only one or two antituberculosis agents due to the risk of hepatotoxicity. If during treatment transaminase levels exceed 100 IU/L or bilirubin concentration exceeds twice the upper limit of normal, pyrazinamide therapy should be interrupted or discontinued.

Due to possible liver parenchyma damage during pyrazinamide therapy, prolonged coagulation time may occur due to reduced synthesis of coagulation factors.

Patients should be warned to discontinue the drug immediately if any prodromal signs of hepatotoxicity (e.g., weakness, anorexia, nausea, vomiting) occur and to consult a physician.

Pyrazinamide may affect the results of the following diagnostic tests:

determination of bilirubin, uric acid, and thyroxine levels, as well as prothrombin time, serum aminotransferase activity, and serum iron using the Ferrochem II analyzer.

Ethambutol hydrochloride

Ethambutol may cause unilateral or bilateral axial retrobulbar optic neuritis, manifesting as impaired perception of red and green colors, visual disturbances, and central scotoma; periaxial neuritis, manifesting as limitation of the outer visual field boundaries. Regular ophthalmological examinations (visual acuity testing) should be performed before starting treatment and every 4 weeks throughout the treatment course. More frequent examinations may be necessary for patients with renal insufficiency.

In cases of renal dysfunction, dose adjustment based on serum ethambutol levels is required.

Ethambutol should be used with caution in patients with hyperuricemia and gout.

Skin and subcutaneous tissue disorders

During the post-marketing period, severe skin adverse reactions associated with ethambutol use have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced eosinophilia with systemic symptoms (DRESS syndrome), which may be life-threatening or fatal.

Patients should be informed about signs and symptoms of skin reactions and closely monitored for their occurrence during drug administration.

If signs and symptoms indicating these reactions occur, ethambutol should be discontinued immediately, and alternative treatment should be considered (if necessary).

If a serious reaction such as SJS, TEN, or DRESS develops in a patient during ethambutol therapy, ethambutol treatment must not be resumed under any circumstances.

In children, rash may be mistakenly interpreted as the primary infection or an alternative infectious process. Physicians should consider the possibility of an ethambutol reaction in children who develop rash and fever during ethambutol therapy.

Use during pregnancy or breastfeeding.

Pregnancy

Rifampicin

Animal studies have shown teratogenic effects of high doses in rats and mice.

According to currently available limited data, clinical use of rifampicin during pregnancy has not caused specific developmental abnormalities or fetotoxic effects. Although rifampicin crosses the placental barrier and is detected in umbilical cord blood, further studies are needed to evaluate its effects during pregnancy. Therefore, the use of rifampicin during pregnancy should be considered only in the absence of therapeutic alternatives.

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 causing developmental defects in humans have been found to be teratogenic in animals in properly conducted studies on two species. Limited clinical use of isoniazid in pregnant women has not shown specific developmental abnormalities or fetotoxic effects. However, additional studies are needed to evaluate the effects during pregnancy.

Therefore, the use of this combination during pregnancy should be considered only when necessary, keeping in mind that effective treatment of active tuberculosis in pregnant women should continue as prescribed before pregnancy. The drug should preferably be used concomitantly with pyridoxine due to the effects of isoniazid.

Use at the end of pregnancy may lead to early bleeding in the mother and newborn. The use of rifampicin 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.

Pyrazinamide

There are insufficient clinical data confirming the effect of pyrazinamide on pregnant women.

Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development.

Ethambutol hydrochloride

Ethambutol crosses the placenta. Data from a limited number of pregnancies indicate no harmful effects of ethambutol at therapeutic doses on pregnancy or fetal/newborn health. Animal studies have shown reproductive toxicity of high doses of ethambutol.

Lactation period

Rifampicin and isoniazid

Rifampicin and isoniazid pass into breast milk.

Isoniazid is weakly bound to plasma proteins, and passage into breast milk has been demonstrated, with concentrations equivalent to those in maternal plasma. Due to the potential risk of acetylation defect in the newborn and considering the neurotoxic and hepatotoxic effects of isoniazid, breastfeeding is not recommended.

Pyrazinamide

Breastfeeding is possible during pyrazinamide therapy, as the concentrations received by the infant through milk are too low to cause adverse effects in the infant.

However, pyrazinamide should be used during pregnancy and breastfeeding only after careful risk-benefit assessment.

Ethambutol hydrochloride

Ethambutol passes into breast milk. Concentrations in breast milk correspond to maternal blood levels.

Ethambutol hydrochloride should be used during pregnancy and breastfeeding only after careful risk-benefit analysis.

Fertility

There are no data on the effect of the medicinal product on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Rifampicin and isoniazid

Adverse reactions associated with isoniazid use, such as dizziness, visual disturbances, and psychotic reactions, have been reported (see section "Adverse reactions"). Patients should be warned that if these symptoms occur, they should not drive, operate machinery, or engage in any activity where these symptoms could endanger themselves or others.

Pyrazinamide, ethambutol hydrochloride

Even when used as prescribed, pyrazinamide and ethambutol hydrochloride may alter reaction speed to such an extent that the ability to drive or operate machinery is impaired. Taking pyrazinamide with alcohol further alters reaction speed. Rapid and purposeful reactions become impossible.

Additionally, the ability to drive or operate machinery is also impaired if visual disturbances occur due to ethambutol use.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

For adult patients, a single daily dose should be administered, preferably on an empty stomach, at least 30 minutes before a meal or 2 hours after a meal:

• Patients with body weight less than 50 kg should receive 3 tablets per day.
• Patients with body weight 50 kg and above should receive 4 tablets per day.

Renal Impairment

Since dose adjustment may be required for patients with renal impairment (creatinine clearance ≤ 50 mL/min), it is recommended to use separate formulations of ethambutol, isoniazid, pyrazinamide, and rifampicin.

Hepatic Impairment

Some 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 used in 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 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. Official guidelines on resuming antituberculosis therapy should be consulted.

Children

The medicinal product is not used in children. Alternative medicinal products with appropriate dosage should be used for this patient group.

Overdose

Rifampicin and Isoniazid

Symptoms. Cases of overdose have been reported in adults following ingestion of 9 g of rifampicin, and fatal overdoses have occurred with 14 g of rifampicin.

Observed symptoms are most commonly related to isoniazid overdose, with a lethal dose estimated at 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 red discoloration (due to rifampicin content), hyperbilirubinemia, hepatomegaly, and moderate elevation of alkaline phosphatase and transaminase levels.

With rifampicin overdose, cases of arterial hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest have been reported, some of which were fatal. Facial swelling or periorbital edema 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 the presence of concomitant conditions (e.g., hepatic insufficiency, alcohol abuse). Seizures, coma, and hypoxia may occur, potentially leading to death.

Typical laboratory findings in overdose include metabolic acidosis, ketonuria, and hyperglycemia.

Treatment. Gastric lavage in a specialized facility is required, along with measures to counteract acidosis, cardiopulmonary resuscitation, administration of anticonvulsants, and high doses of pyridoxine. In severe cases, treatment may include hemodialysis.

Pyrazinamide

Symptoms. Specific symptoms of pyrazinamide overdose are not well defined. Cases of acute liver function impairment and hyperuricemia have been reported. Additionally, an exacerbation of known adverse reactions may occur (see section "Adverse Reactions").

In clinical studies, marked erythema and itching over the entire skin surface were observed immediately after ingestion of 4 g of pyrazinamide, which completely resolved within several hours without consequences.

Treatment. In emergency cases, all necessary intensive care measures are indicated, including gastric lavage. No specific antidote is available.

Pyrazinamide and its metabolites are eliminated by hemodialysis.

Ethambutol

Symptoms. Loss of appetite, vomiting, gastrointestinal disturbances, fever, headache, confusion, and hallucinations.

Treatment. No specific antidote is available.

Due to rapid absorption, measures to remove ethambutol from the body are only beneficial if initiated shortly after overdose.

Further treatment is symptomatic. For the management of neurological and ophthalmological adverse effects, administration of vitamins B1, B6, and B12, kallikrein, and corticosteroid medicinal products is recommended.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1000 — < 1/100), rare (≥ 1/10,000 — < 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 appearance of new tuberculosis symptoms and clinical or radiological signs in a patient who previously showed improvement after appropriate antituberculosis treatment). This reaction is diagnosed after excluding poor patient adherence to treatment regimen, drug resistance, adverse reactions to antituberculosis therapy, 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 weekly treatment 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: disseminated intravascular coagulation, sometimes fatal; eosinophilia, agranulocytosis, haemolytic anaemia, coagulation disorders.

Immune System Disorders

Frequency not known: anaphylactic reactions (urticaria, bronchospasm, angioneurotic oedema), anaphylactic shock.

Endocrine Disorders

Frequency not known: decompensation of latent or corticosteroid-treated compensated adrenal insufficiency, manifesting as acute adrenal insufficiency (see section "Special Warnings and Precautions for Use").

Metabolism and Nutrition Disorders

Frequency not known: loss of appetite.

Psychiatric Disorders

Frequency not known: isolated cases of psychiatric or psychological disorders.

Nervous System Disorders

Common: headache, dizziness.

Frequency not known: fatal cerebral haemorrhages have been reported when treatment was continued or resumed after development of purpura — in such cases, rifampicin should be discontinued.

Eye Disorders

Frequency not known: discolouration of tear fluid. Rifampicin may permanently stain contact lenses.

Vascular Disorders

Frequency not known: shock, vasomotor reactions, vasculitis, haemorrhage.

Respiratory, Thoracic and Mediastinal Disorders

Frequency not known: dyspnoea, respiratory and asthmatic disorders, abnormal sputum discolouration, interstitial lung disease (including pneumonia).

Gastrointestinal Disorders

Common: nausea, vomiting.

Uncommon: diarrhoea.

Frequency not known: other gastrointestinal disorders such as abdominal pain, flatulence, tooth discolouration (may be irreversible).

Hepatobiliary Disorders

Frequency not known: hepatitis, hyperbilirubinaemia, cholestasis (see section "Special Warnings and Precautions for Use").

Hepatic injury or hepatitis may occur as a hypersensitivity reaction to rifampicin, most commonly during the first month of treatment. Direct hepatotoxic effects of rifampicin may also occur (see section "Special Warnings and Precautions for Use").

Transient hyperbilirubinaemia may occur in the first days of treatment (see section "Special Warnings and Precautions for Use").

Skin and Subcutaneous Tissue Disorders

Frequency not known: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special Warnings and Precautions for Use"), skin hypersensitivity reactions, pruritus with or without rash, urticaria, allergic dermatitis, pemphigoid, discolouration 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 tubular necrosis or tubulointerstitial nephritis, chromaturia (discolouration of urine). Cortical necrosis.

Pregnancy, Postpartum and Perinatal Conditions

Frequency not known: postpartum haemorrhage.

Reproductive System and Breast Disorders

Frequency not known: menstrual disorders.

Congenital, Familial and Genetic Disorders

Frequency not known: porphyria.

General Disorders and Administration Site Reactions

Very common: febrile episodes (fever), chills.

Frequency not known: oedema.

Laboratory Test Abnormalities

Common: increased blood bilirubin levels, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.

Frequency not known: decreased blood pressure, increased creatinine levels, increased plasma liver enzyme levels.

Adverse Reactions Associated with Isoniazid Use

Reproductive System and Breast Disorders

Gynaecomastia.

Skin and Subcutaneous Tissue Disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special Warnings and Precautions for Use"), rash, acne, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome (see section "Special Warnings and Precautions for Use"), exfoliative dermatitis, bullous pemphigoid.

Gastrointestinal Disorders

Nausea, vomiting, epigastric pain.

Frequency not known: pancreatitis.

Hepatobiliary Disorders

Hepatotoxicity: relatively frequent 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 through 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 pyridoxine deficiency): peripheral neuropathies manifesting as distal paraesthesias, particularly in slow acetylators, malnourished patients, and those with alcoholism.

Seizures.

Psychiatric Disorders

Psychiatric disorders resembling neuropsychiatric excitation: hyperactivity, euphoria, insomnia.

In predisposed individuals, particularly when co-administered 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 rare cases: rheumatoid syndrome, algodystrophy (shoulder-hand syndrome), lupus-like syndrome.

Immune System Disorders

Many toxic effects are associated with hypersensitivity and/or high-dose administration (over 10 mg/kg).

Hypersensitivity Reactions

Rare: fever, rash, acne, jaundice or hepatitis, lymphadenopathy, eosinophilia, blood dyscrasias.

Adverse Reactions Associated with Pyrazinamide Use

Blood and Lymphatic System Disorders

Very rare: blood dyscrasias, sideroblastic anaemia, thrombocytopenia.

Immune System Disorders

Rare: hypersensitivity reactions.

Endocrine Disorders

Very rare: adrenal gland dysfunction (urinary excretion of 17-ketosteroids).

Metabolism and Nutrition Disorders

Common: hyperuricaemia (see section "Special Warnings and Precautions for Use").

Very rare: gout attacks, porphyria, pellagra.

Nervous System Disorders

Rare: headache, dizziness, irritability, insomnia.

Vascular Disorders

Very rare: arterial hypertension.

Gastrointestinal Disorders

Common: loss of appetite, nausea, vomiting, heartburn, lower abdominal cramps, weight loss.

Hepatobiliary Disorders

Common: increased serum transaminases, liver function abnormalities.

Rare: marked hepatotoxicity.

Skin and Subcutaneous Tissue Disorders

Common: photosensitization.

Rare: histamine-induced flushes.

Very rare: erythema multiforme.

Musculoskeletal and Connective Tissue, Bone Disorders

Rare: arthralgia.

Renal and Urinary Disorders

Very rare: tubulointerstitial nephritis.

Adverse Effects Associated with Ethambutol Hydrochloride Use

Nervous System Disorders

Common — very common: optic neuritis (see also section "Special Warnings and Precautions for Use"), occurring depending on dose and duration of treatment, after onset of initial symptoms, and more frequently in renal impairment. Symptoms are usually reversible upon discontinuation or interruption of therapy, and the recovery time depends on the degree of optic nerve damage. However, irreversible damage has also been reported.

Sensory disturbances (numbness of extremities), headache, dizziness, confusion, disorientation and hallucinations, finger tremor are commonly observed.

Renal Disorders

Uncommon: nephrotoxic effects.

Increased blood uric acid levels occur in approximately 50% of treated patients, particularly in those with gout. A competing mechanism in tubular excretion of uric acid is presumed. This phenomenon may occur as early as 24 hours after a single dose or within 90 days of therapy and may be intensified by concomitant use of isoniazid and pyridoxine.

Allergic Reactions

Uncommon: exanthema, pruritus, fever, leukopenia, Stevens-Johnson syndrome, severe acute hypersensitivity symptoms, including anaphylactic shock (see subsection "Management of Severe Hypersensitivity Reactions" below).

Gastrointestinal Disorders

Flatulence, bloating, abdominal discomfort, nausea.

Skin and Skin Appendages

Pruritus, exanthema, lichen.

Frequency not known: drug-induced eosinophilia with systemic symptoms (DRESS syndrome) (see section "Special Warnings and Precautions for Use").

Liver and Pancreas Disorders

Uncommon: liver function abnormalities, especially with high doses of ethambutol.

Blood System Disorders

Rare: blood parameter changes, e.g., thrombocytopenia.

Management of Severe Hypersensitivity Reactions

In case of severe acute hypersensitivity reactions (such as anaphylaxis), ethambutol hydrochloride treatment must be immediately discontinued and appropriate emergency measures initiated, including administration of antihistamines, corticosteroids, sympathomimetics, and, if necessary, lung ventilation.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: 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 and sight of children.

Packaging

28 tablets in a blister. 24 blisters in a cardboard pack.

Prescription Status

Prescription only.

Manufacturer

LUPIN LIMITED.

Manufacturer's Address and Location of Operations

A-28/1, MIDC Industrial Area, Chikalthana, Aurangabad, Maharashtra 431210, India.