Rifafor (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis SA (Pty), Ltd. (South Africa)

Manufactured By

Winthrop Pharmaceuticals (Pty), Ltd. (South Africa)

ATC Code

J04AM06 (Rifampicin, Pyrazinamide, Ethambutol and Isoniazid)

Dosage Form

Rifafor

Film-coated tablets, 75 mg+400 mg+150 mg+275 mg: 28, 56, 84, or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of pinkish-lilac color, round, biconvex; on the cross-section, a granular mass is predominantly red-brown in color with numerous inclusions (lighter or almost white).

Excipients: povidone-K-25 47.828 mg, sodium lauryl sulfate 5.714 mg, croscarmellose sodium 34.286 mg, glyceryl tribehenate 34.286 mg, sodium ascorbate 5.714 mg, magnesium stearate 4.286 mg, lactose monohydrate 54.664 mg, corn starch 18.221 mg.

Film coating composition: macrogol-6000 2.902 mg, titanium dioxide (E 171) 8.701 mg, azorubine color 1.106 mg, indigo carmine 0.294 mg, talc 2.174 mg, hypromellose 29.023 mg, simethicone 30% emulsion 0.17 mg.

14 pcs. – Al/Al blisters (2) – cardboard packs.
14 pcs. – Al/Al blisters (4) – cardboard packs.
14 pcs. – Al/Al blisters (6) – cardboard packs.
14 pcs. – Al/Al blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Rifafor^® is a combination of the four first-line drugs listed below for the treatment of tuberculosis.

Rifampicin is an antibiotic from the rifamycin group. It is a semi-synthetic broad-spectrum bactericidal antibiotic.

Isoniazid is a synthetic antituberculosis agent with a bacteriostatic effect against bacilli in the latent state and bactericidal against actively dividing mycobacteria.

Pyrazinamide is a synthetic antituberculosis agent that can be bactericidal or bacteriostatic depending on its concentration and the sensitivity of the microorganism.

Ethambutol is a synthetic bacteriostatic antituberculosis agent.

The combined use of active substances reduces the risk of developing resistance, which occurs with monotherapy.

Mechanism of action

Rifampicin

Rifampicin has a bactericidal effect on Mycobacterium tuberculosis, observed both in vitro and in vivo. It also has varying degrees of activity against other atypical mycobacterial species.

In vivo, Rifampicin has an antibacterial effect against both extracellular and intracellular microorganisms.

Rifampicin inhibits DNA-dependent RNA polymerase of sensitive strains without affecting the host enzyme systems.

Cross-resistance of microorganisms to rifampicin has been observed only with their existing resistance to other rifamycins.

Isoniazid

Isoniazid exerts a bactericidal effect primarily on rapidly growing populations of Mycobacterium tuberculosis. Its mechanism of action appears to be based mainly on the inhibition of mycolic acid synthesis, which is an important component of the mycobacterial cell wall.

Pyrazinamide

The exact mechanism of action has not been established. In vitro and in vivo studies have shown that Pyrazinamide is active only in a slightly acidic environment (pH 5.5).

Ethambutol

The mechanism of action of ethambutol is not fully known. It penetrates the mycobacterium and suppresses its reproduction by disrupting ribonucleic acid (RNA) synthesis. It is effective only against actively dividing mycobacteria.

Microbiological sensitivity

Rifampicin at concentrations from 0.005 to 0.2 µg/ml inhibits the growth of M. tuberculosis in vitro. In vitro, Rifampicin increases the activity of streptomycin and isoniazid (but not ethambutol) against M. tuberculosis.

Isoniazid has a bacteriostatic effect against bacteria in the latent state and bactericidal against actively dividing mycobacteria. Its minimum tuberculostatic concentration ranges from 0.025 to 0.05 µg/ml.

Pyrazinamide has a minimum inhibitory concentration (MIC) against M. tuberculosis of 12.5-20 µg/ml.

Ethambutol had an MIC for M. tuberculosis, determined in various types of liquid and solid media, ranging from 0.5 to 2 µg/ml. The antimicrobial effect of ethambutol is delayed by at least 24 hours, and the degree of microbial growth suppression is more determined by the exposure time than by increasing ethambutol concentrations in the nutrient medium.

Upon completion of the initial intensive phase of treatment of the tuberculous process, treatment can be continued with daily intake of only the double combination Rifampicin+Isoniazid.

This tuberculosis treatment regimen (initial intensive phase of treatment followed by a continuation phase) is suitable for the treatment of newly diagnosed tuberculosis, relapse of the tuberculous process, resumption of treatment after a break, or treatment failure.

Pharmacokinetics

Rifampicin

Rifampicin is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached 2 hours after administration. C_max of the drug in the blood can vary greatly between individuals (healthy adults and children). Food intake reduces the absorption of rifampicin.

After absorption, Rifampicin is rapidly excreted into the bile, after which it undergoes enterohepatic recirculation. Due to the saturation of biliary excretion mechanisms at high doses of rifampicin, its excretion into bile may slow down. During enterohepatic recirculation, rifampicin is gradually deacetylated. The resulting metabolite retains antibacterial activity. Deacetylation reduces intestinal reabsorption and promotes the elimination of rifampicin.

Rifampicin is well distributed in the human body, creating effective concentrations in many organs and fluids, including cerebrospinal fluid. However, under normal conditions, except for meningitis, the concentration in the cerebrospinal fluid is low. Approximately 80% of rifampicin is bound to plasma proteins. Most of the free fraction is non-ionized and therefore freely penetrates tissues.

T_1/2 ranges from 3 to 5 hours, decreasing to 2-3 hours with repeated doses. The elimination rate increases during the first 6-10 days of treatment due to autoinduction of hepatic microsomal oxidation enzymes.

Isoniazid

Isoniazid is rapidly absorbed after oral administration. The rate and extent of absorption are reduced when taken with food. Maximum plasma concentrations are reached 1-2 hours after taking the dose. Isoniazid is well distributed and penetrates most organs, tissues, and fluids of the human body (cerebrospinal, pleural, ascitic, saliva, sweat), as well as feces. The drug crosses the placental barrier and into breast milk in concentrations comparable to those in plasma. Binding to blood proteins is very low, approximately 0 to 10%.

Isoniazid is acetylated by N-acetyltransferase to form N-acetylisoniazid. It is then transformed into isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity due to the formation of a reactive intermediate metabolite (diacetylhydrazine). The rate of acetylation is genetically determined: “slow” acetylators are characterized by a relative deficiency of hepatic N-acetyltransferase. About 50% of Caucasians and African Americans are “slow” acetylators. Most Eskimos and Asians of Mongoloid origin, namely Japanese, Chinese, and Vietnamese, are “fast” acetylators.

T_1/2 is mainly 1-4 hours, but depending on the rate of acetylation, it can vary between 0.5 and 6 hours. About 75-95% of the dose is excreted by the kidneys within 24 hours, primarily in the form of inactive metabolites N-acetylisoniazid and isonicotinic acid.

Pyrazinamide

Pyrazinamide is well absorbed from the gastrointestinal tract. Concomitant food intake does not affect absorption. Maximum plasma concentrations are reached in 1-2 hours in adults and about 3 hours in children.

Pyrazinamide is rapidly distributed throughout the body. Pyrazinamide is hydrolyzed by microsomal deaminase to pyrazinoic acid, an active metabolite, and then hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid.

Pyrazinamide is excreted by the kidneys, mainly in the form of metabolites. Only 3% of the dose is excreted by the kidneys unchanged. T_1/2 is about 10 hours.

Ethambutol

Ethambutol is well absorbed after oral administration. Its bioavailability is approximately 80%. Concomitant food intake does not affect absorption. Maximum plasma concentrations are reached 2-4 hours after taking the dose.

Ethambutol is well distributed in most tissues. It does not pass into the cerebrospinal fluid. However, in patients with tuberculous meningitis, therapeutic concentrations can be achieved in the cerebrospinal fluid. The concentration in erythrocytes is 2-3 times higher than in serum. Binding to blood proteins is low (from 20 to 30%).

Ethambutol is metabolized in the liver, up to 15% of the drug is metabolized to inactive metabolites. T_1/2 of ethambutol is from 3 to 4 hours, but increases to 8 hours in patients with impaired renal function. Up to 80% is excreted by the kidneys within 24 hours (at least 50% unchanged and up to 15% as inactive metabolites). About 20% of the drug is excreted in the feces unchanged.

Indications

Tuberculosis (initial intensive phase of treatment of pulmonary and extrapulmonary processes) including when necessary in combination with other antituberculosis drugs.

ICD codes

Dosage Regimen

Rifafor^® is a fixed combination of drugs intended for use during the initial phase of tuberculosis treatment. Treatment with Rifafor^® is recommended to be carried out under the supervision of a phthisiatrician. The drug is taken orally.

Antituberculosis treatment

The recommended doses and dosage regimen for Rifafor^® are based on current WHO recommendations for the treatment of tuberculosis and may differ from other official guidelines.

The recommended daily therapeutic doses per kilogram of body weight for daily administration during the 2-month initial phase of treatment in adults and children are presented below.

Rifampicin – 8-12 mg/kg (not more than 600 mg); Isoniazid – 4-6 mg/kg (not more than 300 mg); Pyrazinamide – 20-30 mg/kg (not more than 3 g); Ethambutol – 15-25 mg/kg (children) (not more than 1 g), 15-20 mg/kg (adults) (not more than 2 g).

Treatment with Rifafor^®

Rifafor^® should be taken orally once daily in the dose indicated below for 2 months of the initial phase of treatment.

For body weight 30-37 kg – 2 tablets, for body weight 38-54 kg – 3 tablets, for body weight 55-70 kg – 4 tablets, for body weight 71 kg and more – 5 tablets.

For special categories of patients (WHO category IV) in cases of chronic tuberculosis and multidrug resistance (persistent positive sputum test for BK (Koch’s bacillus) after repeated supervised treatment), specially developed standardized or individualized regimens are proposed.

According to indications, other antituberculosis drugs, for example, streptomycin, may be added to the initial phase of treatment.

Use in children

Rifafor^® is not recommended for children weighing less than 30 kg, since the dosage form of Rifafor^® is not adapted for dosing in such children.

Special patient groups

Patients with malnutrition, elderly patients, and patients suffering from diabetes

No special dosage regimen is required, but concomitant hepatic and/or renal insufficiency should be taken into account.

Additional use of pyridoxine (vitamin B₆) may be useful.

Pregnant women

Additional use of pyridoxine (vitamin B₆) and vitamin K may be useful.

Patients with renal insufficiency

Rifafor^® is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min) and is not recommended for patients with moderate renal impairment (creatinine clearance 30-50 ml/min), as it is impossible to select the dose of ethambutol.

Patients with hepatic insufficiency

Rifafor^® is contraindicated in patients with a history of drug-induced hepatitis and in patients with acute liver diseases. Rifafor^® is not recommended for patients with chronic liver diseases, as it is impossible to correctly select the dose of each active ingredient. In other cases of liver dysfunction, Rifafor^® should be used with caution under strict medical supervision.

Method of administration

Rifafor^® tablets are taken whole and washed down with a full glass of water, one hour before or 2 hours after a meal. In case of gastrointestinal irritation, the tablets may be taken with food.

When taking aluminum-containing antacids, enterosorbents, including activated charcoal, simultaneously, they should be taken 2 hours before or 2 hours after taking the Rifafor^® tablet.

Interruption of treatment

If the initial intensive phase of treatment with Rifafor^® was interrupted for any reason, it is necessary to refer to the relevant official recommendations for resuming treatment with antituberculosis drugs.

Adverse Reactions

Side effects are classified by organ systems and frequency of occurrence using the following designations: very common – ≥1/10; common – from ≥1/100 to <1/10; uncommon – from ≥1/1000 to <1/100; rare – from ≥1/10000 to <1/1000; very rare – <1/10000; unknown frequency – based on available data, it is impossible to estimate the frequency of the side effect.

Side effects of rifampicin

Disorders of the blood and lymphatic system rare – eosinophilia, transient leukopenia, hemolysis, hemolytic anemia, thrombocytopenia and thrombocytopenic purpura, cerebral hemorrhage and fatalities; very rare – agranulocytosis.

Disorders of the immune system unknown frequency – lupus-like syndrome.

Disorders of the endocrine system rare – stimulation of crisis in patients with Addison’s disease, adrenal insufficiency (in patients with impaired adrenal function), menstrual cycle disorders (in exceptional cases amenorrhea).

Mental disorders rare – confusion, psychoses.

Disorders of the nervous system common – fatigue, drowsiness, headache, dizziness; rare – ataxia, muscle weakness, myopathy; unknown frequency – feeling of numbness, disorientation.

Disorders of the organ of vision common – eye irritation, eye redness, persistent staining of soft contact lenses in a red-orange color; rare – visual disturbances, blurred vision, exudative conjunctivitis.

Vascular disorders rare – disseminated intravascular coagulation (DIC syndrome).

Gastrointestinal disorders common – anorexia, nausea; abdominal pain, abdominal distension; rare – vomiting or diarrhea, isolated episodes of erosive gastritis and pseudomembranous colitis.

Disorders of the liver and biliary tract common – asymptomatic increase in the activity of “liver” transaminases in the blood serum; rare – hepatitis, jaundice, induction of porphyria attacks; unknown frequency – hyperbilirubinemia.

Disorders of the skin and subcutaneous tissues common – in some patients, a skin syndrome (skin hyperemia, itching with or without skin rash, urticaria) may occur within 2-3 hours after administration, both with daily and irregular use of the drug; rare – severe skin reactions, such as generalized hypersensitivity reactions, including those such as exfoliative dermatitis (including Lyell’s syndrome), erythema multiforme (including Stevens-Johnson syndrome), pemphigoid reactions, vasculitis.

Disorders of the kidneys and urinary tract rare – increase in blood urea nitrogen and uric acid in the blood serum, acute renal failure (hemoglobinuria, hematuria) due to interstitial nephritis, glomerulonephritis and tubular necrosis.

Metabolism and nutrition disorders unknown frequency – hyperuricemia, exacerbation of gout.

General disorders and administration site conditions common – reddish coloration of body fluids and secretions (such as urine, sputum, tear fluid, feces, saliva, sweat); rare – collapse, decreased blood pressure and shock, edema.

Side effects of rifampicin, usually occurring with irregular use or when returning to treatment after a temporary break.

In patients who take Rifampicin not daily, as well as in those who return to treatment with this drug after a temporary break, a flu-like syndrome, most likely of an immunopathological nature, may occur. It is characterized by fever, chills and possibly headache, dizziness and muscle pain. In rare cases, this flu-like syndrome may be accompanied by thrombocytopenia, purpura, shortness of breath, asthmatic-like attacks (breathing difficulty and wheezing), acute hemolytic anemia, decreased blood pressure, shock, anaphylaxis and acute renal failure (usually due to acute tubular necrosis or acute interstitial nephritis).

These serious complications may, however, occur unexpectedly, without a preceding flu-like syndrome, mainly when treatment is resumed after a temporary interruption or when Rifampicin is given only once a week in a high dose (≥25 mg/kg).

Adverse reactions of isoniazid

Blood and lymphatic system disorders rare – anemia (hemolytic, sideroblastic), eosinophilia, thrombocytopenia, lymphadenopathy; very rare – agranulocytosis; unknown frequency – aplastic anemia, neutropenia, tendency to bleeding and hemorrhage,

Endocrine disorders rare – Isoniazid may affect the hepatic metabolism of a number of hormones, leading to menstrual disorders, gynecomastia, Cushing’s syndrome, precocious puberty, difficulties in controlling diabetes mellitus, hyperglycemia, and metabolic acidosis.

Psychiatric disorders infrequent – toxic psychoses; rare – euphoria, hyperactivity, insomnia.

Nervous system disorders frequent – toxic peripheral neuropathy, polyneuritis, manifesting as muscle weakness, loss of tendon reflexes, usually preceded by paresthesia in the hands and feet; infrequent – convulsions, memory impairment, optic neuritis and atrophy, toxic encephalopathy; rare – dizziness, feeling faint, headache, increased frequency of seizures in patients with epilepsy; unknown frequency – excessive fatigue or weakness, irritability, emotional lability, depression.

Cardiac disorders unknown frequency – palpitations, angina pectoris, increased blood pressure.

Gastrointestinal disorders frequent – anorexia, gastric discomfort, nausea, vomiting; rare – dry mouth, heartburn; unknown frequency – pancreatitis, gastralgia.

Hepatobiliary disorders frequent – impaired liver function (usually moderate and transient increase in serum “liver” transaminase activity); rare – hepatitis, severe, sometimes fatal; unknown frequency – hyperbilirubinemia, bilirubinuria, jaundice.

Skin and subcutaneous tissue disorders rare – lupus-like reactions, acne, vasculitis; unknown frequency – rash, exfoliative dermatitis, pemphigus, erythema multiforme (Stevens-Johnson syndrome).

Musculoskeletal and connective tissue disorders rare – rheumatic syndrome.

Renal and urinary disorders rare – urinary disorders; unknown frequency – urinary retention.

Immune system disorders frequent – allergic and other reactions such as exanthema and fever; unknown frequency – allergic skin rash (measles-like maculopapular, purpura), pruritus, arthralgia.

Metabolism and nutrition disorders unknown frequency – vitamin B₆ deficiency, pellagra.

Adverse reactions of pyrazinamide

Blood and lymphatic system disorders rare – sideroblastic anemia, splenomegaly, thrombocytopenia with or without purpura, hypercoagulation; unknown frequency – erythrocyte vacuolization.

Gastrointestinal disorders frequent – abdominal pain, anorexia, gastric discomfort, nausea, vomiting; unknown frequency – exacerbation of peptic ulcer, diarrhea, “metallic” taste in the mouth.

Hepatobiliary disorders liver damage is the most common side effect; frequent – moderate and transient increase in serum “liver” transaminase activity during the early phase of treatment, porphyria; rare – hepatomegaly, dose-dependent hepatotoxicity, severe and fatal in some cases, jaundice; unknown frequency – liver tenderness, acute yellow liver atrophy.

Central nervous system disorders unknown frequency – dizziness, headache, sleep disturbances, increased excitability, depression, in isolated cases hallucinations, convulsions, confusion.

Skin and subcutaneous tissue disorders rare – acne, photosensitivity, pruritus, urticaria, skin rash; very rare – angioedema.

Musculoskeletal and connective tissue disorders frequent – joint pain, muscle pain.

Renal and urinary disorders rare – interstitial nephritis, dysuria.

General disorders and administration site conditions rare – fever (hyperthermia); unknown frequency – malaise.

Metabolism and nutrition disorders frequent – hyperuricemia (often asymptomatic); unknown frequency – exacerbation of gout, increased serum iron concentration.

Adverse reactions of ethambutol

Blood and lymphatic system disorders rare – thrombocytopenia, leukopenia.

Psychiatric disorders infrequent – hallucinations.

Nervous system disorders infrequent – dizziness, disorientation, confusion, headache, malaise; rare – peripheral neuritis (numbness, tingling sensation, burning pain or weakness in the hands and feet); unknown frequency – weakness, depression.

Eye disorders rare – dose-dependent retrobulbar optic neuritis (decreased visual acuity, narrowing of the visual field, central or peripheral scotoma, blurred vision, eye pain, red-green color blindness, loss of vision), retinal hemorrhage (less frequent).

Gastrointestinal disorders infrequent – abdominal pain, loss of appetite, anorexia, nausea, vomiting; unknown frequency – “metallic” taste in the mouth.

Hepatobiliary disorders unknown frequency – jaundice, transient hepatic dysfunction, increased serum “liver” transaminase activity.

Skin and subcutaneous tissue disorders infrequent – pruritus, urticaria, rash, allergic dermatitis.

Renal and urinary disorders infrequent – hyperuricemia.

General disorders and administration site conditions rare – hypersensitivity (skin rash, fever, joint pain), anaphylactic reactions.

Metabolism and nutrition disorders unknown frequency – exacerbation of gout.

Adverse effects associated with the presence of certain excipients in the drug Rifafor^®

Due to the presence of the dye azorubine in the drug composition, Rifafor^® may cause allergic reactions.

If you experience serious or unexpected (not listed above) side effects, you should report them to the marketing authorization holder and/or health authorities, in accordance with local regulations.

Contraindications

• Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or other chemically related drugs and/or to excipients included in the drug Rifafor^®;
• Porphyria (due to the presence of rifampicin in the drug composition, exacerbation of porphyria is possible);
• Acute gouty arthritis;
• Chronic renal failure;
• Optic neuritis;
• History of drug-induced hepatitis or acute hepatitis; exacerbation of chronic liver diseases, regardless of their origin, jaundice, recently (less than one year) suffered infectious hepatitis, hepatic failure observed during previous treatment with isoniazid;
• Severe cardiopulmonary insufficiency;
• Cataract, diabetic retinopathy, inflammatory eye diseases;
• Children under 13 years of age or with a body weight of less than 30 kg;
• Concomitant use of midazolam;
• Concomitant use of voriconazole and protease inhibitors (except ritonavir, if taken at full dose or 600 mg twice a day);
• Congenital lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

With caution

• In hyperuricemia, history of gouty arthritis (Pyrazinamide may reduce the excretion of uric acid);
• In diabetes mellitus (due to the presence of isoniazid in the drug composition, deterioration of glycemic control is possible);
• In epilepsy (due to the presence of isoniazid and ethambutol in the drug composition, increased seizures are possible);
• In hormonal contraception (due to the presence of rifampicin in the drug composition, reduced effectiveness of oral contraceptives is possible);
• In hemoptysis (Pyrazinamide may increase blood clotting time and adversely affect the integrity of the vascular wall);
• In the presence of a history of psychosis;
• In visual impairments, except for optic neuritis, for which the drug is contraindicated) (due to the presence of ethambutol in the drug composition, increased visual disturbances are possible);
• In persons over 35 years of age;
• In case of history of isoniazid treatment discontinuation;
• In peripheral neuropathy;
• In HIV infection;
• In decompensated cardiovascular diseases (chronic heart failure, angina pectoris, arterial hypertension);
• In hypothyroidism;
• In elderly persons, poorly nourished patients, “slow” acetylators, pregnant women, patients with diabetes mellitus and alcoholism (in these patients, due to the presence of isoniazid in the drug composition, development of vitamin B₆ deficiency is possible);
• In liver function disorders (difficulty in selecting doses of active ingredients when using their fixed combination and increased risk of developing hepatotoxic effects of the active ingredients of Rifafor^®);
• In pregnancy and during breastfeeding.

Use in Pregnancy and Lactation

The degree of safety of using the drug Rifafor^® during pregnancy has not been fully established. Rifampicin, Isoniazid, ethambutol pass through the placental barrier. Plasma concentrations of ethambutol in the fetus can reach up to 30% of its plasma concentrations in the mother.

According to limited clinical data on the use of rifampicin, isoniazid and ethambutol during pregnancy, no increase in the frequency of fetal malformations was found. It is not known whether Pyrazinamide can cause fetal damage when used during pregnancy.

Treatment with the drug Rifafor^® during pregnancy can be carried out only if the potential benefit to the mother outweighs the potential risk to the fetus. Additional administration of pyridoxine (vitamin B₆) during pregnancy is recommended. Isoniazid may have a neurotoxic effect on the child. Since Rifampicin may cause postnatal bleeding in the mother and newborn, if taken in the third trimester of pregnancy, the mother should take phytomenadione (vitamin K) orally during the last month of pregnancy.

Rifampicin, Isoniazid, Pyrazinamide and ethambutol are excreted in breast milk. No adverse effects on breastfed infants have been found, however, given the potential for neurotoxic effect due to the presence of isoniazid and ethambutol in the drug composition, a decision to use the drug Rifafor^® in a breastfeeding mother should be made only if the potential benefit to the patient outweighs the potential risk to the child.

Use in Hepatic Impairment

Contraindicated in history of drug-induced hepatitis or acute hepatitis; exacerbation of chronic liver diseases, regardless of their origin, jaundice, recently (less than one year) suffered infectious hepatitis, hepatic failure observed during previous treatment with isoniazid.

Use with caution in liver function disorders (difficulty in selecting doses of active ingredients when using their fixed combination and increased risk of developing hepatotoxic effects of the active ingredients of Rifafor^®).

Use in Renal Impairment

Contraindicated in chronic renal failure.

Pediatric Use

Contraindicated in children under 13 years of age or with a body weight of less than 30 kg.

Geriatric Use

Use with caution in persons over 35 years of age, especially in elderly patients.

Special Precautions

Effect on laboratory and instrumental tests

Microbiological methods used to determine plasma concentrations of folic acid and cyanocobalamin (vitamin B₁₂)

These tests cannot be used during therapy with the drug Rifafor^® (due to the content of rifampicin in its composition).

Bromsulphthalein (BSP) test

Since Rifampicin transiently competes with bilirubin and bromsulphthalein, to exclude false positive reactions, the BSP test should be performed in the morning before the morning dose of the drug Rifafor^®.

Studies with contrast agent for gallbladder imaging

Rifampicin, due to competition for biliary excretion, may disrupt the biliary excretion of the contrast agent used for gallbladder imaging. Thus, such studies should be performed in the morning before the morning dose of the drug Rifafor^®.

Determination of urine glucose with copper sulfate

Due to the presence of isoniazid in the drug Rifafor^®, false positive reactions for the determination of urine glucose with copper sulfate may occur.

Determination of ketone bodies in urine

Pyrazinamide may interfere with the detection of ketone bodies in urine.

Interaction with food

Refers to isoniazid

Because Isoniazid has some monoamine oxidase (MAO) inhibitory activity, interaction with foods containing tyramine (cheese, red wine, etc.) may occur when taking it. In addition, inhibition of diamine oxidase is possible, which can cause a very pronounced reaction (e.g., headache, sweating, palpitations, “flushing,” excessive decrease in blood pressure) to food containing histamine (e.g., sardines, tuna, other tropical fish). Food containing tyramine and histamine in patients receiving Rifafor^® should be excluded.

When treating with the drug Rifafor^®, official recommendations for the use of anti-tuberculosis drugs should be taken into account.

According to the EuroTB program, 2007, the WHO/International Union Against Tuberculosis and Lung Disease global review for 1999-2002 and the US Centers for Disease Control and Prevention, in newly diagnosed disease (never treated patients) in different regions of the world, resistance values indicated below were observed.

Patients should be warned about the dangers of interrupting treatment, consuming alcohol, and also informed about recommended methods of contraception.

Laboratory and clinical monitoring of patients before and during treatment

In adult patients undergoing treatment with the drug Rifafor^® for tuberculosis, before starting treatment and then regularly during treatment, serum activity of “liver” transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (AST)), concentrations of bilirubin, creatinine, uric acid in the blood serum should be determined, and a complete blood count (including platelet count) should be performed.

In children, these tests before treatment are not mandatory, except in cases where the child is known to have aggravating conditions (liver, kidney damage) or if they are suspected.

During treatment, the patient should be examined by a doctor at least once a month. He/she should be specifically asked about symptoms related to side effects. All patients with any abnormalities should be under observation, including laboratory tests if necessary.

Regular observation by an ophthalmologist before and during treatment is recommended.

Liver function disorders (associated with rifampicin, isoniazid, pyrazinamide and ethambutol)

Rifampicin, Isoniazid, Pyrazinamide and ethambutol are metabolized in the liver. Rifampicin, Isoniazid and Pyrazinamide are associated with the development of hepatitis. The most hepatotoxic is Pyrazinamide. Rifampicin causes hepatocellular disorders less than other active ingredients of this combination, but it is associated with the development of cholestatic jaundice.

When taking the drug Rifafor^®, an increase in serum transaminase activity above the upper limit of normal often occurs. Liver dysfunction, which may occur in the first few weeks of treatment, usually decreases and liver function indicators return to normal spontaneously, without interrupting treatment (usually by the third month of treatment). Isolated moderate increase in bilirubin and/or serum transaminase activity is not a reason to interrupt treatment. To decide whether to continue or interrupt treatment, repeated studies of liver function indicators should be performed and the trend in the change of these indicators and their correspondence to the patient’s clinical condition should be determined. Discontinuation of treatment with the drug Rifafor^® is recommended in case of clinically significant jaundice, failure of liver function indicators to return to normal or more than three times the upper limit of normal for serum transaminase activity: Rifafor^® should be replaced by taking each of its active ingredients separately (not in a fixed combination) in order to facilitate the selection of the necessary dosing regimens for each of the active ingredients.

In patients with liver function disorders, careful monitoring of its function should be carried out, in particular regular determination of serum ALT and AST activity before starting treatment and every week or every two weeks during treatment. If signs of hepatocellular disorders occur, then Rifafor^® should be discontinued.

In patients with chronic liver diseases, the therapeutic benefit from treatment with the drug Rifafor^® should be weighed against the possible risk. If the need for anti-tuberculosis treatment in such patients is recognized, then the use of the fixed combination of drugs Rifafor^® is not recommended, as for ease of selecting doses of each of its active ingredients, their separate use is more appropriate.

Patients without proven chronic liver diseases can receive standard short-course chemotherapy regimens.

Severe and sometimes fatal hepatitis associated with isoniazid may develop even after many months of treatment. The risk of developing hepatitis is related to age. Isoniazid-associated hepatotoxicity (considered to be related to its metabolite diacetylhydrazine) rarely occurs in patients under 20 years of age, but becomes more frequent with increasing age, with the highest frequency in patients after 35 years and affecting up to 3% of patients after 50 years of age. Determination of transaminase activity in patients over 35 years of age should be performed before starting and at least once a month during treatment.

Other factors that increase the risk of developing hepatitis are daily alcohol consumption, chronic liver disease, use of intravenous drugs, and genetically determined reduction in acetylating function of the liver.

Patients should be monitored for the occurrence of prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea and vomiting. If these symptoms occur or signs of liver damage are detected, treatment should be stopped immediately. Continued use of the drug Rifafor^® in such patients may lead to more severe forms of liver damage.

Alcohol

During treatment with Rifafor^®, alcohol consumption must be avoided. Regular neurological examination and special treatment are required for patients who abuse alcohol.

“Rapid” and “slow” acetylators (due to the presence of isoniazid in the composition)

In cases of known acetylation phenotypes, patients with very rapid or very slow acetylating capacity should receive these four components separately to facilitate isoniazid dose adjustment.

Hypersensitivity reactions

In case of severe acute hypersensitivity reactions, such as thrombocytopenia, purpura, hemolytic anemia, shortness of breath and asthmatic-like attacks, shock, or renal failure, Rifafor^® must be immediately discontinued. Patients who have developed such reactions should never take Rifafor^® again.

Rifafor^® should also be discontinued if other hypersensitivity reactions occur, such as fever or skin reactions.

Interrupted therapy or resumption of treatment after a temporary break (due to the presence of rifampicin in the composition)

Patients should be warned and monitored for interruptions in taking the drug due to the possibility of developing immunological reactions that occur with intermittent therapy (less than 2-3 times per week).

Combination with other drugs (due to the presence of rifampicin and isoniazid in the composition)

Rifampicin is a potent inducer of microsomal enzymes; it can accelerate the metabolism of endogenous substrates of these enzymes, including adrenal hormones and vitamin D.

There are isolated reports of porphyria exacerbation associated with rifampicin intake.

Rifampicin can accelerate the metabolism of concurrently administered drugs, leading to a decrease in their plasma concentrations below therapeutic levels and reduced efficacy. Drugs eliminated via hepatic metabolism should be used concomitantly with Rifafor^® only if it is possible to monitor their plasma concentrations or clinical and side effects, and their dose must be carefully adjusted.

The use of the following drugs concomitantly with Rifafor^® is not recommended:

• Due to interaction with rifampicin: nevirapine, ritonavir (when used in low doses), oral contraceptives, halothane, praziquantel, simvastatin, telithromycin, and tyrosine kinase inhibitors;
• Due to interaction with isoniazid: carbamazepine and disulfiram.

Contraception method (due to the presence of rifampicin in the composition)

Rifampicin may reduce the effectiveness of oral contraceptives. To prevent pregnancy during treatment with Rifafor^® and for one additional menstrual cycle after discontinuation of treatment, non-hormonal methods of contraception should be used.

Reddish discoloration of fluids (due to the presence of rifampicin in the composition)

Rifampicin may cause reddish discoloration of body fluids and secretions (urine, sweat, sputum, feces, saliva, and tears), and the patient should be warned about this in advance. Soft contact lenses may become stained.

Visual disturbances (due to the presence of ethambutol in the composition)

Rifafor^® should be used with caution in patients with visual impairments.

An examination by an ophthalmologist (assessment of visual acuity, color vision, and visual fields) is recommended before starting treatment and regularly during treatment, especially when using high doses of the drug.

The degree of visual impairment has been found to be dose-dependent and related to the duration of therapy.

Patients should be questioned about their vision at every visit. Progressive deterioration of visual acuity during therapy should be considered a side effect of ethambutol. If corrective glasses were used before treatment, they should be worn during visual acuity assessment. A refractive error may develop within 1-2 years of therapy, which should be corrected to obtain accurate test results. Visual acuity testing through a pinhole eliminates refractive error.

Discontinuation of Rifafor^® is recommended if visual disturbances become clinically significant. Recovery of visual acuity usually occurs within weeks or months after drug discontinuation.

Supplemental pyridoxine administration (due to the presence of isoniazid in the composition)

Since Isoniazid in high doses can lead to the development of pyridoxine (vitamin B₆) deficiency, supplemental pyridoxine administration may be beneficial to prevent peripheral neuropathy, as well as most other nervous system dysfunctions. These side effects are dose-dependent and occur most frequently in undernourished patients, the elderly, patients who are “slow” acetylators, patients with diabetes, individuals suffering from alcoholism, and during pregnancy. Pyridoxine should be used in accordance with official recommendations.

Patients with gout or a history of gout (due to the presence of pyrazinamide and ethambutol in the composition)

Pyrazinamide and ethambutol should be used with caution in patients with a history of gout. Pyrazinamide has been reported to reduce urate excretion. Regular monitoring of plasma uric acid concentrations should be performed. If hyperuricemia occurs during treatment in combination with acute gouty arthritis, Rifafor^® should be discontinued.

Patients with diabetes mellitus (due to the presence of isoniazid and pyrazinamide in the composition)

Treatment of diabetes mellitus is significantly complicated when taking isoniazid.

Pyrazinamide may interfere with the detection of ketone bodies in urine.

Patients with epilepsy (due to the presence of isoniazid and ethambutol in the composition)

Given the possible neurotoxic effects of isoniazid and ethambutol, patients who experience seizures should be under special supervision during treatment with Rifafor^®.

High doses of isoniazid may increase the frequency of seizures in epileptic patients.

Patients with impaired renal function (due to the presence of rifampicin, isoniazid, pyrazinamide, and ethambutol in the composition)

In severe renal failure, the elimination of isoniazid, pyrazinamide, and ethambutol may be slowed, which can lead to increased plasma concentrations and contribute to enhanced side effects. Therefore, Rifafor^® is contraindicated in patients with severe renal failure (creatinine clearance <30 ml/min). Rifafor^® is also not recommended for patients with moderate renal failure (creatinine clearance 30-50 ml/min). In case of acute renal failure development, Rifafor^® should be immediately discontinued without subsequent resumption.

Elderly patients

Increased risk of toxic events. Careful monitoring of patients for toxic effects is required.

Patients with hemoptysis (due to the presence of pyrazinamide in the composition)

In patients with hemoptysis, the possibility of an adverse effect of pyrazinamide on clotting time or vascular wall permeability should be considered.

Patients with a history of psychosis (due to the presence of rifampicin and isoniazid in the composition)

Caution should be exercised when using the drug in such patients.

Patients with lactose intolerance (related to excipients in the composition of Rifafor^®)

Patients with hereditary lactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Need to avoid consumption of foods containing tyramine and histamine (such as cheese, red wine, horse mackerel, tuna, other tropical fish)

Patients taking Rifafor^® tablets should avoid consuming foods containing tyramine and histamine (such as cheese, red wine, horse mackerel, tuna, other tropical fish).

Effect on ability to drive vehicles or engage in other potentially hazardous activities

The effect of Rifafor^® on the ability to drive vehicles or engage in other potentially hazardous activities is minor or moderate. Caution should be exercised when driving vehicles or operating machinery. In case of side effects such as confusion, disorientation, hallucinations, dizziness, malaise, and visual disturbances (blurred vision, red-green color blindness, vision loss), the patient’s ability to drive vehicles or engage in other potentially hazardous activities may be impaired.

Overdose

Treatment applicable to Rifafor^® overdose

In cases of Rifafor^® overdose, gastric lavage should be performed as soon as possible. After evacuation of stomach contents, administration of activated charcoal with water is useful to absorb the remaining drug from the gastrointestinal tract. Antiemetics are used to treat severe nausea and vomiting. Intensive measures to maintain vital functions should be initiated, including maintaining airway patency, and symptomatic treatment should be provided if specific symptoms occur.

Signs and symptoms of rifampicin overdose

Toxicity

As practice has shown, overdose symptoms and outcomes are variable. Rifampicin doses from 15 g to 60 g in adults have led to fatal outcomes, while a dose of 9 g in adults caused severe intoxication, and a dose of 12 g in adolescents caused moderate intoxication.

Some reports of fatal and non-fatal overdoses involved alcohol abuse or a history of alcohol abuse.

Symptoms

Gastrointestinal complaints, including abdominal pain, nausea, vomiting, sweating, shortness of breath, convulsions, headache, and increasing lethargy may occur shortly after ingestion; loss of consciousness may occur with severe liver damage. Transient increase in serum “liver” transaminase activity and/or bilirubin, renal failure, generalized itching may appear. Red-brown or reddish-orange discoloration of the skin, urine, sweat, saliva, tears, and feces is possible, and the intensity depends on the amount of rifampicin ingested.

Facial or periorbital edema has also been observed in sick children. In some fatal cases, arterial hypotension, sinus tachycardia, ventricular arrhythmias, convulsive seizures, and cardiac arrest were observed. Pulmonary edema is possible.

Treatment

Evacuation of stomach contents and repeated doses of activated charcoal are indicated.

Signs and symptoms of isoniazid overdose

Toxicity

Toxicity is enhanced by alcohol. The lethal dose is 80-150 mg/kg of body weight.

• Ingestion of 5 g of isoniazid resulted in fatal intoxication in a 15-year-old adolescent.
• Ingestion of 900 mg of isoniazid resulted in moderately severe intoxication in an 8-year-old child.
• Ingestion of 2-3 g of isoniazid resulted in severe intoxication in a 3-year-old child.
• Ingestion of 3 g (15-year-old adolescent) and 5-7.5 g (adults) of isoniazid led to extremely severe intoxication.

Symptoms

In overdose, characteristic signs and symptoms appear within 0.5-3 hours after ingestion. Nausea, vomiting, dizziness, slurred speech, blurred vision, and visual hallucinations (including bright colors and strange images) are early signs. Other typical symptoms are convulsive seizures and severe metabolic acidosis, ketonuria, hyperglycemia, periorbital myoclonus, tinnitus, tremor, hyperreflexia, paresthesia, impaired consciousness. Respiratory disorders and CNS depression, rapidly progressing from stupor to deep coma, as well as severe, intractable convulsive seizures, may occur. Apnea, tachycardia, arrhythmia, decreased blood pressure, fever, acute skeletal muscle necrosis, DIC syndrome, hyperkalemia, and liver damage have also been reported.

Isoniazid doses exceeding 10 mg/kg may adversely affect the nervous system (possible occurrence of peripheral neuropathy) and, consequently, impair the patient’s ability to drive a car or operate machinery.

Treatment

Evacuation of stomach contents (if the patient is not having a seizure), oral or gastric administration of activated charcoal. Urgent determination of blood gas levels, electrolyte concentrations, blood urea nitrogen, glucose, etc., is required.

In case of convulsive seizures and metabolic acidosis, pyridoxine (vitamin B₆) is administered intravenously at a dose of 1 g per 1 g of isoniazid.

In case of convulsive seizures and an unknown dose of isoniazid, 5 g of pyridoxine is administered intravenously.

In the absence of seizures, 2-3 g of pyridoxine is administered intravenously for prophylaxis.

Pyridoxine should be administered in a diluted form over 30 minutes (to reduce the irritant effect on blood vessels). If necessary, pyridoxine can be re-administered in the above doses.

Diazepam potentiates the anticonvulsant effect of pyridoxine. In the absence of pyridoxine, high doses of diazepam can be administered to stop seizures. In severe cases, artificial ventilation may be required. Patients should undergo correction of metabolic acidosis with sodium bicarbonate and correction of electrolyte disturbances. Good diuresis should be ensured. In cases of extremely severe intoxication, hemodialysis or hemoperfusion may be needed. If these blood purification methods are unavailable, peritoneal dialysis can be used, either alone or with forced diuresis.

Signs and symptoms of pyrazinamide overdose

Toxicity

There is limited information on pyrazinamide overdose. Hepatic toxicity (acute liver injury) and hyperuricemia may occur in overdose.

Treatment

Treatment is mainly symptomatic. Within the first hours after ingestion, vomiting should be induced and/or gastric lavage performed. There is no specific antidote. Treatment is supportive and symptomatic.

Signs and symptoms of ethambutol overdose

Toxicity

There is limited information on ethambutol overdose.

Symptoms

Loss of appetite, gastrointestinal disorders, fever, headache, dizziness, confusion, hallucinations.

Treatment

Within the first hours after ingestion, vomiting should be induced and/or gastric lavage performed. Hemodialysis may be beneficial. There is no specific antidote. Treatment is supportive and symptomatic.

Drug Interactions

With antacids, enterosorbing agents, including activated charcoal

These drugs may reduce the bioavailability of rifampicin, isoniazid, and ethambutol. Therefore, Rifafor^® should be taken at least 2 hours before or 2 hours after taking antacids, enterosorbing agents, including activated charcoal.

With glucocorticosteroids

Corticosteroids may reduce plasma concentrations of isoniazid by accelerating its metabolism and/or renal clearance.

With para-aminosalicylic acid

Para-aminosalicylic acid may increase plasma concentrations and half-life of isoniazid due to competition for acetylating enzymes. Para-aminosalicylic acid preparations should be administered no earlier than 4 hours after rifampicin intake, as para-aminosalicylic acid impairs its absorption.

With ethanol, paracetamol, and other hepatotoxic drugs

Concomitant use with Rifafor^® may promote the manifestation of hepatotoxicity of rifampicin, isoniazid, and pyrazinamide. Careful monitoring of patients simultaneously receiving Rifafor^® and hepatotoxic drugs is necessary to detect liver damage.

With vaccines

Oral live combined typhoid vaccine may be inactivated by Rifafor^®.

With drugs for the treatment of gout (allopurinol, colchicine, probenecid, or sulfinpyrazone)

A decrease in the effectiveness of antigout drugs is possible because Pyrazinamide, which is part of Rifafor^®, may reduce uric acid excretion.

With neurotoxic drugs

When taken concomitantly with ethambutol, an increase in the neurotoxic effects of the latter (development of optic neuritis, peripheral neuritis) is possible. Ethambutol enhances the neurotoxicity of ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium salts, imipenem, methotrexate, quinine.

With drugs metabolized by cytochrome P450 system enzymes and UDP (uridine diphosphate)-glucuronosyltransferase

Rifampicin is known to induce, and Isoniazid to inhibit, certain cytochrome P450 (CYP450) family enzymes. Thus, Rifampicin is the most potent inducer of cytochrome P450 system isoenzymes, namely the CYP3A and CYP2C subfamilies, which account for more than 80% of cytochrome P450 isoenzymes. Therefore, Rifampicin can accelerate the metabolism of many concurrently administered drugs that are completely or partially metabolized by these two cytochrome P450 isoenzyme subfamilies. Moreover, Rifampicin also stimulates UDP-glucuronosyltransferase, another enzyme involved in the metabolism of a number of drugs. This can lead to a decrease in plasma concentrations of these co-administered drugs below therapeutic levels, with a reduction or even loss of their efficacy. On the other hand, Isoniazid inhibits the metabolism of some drugs, leading to an increase in their plasma concentrations. Furthermore, some drugs are subject to opposing influences from rifampicin and isoniazid, for example, phenytoin, warfarin, and theophylline, with unpredictability of the overall effect, which may also change over time.

When such drugs are used concomitantly with Rifafor^®, adjustment of their dosage regimen may be required. Drugs eliminated via metabolic transformations should be used concomitantly with Rifafor^® only when it is possible to monitor their plasma concentrations and/or clinical and side effects, which may allow for adequate adjustment of their dosage regimen. It should be noted that after starting rifampicin, the enzyme induction effects reach a maximum within 10 days, and after discontinuation of rifampicin, they gradually decrease over 2 or more weeks. This should be taken into account when discontinuing Rifafor^®, in case the dose of other drugs was increased during its administration. Therefore, regular monitoring of such patients should be carried out during treatment with Rifafor^® and for 2-3 weeks after its discontinuation.

Drugs interacting with rifampicin

Contraindicated combinations

With midazolam, protease inhibitors (except ritonavir when it is taken at a full dose or at 600 mg twice a day), voriconazole.

Not recommended combinations

With nevirapine, ritonavir (a significant decrease in their plasma concentrations may occur when they are taken in low doses as a booster); oral contraceptives; halothane; praziquantel; simvastatin; telithromycin; tyrosine kinase inhibitors.

Combinations requiring special caution and possible dose adjustment of the following drugs

Class IA antiarrhythmic drugs (disopyramide, quinidine); indirect anticoagulants (warfarin); oral hypoglycemic drugs of the sulfonylurea group; azole antifungal drugs (fluconazole, ketoconazole) except voriconazole, which is contraindicated; barbiturates (hexobarbital); benzodiazepines (diazepam) and benzodiazepine-related drugs (zopiclone, zolpidem); hepatically metabolized beta-blockers (metoprolol, propranolol); “slow” calcium channel blockers (diltiazem, nifedipine, verapamil); digitalis preparations (digoxin, digitoxin); corticosteroids (hydrocortisone); estrogens and progestogens (for hormone replacement therapy); fluoroquinolones; thyroid hormones (levothyroxine); immunosuppressants (cyclosporine, tacrolimus, sirolimus, azathioprine); thiazolidinediones (rosiglitazone); tricyclic antidepressants (amitriptyline, nortriptyline); atovaquone; buspirone; carbamazepine; carvedilol; chloramphenicol; cimetidine; clarithromycin; clofibrate; clozapine; dapsone; doxycycline; efavirenz; enalapril; etoricoxib; exemestane; fluvastatin; gestrinone; haloperidol; imidapril; irinotecan; losartan; methadone; mexiletine; montelukast; morphine; ondansetron; para-aminosalicylic acid; phenytoin; propafenone; quinine; repaglinide; riluzole; rofecoxib; sulfasalazine; tamoxifen; terbinafine; theophylline (and by extrapolation aminophylline); tiagabine; tocainide; toremifene; tropisetron; zaleplon; zidovudine.

Drugs interacting with isoniazid

Not recommended combinations with carbamazepine; disulfiram.

Combinations requiring special caution and possible dose adjustment of the following drugs

Benzodiazepines; coumarin anticoagulants; glucocorticoids; halogenated inhalational anesthetics (enflurane); alfentanil; chlorzoxazone; cycloserine; ethosuximide; ketoconazole; miconazole; phenytoin (and by extrapolation fosphenytoin); stavudine; theophylline.

Isoniazid inhibits the metabolism of phenytoin, leading to an increase in its blood concentration and an enhancement of the toxic effect (adjustment of the phenytoin dosage regimen may be required, especially in patients with slow acetylation of isoniazid).

When used concomitantly with enflurane, Isoniazid may increase the formation of an inorganic fluoride metabolite that has a nephrotoxic effect.

Isoniazid increases the blood concentration of valproic acid (monitoring of valproic acid concentration is necessary; adjustment of the dosage regimen may be required).

Storage Conditions

Store the drug out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.