Rifafor® (Rifafor®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspfilm-coated tablets
Composition:

The tablet contains:

active substances: isoniazid 75.0 mg, pyrazinamide 400.0 mg, rifampicin 150.0 mg, ethambutol (as hydrochloride) 275.0 mg;

Excipients:

core: povidone-K25 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;

shell: macrogol-6000 2.902 mg, titanium dioxide (E 171) 8.701 mg, azorubin dye 1.106 mg, indigocarmine 0.294 mg, talc 2.174 mg, hypromellose 29.023 mg, simethicone 30% emulsion 0.170 mg.

Description:Round, biconvex tablets, covered with a film membrane of a pinkish-lilac color. On the cross-section - granular mass predominantly of red-brown color with numerous impregnations (more light and almost white color).
Pharmacotherapeutic group:anti-tuberculosis drug
ATX: & nbsp
  • Combinations of antituberculous drugs
    • Pharmacodynamics:

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

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

    Isoniazid - synthetic antituberculous agent with bacteriostatic action against bacilli in a latent state and bactericidal against actively dividing mycobacteria.

    Pyrazinamide - a synthetic antituberculous agent, which can be bactericidal or bacteriostatic depending on its concentration and the sensitivity of the microorganism.

    Ethambutol - a synthetic bacteriostatic antituberculous agent.

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

    Mechanism of action

    Rifampicin

    Rifampicin has a bactericidal effect on Mycobacterium tuberculosis, observed as in vitro, and in vivo. He also has a different activity for other atypical species of mycobacteria.

    In vivo rifampicin has antibacterial action against both extracellular and intracellular microorganisms.

    Rifampicin inhibits the decolusibonucleic acid-dependent polymerase of ribonucleic acid (DNA-dependent RNA polymerase) of sensitive strains without affecting the enzyme systems of the host.

    Cross-resistance of microorganisms to rifampicin was observed only with their resistance to other rifamycins.

    Isoniazid

    Isoniazid has a bactericidal effect mainly on rapidly growing populations Mycobacterium tuberculosis. Its mechanism of action, apparently, mainly, is based on inhibiting the synthesis of mycolic acid, which is an important element of the cell membrane of mycobacteria.

    Pyrazinamide

    The exact mechanism of action is not established. In vitro and in vivo The research showed that pyrazinamide is active only with a weakly acid reaction of the medium (pH 5.5).

    Ethambutol

    The mechanism of action of ethambutol is completely unknown. It penetrates into the mycobacterium and suppresses its multiplication by breaking the synthesis of ribonucleic acid (RNA). It is effective only against actively dividing mycobacteria.

    Microbiological sensitivity

    Rifampicin in a concentration of 0.005 to 0.2 μg / ml inhibits the growth M. tuberculosis in vitro. In vitro rifampicin increases the activity of streptomycin and isoniazid (but not ethambutol) with respect to M. tuberculosis.

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

    Pyrazinamide has a minimum inhibitory concentration (MIC) in relation to M. tuberculosis 12.5-20 μg / ml.

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

    At the end of the initial intensive phase of treatment of the tuberculosis process, treatment can be continued with a daily intake of only a double combination rifampicinisoniazid.

    This scheme of treatment of tuberculosis (the initial intensive phase of treatment followed by the continuation phase of treatment) is suitable for the treatment of newly diagnosed tuberculosis, relapse of the tuberculosis process, resumption of treatment after a break or in case of ineffective treatment.

    Pharmacokinetics:

    Rifampicin

    Rifampicin is rapidly absorbed from the gastrointestinal tract. The maximum plasma concentration is achieved 2 hours after admission.In different individuals (healthy adults and children), the maximum concentrations of the drug in the blood can vary greatly. Eating a meal reduces the absorption of rifampicin.

    After absorption rifampicin quickly stands out in bile, after which it undergoes hepatic intestinal recirculation. Because of the saturation of the mechanisms of biliary excretion when taking high doses of rifampicin, its excretion into bile can slow down. During the course of hepatic intestinal recirculation, gradual deacetylation of rifampicin takes place. The resulting metabolite retains antibacterial activity. Deacetylation reduces intestinal reabsorption and promotes excretion of rifampicin.

    Rifampicin is well distributed in the human body, creating effective concentrations in many organs and liquids, including cerebrospinal fluid. However, in normal conditions, with the exception of meningitis, the concentration in the cerebrospinal fluid is low. Approximately 80% of rifampicin binds to plasma proteins. Most of the free fraction is non-ionized and therefore freely penetrates into the tissue.

    The half-life is 3 to 5 hours, decreasing to 2-3 hours with repeated administration.The rate of elimination during the first 6-10 days of treatment increases in connection with the autoinduction of hepatic enzymes of microsomal oxidation.

    Isoniazid

    Isoniazid is rapidly absorbed after ingestion. The speed and degree of absorption decrease with admission with food. Maximum plasma concentrations are achieved 1-2 hours after taking the dose. Isoniazid well distributed and penetrates most organs, tissues and fluids of the human body (spinal, pleural, ascites, saliva, sweat), as well as in faeces. The drug penetrates the placental barrier and into breast milk in concentrations comparable to those in plasma. Binding to blood proteins is very low, from about 0 to 10%.

    Isoniazid is acetylated with N-acetyltransferase with formation N/ RTI & gt; Further, it is 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 the 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.

    The elimination half-life is generally 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-acetylisoiniazide and isonicotinic acid.

    Pyrazinamide

    Pyrazinamide is well absorbed from the gastrointestinal tract. The concomitant intake of food for absorption is not affected. Maximum plasma concentrations are achieved in 1-2 hours in adults and about 3 hours in children.

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

    Pyrazinamide is excreted by the kidneys, mainly in the form of metabolites. Only 3% of the dose is excreted by the kidneys unchanged.Half-life is about 10 hours.

    Ethambutol

    Etambutol is well absorbed after ingestion. Its bioavailability is approximately 80%. The concomitant intake of food for absorption is not affected. The maximum plasma concentrations are achieved 2-4 hours after the dose.

    Etambutol is well distributed in most tissues. It does not pass into the cerebrospinal fluid. However, in patients with tuberculous meningitis in the cerebrospinal fluid, therapeutic concentrations can be achieved. In erythrocytes, the concentration 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. The half-life of ethambutol is between 3 and 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% in the form of inactive metabolites). About 20% of the drug is excreted in feces unchanged.

    Indications:

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

    Contraindications:

    - Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or other chemically related drugs and / or to the adjuvants of the Rifafore® preparation;

    - POrphyria (due to the presence of rifampicin in the composition may increase the flow of porphyria);

    - aboutsevere arthritic arthritis;

    - xrenal failure (see "Method of administration and dose");

    - Mr.euritis of the optic nerve;

    - lhereditary hepatitis in history and acute or exacerbation of chronic liver diseases, regardless of their origin, jaundice, recently transferred (less than one year) infectious hepatitis, liver failure, observed against the background of previous treatment with isoniazid;

    - tsevere cardiopulmonary insufficiency;

    - toatarakta, diabetic retinopathy, inflammatory diseases of the eyes;

    - dThe age of children under 13 years of age or weighing less than 30 kg;

    - aboutsimultaneous reception of midazolam;

    - aboutsimultaneous reception of voriconazole and protease inhibitors (except for ritonavir, if taken at full dose or 600 mg twice daily);

    - atborn lactose intolerance, insufficiency of lactase or glucose-galactose malabsorption.

    Carefully:

    - With hyperuricemia, gouty arthritis in the anamnesis (pyrazinamide can reduce the excretion of uric acid);

    - with diabetes mellitus (due to the presence of isoniazid in the formulation of possible deterioration of glycemic control);

    - with epilepsy (due to the presence of isoniazid and ethambutol in the composition of the drug may increase seizures);

    - with hormonal contraception (in connection with the presence of rifampicin in the composition of the possible decrease in the effectiveness of oral contraceptives);

    - with hemoptysis (pyrazinamide can increase clotting time and adversely affect the integrity of the vascular wall);

    - if there is a history of psychosis;

    - with visual impairment, with the exception of optic neuritis, in which the drug is contraindicated) (in connection with the presence of ethambutol in the composition of the drug may increase visual disorders);

    - in persons over the age of 35;

    - with cancellation of treatment with isoniazid in the anamnesis;

    - with peripheral neuropathy;

    - with HIV infection;

    - with decompensated diseases of the cardiovascular system (chronic heart failure, angina pectoris, arterial hypertension);

    - hypothyroidism;

    - in the elderly, malnourished patients,"slow" acetylators, pregnant women, patients with diabetes mellitus and alcoholism (in these patients, due to the presence of isoniazid in the formulation of a possible vitamin B deficiency6);

    - with violations of liver function (difficulty in selecting doses of active ingredients when using their fixed combination and increased risk of hepatotoxic action of Rifaforex active ingredients);

    - during pregnancy and during breastfeeding (see "Application during pregnancy and during breastfeeding").

    Pregnancy and lactation:

    Pregnancy

    The degree of safety of the use of the drug Rifaforea during pregnancy is not established to the end. Rifampicin, isoniazid, ethambutol pass through the placental barrier. Plasma concentrations of ethambutol in fetal plasma can be up to 30% of its plasma concentrations in the mother.

    For limited clinical data on the use of rifampicin, isoniazid, and ethambutol, no increase in the incidence of fetal malformations was found during pregnancy. It is not known whether pyrazinamide cause fetal damage when applied during pregnancy.

    Treatment with Rifafor® during pregnancy can be carried out only if the potential benefit to the mother exceeds the potential risk to the fetus. It is recommended additional administration of pyridoxine (vitamin B6) during pregnancy. Isoniazid may have a neurotoxic effect on the child. Because the rifampicin can cause postnatal bleeding in the mother and newborn, then in the case of its reception in the third trimester of the mother's pregnancy it is necessary to take phytomenadione (vitamin K) inside the last month of pregnancy.

    Breastfeeding period

    Rifampicin, isoniazid, pyrazinamide and ethambutol excreted into breast milk.

    No adverse effects have been observed on infants, however, taking into account the potential for neurotoxic effect due to the presence of isoniazid and ethambutol in the formulation, it is necessary to decide on the use of Rifafor® in continuing breastfeeding of the mother, only in that case if the potential benefit to the patient outweighs the potential risk to the child.

    Dosing and Administration:

    Rifafor® is a fixed combination of drugs intended for use during the initial phase of tuberculosis treatment. Treatment with Rifafor® is recommended under the supervision of a phthisiatrician.

    The drug is taken internally.

    Anti-TB treatment

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

    Below are the recommended daily medical doses in terms of kilogram of body weight for daily intake during 2 months of the initial phase of treatment in adults and children:

    - 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 daily once a day at the dose indicated below for 2 months of the initial phase of treatment:

    - With a body weight of 30-37 kg - 2 tablets

    - With a body weight of 38-54 kg - 3 tablets

    - With a body weight of 55-70 kg - 4 tablets

    - With a body weight of 71 kg and more - 5 tablets

    For special categories of patients (category IV according to WHO recommendations) in cases of chronic tuberculosis and multiple drug resistance (continued positive sputum analysis on BC (Koch bacterium) after repeated treatment under control), specially designed standardized or individualized schemes are proposed.

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

    Use in children

    Rifafor® is not recommended for children with a body weight of less than 30 kg, since the dosage form of the drug Rifafor® is not suitable for dosing in such children.

    Special patient groups

    - Patients with malnutrition, the elderly and patients with diabetes mellitus

    A special dosage regimen is not required, but concomitant hepatic and / or renal failure must be considered.

    Additional use of pyridoxine (vitamin B6) (see "With caution").

    - Pregnant women

    Additional use of pyridoxine (vitamin B6) and vitamin K (see Fig."Pregnancy and the period of breastfeeding").

    - Patients with renal insufficiency

    Rifafor® contraindicated in patients with severe renal impairment (creatinine clearance <30 mL / min and is not recommended for patients with moderate renal impairment (creatinine clearance of 30-50 ml / min), since it is not possible to choose the dosage of ethambutol.

    - Patients with hepatic insufficiency

    Rifafor® contraindicated in patients with a history of hepatitis drugs and patients with acute liver disease (see. "Contraindications for use").

    Rifafor® not recommended for patients with chronic liver diseases, since it is not possible to choose the correct dosage of each active ingredient (cm. "Contraindications for use" "FROM caution "and" Special instructions ").

    In other cases, hepatic dysfunction Rifafor® should be used with caution under close medical supervision (see. "Special instructions").

    Mode of application

    Rifafor® tablets are taken entirely whole and drink a glass of water, one hour before or 2 hours after a meal. In case of irritation of the gastrointestinal tract, taking of tablets together with food is possible.

    When concurrently taking aluminum containing antacids, enterosorbents, including activated charcoal, they should be taken two hours before or two hours after taking the Rifafore® tablets (see "Interaction with Other Drugs").

    Interruption of treatment

    If the initial intensive phase of Rifafore® treatment has been interrupted for any reason, it is necessary to consult the official official recommendations for the resumption of treatment with anti-TB drugs (see "Special instructions" and "Side effects").

    Side effects:

    Side effects (PE) are classified according to organ systems and frequency of occurrence using the following notations: very frequent: ≥1 / 10; Frequent: from ≥1 / 100 to <1/10; Infrequent: from ≥1 / 1000 to <1/100; Rare: from ≥1 / 10000 to <1/1000; very rare: <1/10000; unknown frequency: according to the available data, it is impossible to estimate the frequency of occurrence of PE.

    Side effects of rifampicin

    Violations of the blood and lymphatic system

    Rare: eosinophilia, transient leukopenia, hemolysis, hemolytic anemia, thrombocytopenia and thrombocytopenic purpura, cerebral hemorrhage and death (see "Special instructions").

    Very rare: agranulocytosis

    Immune system disorders

    Unknown frequency: lupus-like syndrome.

    Disorders from the endocrine system

    Rare: stimulation of the crisis in patients with Addison's disease, adrenal insufficiency (in patients with impaired adrenal function), menstrual cycle disorders (in exceptional cases amenorrhea).

    Disorders of the psyche

    Rare: confusion, psychosis.

    Disturbances from the nervous system

    Frequent: fatigue, drowsiness, headache, dizziness.

    Rare: ataxia, muscle weakness, myopathy.

    Unknown frequency: feeling of numbness, disorientation.

    Disturbances on the part of the organ of sight

    Frequent: eye irritation, red eyes, persistent staining of soft contact lenses in red-orange color.

    Rare: visual disorders, blurred vision, exudative conjunctivitis.

    Vascular disorders

    Rare: Disseminated intravascular coagulation (DIC syndrome).

    Disorders from the gastrointestinal tract

    Frequent: anorexia, nausea; abdominal pain, bloating.

    Rare: vomiting or diarrhea, isolated episodes of erosive gastritis (see."Special instructions") and pseudomembranous colitis.

    Disturbances from the liver and bile ducts

    Frequent: an asymptomatic increase in the activity of "hepatic" transaminases in the serum (see "Special instructions").

    Rare: hepatitis (see "Special instructions"), jaundice, inducing porphyria attacks. Unknown frequency: hyperbilirubinemia.

    Disturbances from the skin and subcutaneous tissues

    Frequent: in some patients, skin syndrome (skin flushing, itching with or without skin rash, urticaria) may occur within 2-3 hours after admission, both with daily and irregular intake of the drug.

    Rare: severe skin reactions, such as generalized reactions hypersensitivity, including such as exfoliative dermatitis (including Lyell's syndrome), erythema multiforme (including Stevens-Johnson syndrome), pemphigoid reactions, vasculitis.

    Disorders from the kidneys and urinary tract

    Rare: increased urea nitrogen in the blood and uric acid and serum, acute renal failure (hemoglobinuria, hematuria) due to interstitial nephritis, glomerulonephritis, and tubular necrosis (see Fig."Special instructions").

    Disorders from the metabolism and nutrition

    Unknown frequency: hyperuricemia, exacerbation of gout.

    General disorders and disorders at the site of administration

    Frequent: reddish staining of liquids and secrets of the human body (such as urine, sputum, tear fluid, feces, saliva, sweat).

    Rare: collapse; lowering blood pressure and shock, swelling.

    Side effects of rifampicin, arising, as a rule, with irregular reception or when returning to treatment after a temporary break.

    Patients who take rifampicin not every day, as well as those who return to treatment with this medication after a temporary interruption, there may be an influenza-like syndrome, most likely an immunopathological nature. It is characterized by fever, chills and, possibly, headache, dizziness and muscle pain. In rare cases, this flu-like syndrome can be accompanied by thrombocytopenia, purpura, dyspnea, seizures similar to asthmatic (difficulty breathing and wheezing), acute hemolytic anemia, lowering of blood pressure, shock,anaphylaxis and acute renal failure (usually due to acute tubular necrosis or acute interstitial nephritis).

    These serious complications can, however, occur unexpectedly, without a prior influenza-like syndrome, mainly when treatment resumes after a temporary interruption or when rifampicin is given only once a week in a high dose (> 25 mg / kg).

    Side effects of isoniazid

    Violations of the blood and lymphatic system

    Rare: anemia (hemolytic, sideroblastic), eosinophilia, thrombocytopenia, lymphadenopathy.

    Very rare: agranulocytosis.

    Unknown frequency: aplastic anemia, neutropenia, a tendency to bleeding and hemorrhage,

    Disorders from the endocrine system

    Rare: isoniazid can affect the hepatic metabolism of a number of hormones, leading to menstrual irregularities, gynecomastia, Cushing's syndrome, premature puberty, difficulties in controlling diabetes, hyperglycemia and metabolic acidosis.

    Disorders of the psyche

    Infrequent: toxic psychosis.

    Rare: euphoria, hyperactivity, insomnia.

    Disturbances from the nervous system

    Frequent: toxic peripheral neuropathy, polyneuritis, manifested as muscle weakness, the disappearance of tendon reflexes, which are usually preceded by paresthesias in the hands and feet (see section "Special instructions")

    Infrequent: convulsions, memory disorders, inflammation and atrophy of the optic nerve, toxic encephalopathy.

    Rare: dizziness, a feeling of faintness, headache, an increased incidence of seizures in epileptic patients (see "Special instructions".

    Unknown frequency: excessive fatigue or weakness, irritability, emotional lability, depression.

    Disorders from the cardiovascular system

    Unknown frequency: heart palpitations, angina, increased blood pressure.

    Disorders from the gastrointestinal tract

    Frequent: anorexia, gastric discomfort, nausea, vomiting.

    Rare: dry mouth, heartburn.

    Unknown frequency: pancreatitis, gastralgia.

    Disturbances from the liver and bile ducts

    Frequent: violations of the liver (usually a moderate and transient increase in the activity of "hepatic" transaminases in the serum) (see "Special instructions").

    Rare: hepatitis, severe, sometimes fatal.

    Unknown frequency: Hyperbilirubinemia, bilirubinuria, jaundice.

    Disturbances from the skin and subcutaneous tissues

    Rare: reactions such as lupus erythematosus, acne, vasculitis.

    Unknown frequency: rash, exfoliative dermatitis, pemphigus, erythema multiforme (Stevens-Johnson syndrome).

    Disturbances from musculoskeletal and connective tissue

    Rare: rheumatic syndrome.

    Disorders from the kidneys and urinary tract

    Rare: disorders of urination.

    Unknown frequency: retention of urine.

    Immune system disorders

    Frequent: allergic and other reactions, such as exanthema and fever.

    Unknown frequency: an allergic skin rash (cortical maculopapular, purpura), itching, arthralgia.

    Disorders from the metabolism and nutrition

    Unknown frequency: hypovitaminosis B6, pellagra.

    Side effects of pyrazinamide

    Violations of the blood and lymphatic system

    Rare: sideroblastic anemia, splenomegaly, thrombocytopenia with or without purpura (see "Special instructions"), hypercoagulation.

    Unknown frequency: vacuolization of erythrocytes.

    Disorders from the gastrointestinal tract

    Frequent: abdominal pain, anorexia, gastric discomfort, nausea, vomiting.

    Unknown frequency: exacerbation of peptic ulcer, diarrhea, "metallic" taste in the mouth.

    Disturbances from the liver and bile ducts

    Liver involvement is the most common side effect.

    Frequent: moderate and transient increase in the activity of "hepatic" transaminases in the serum during the early phase of treatment (see "Special instructions"), porphyria.

    Rare: hepatomegaly, dose-dependent hepatotoxicity, severe and fatal in some cases, jaundice (see "Special instructions").

    Unknown frequency: liver soreness, yellow dystrophy of the liver.

    Disorders from the central nervous system

    Unknown frequency: dizziness, headache, sleep disturbances, increased excitability, depression, in some cases hallucinations, convulsions, confusion.

    Disturbances from the skin and subcutaneous tissues

    Rare: acne, photosensitivity, itching, urticaria, skin rash.

    Very rare: angioedema.

    Disturbances from musculoskeletal and connective tissue

    Frequent: pain in the joints, pain in the muscles.

    Disorders from the kidneys and urinary tract

    Rare: interstitial nephritis, dysuria.

    General disorders and disorders at the site of administration

    Rare: fever (hyperthermia).

    Unknown frequency: malaise.

    Disorders from the metabolism and nutrition

    Frequent: hyperuricemia (often asymptomatic) (see "Special instructions").

    Unknown frequency: exacerbation of gout, increased serum iron concentration.

    Side effects of ethambutol

    Violations of the blood and lymphatic system

    Rare: thrombocytopenia, leukopenia (see "Special instructions").

    Disorders of the psyche

    Infrequent: hallucinations.

    Disturbances from the nervous system

    Infrequent: dizziness, disorientation, confusion, headache, malaise.

    Rare: peripheral neuritis (numbness, tingling sensation, burning pain or weakness in the hands and feet) (see "Special instructions").

    Unknown frequency: weakness, depression.

    Disturbances on the part of the organ of sight

    Rare: dose-dependent retrobulbar neuritis of the optic nerve (decreased visual acuity, narrowing of the field of vision, central or peripheral scotoma, blurred vision, eye pain, color blindness in red and green, loss of vision)."Special instructions"), hemorrhage in the retina (less often).

    Disorders from the gastrointestinal tract

    Infrequent: abdominal pain, loss of appetite, anorexia, nausea, vomiting.

    Unknown frequency: "metallic" taste in the mouth.

    Disturbances from the liver and bile ducts

    Unknown frequency: jaundice, transient hepatic dysfunction (see "Special instructions"), increased activity of "hepatic" transaminases in the blood serum.

    Disturbances from the skin and subcutaneous tissues

    Infrequent: itching, urticaria, rash, allergic dermatitis.

    Disorders from the kidneys and urinary tract

    Infrequent: hyperuricemia (see "Special instructions").

    General disorders and disorders at the site of administration

    Rare: Hypersensitivity (skin rash, fever, joint pain), anaphylactic reactions.

    Disorders from the metabolism and nutrition

    Unknown frequency: exacerbation of gout.

    Side effects associated with the presence of certain excipients in the formulation of Rifafor®

    Due to the presence of azorubin in the formulation, Rifafor® can cause allergic reactions.

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

    Overdose:

    Treatment applicable to an overdose of Rifafor®

    In cases of an overdose of Rifafor®, gastric lavage should be performed as soon as possible. After evacuation of the contents of the stomach, the absorption of the remaining drug from the gastrointestinal tract is beneficial introduction of activated charcoal with water. Anti-emetics are used to treat severe nausea and vomiting. Intensive care should be initiated to maintain the body's basic functions, including maintaining airway patency and treating certain symptoms if they occur.

    Signs and symptoms of rifampicin overdose

    Toxicity

    As practice has shown, the symptoms and outcomes of overdose are variable. Doses of rifampicin from 15 g to 60 g in adults led to fatalities, while a dose of 9 g in adults caused severe intoxication, and a dose of 12 g in adolescents caused mild intoxication.

    Some reports of deaths leading to death and no overdose have led to alcohol abuse or history of alcohol abuse.

    Symptoms

    Complaints from the gastrointestinal tract, including abdominal pain, nausea, vomiting sweating, dyspnea, convulsions, headache and increasing retardation may occur in the short period after ingestion; loss of consciousness can occur with severe liver damage. Transient increase in the activity of "hepatic" transaminases in serum and / or bilirubin, kidney failure, generalized pruritus may appear. Perhaps a reddish-brown or reddish-orange coloration of the skin, urine, sweat, saliva, tears and feces, and the intensity depends on the amount of rifampicin taken.

    Patients with children also had swelling of the face or periorbital area. In some lethal cases, arterial hypotension, sinus tachycardia, ventricular arrhythmias, convulsions and cardiac arrest were observed. Possible pulmonary edema.

    Treatment

    Evacuation of stomach contents, repeated doses of activated carbon is shown.

    Signs and symptoms of an overdose of isoniazid

    Toxicity

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

    - The intake of 5 g of isoniazid led to intoxication with a fatal outcome in a 15-year-old.

    - The intake of 900 mg of isoniazid led to a moderate intoxication in an 8-year-old child.

    - Taking 2-3 g of isoniazid led to severe intoxication in a 3-year-old child.

    - The intake of 3 g (15 years old teenager) and 5-7.5 g (adults) of isoniazid led to extremely severe intoxication.

    Symptoms

    In case of an overdose, characteristic signs and symptoms appear within 0.5-3 hours after it is taken. Nausea, vomiting, dizziness, blurred speech, blurred vision vision and visual hallucinations (including bright colors and strange images) are early signs. Other typical symptoms are seizures and severe metabolic acidosis, ketonuria, hyperglycemia, periorbital myoclonia, ringing in the ears, tremor, reflex intensification, paresthesia, impaired consciousness. Perhaps the appearance of external respiratory distress and CNS depression, rapidly progressing from stupor to deep coma, as well as severe, unrestrained convulsive seizures.Also reported the occurrence of apnea, tachycardia, arrhythmia, lowering blood pressure, fever, acute necrosis of skeletal muscles, DIC syndrome, hyperkalemia, liver damage.

    Doses of isoniazid, exceeding 10 mg / kg may adversely affect the nervous system (possibly the emergence of peripheral neuropathy) and, in this connection, disrupt the patient's ability to drive or operate machinery.

    Treatment

    Evacuation of the contents of the stomach (if the patient does not have a seizure attack), taking or injecting activated carbons into the stomach. Urgent determination of blood gases, concentrations of electrolytes, urea nitrogen, glucose, etc. is required.

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

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

    In the absence of seizures, 2-3 g of pyridoxine are intravenously administered for prophylactic purposes.

    Pyridoxine should be administered in diluted form for 30 minutes (to reduce irritant effect on the vessels).If necessary, repeated administration of pyridoxine in the above doses is possible.

    Diazepam potentiates the anticonvulsant effect of pyridoxine. In the absence of pyridoxine, the administration of high doses of diazepam is possible to arrest seizures. In severe cases, artificial ventilation may be required. Patients should be corrected metabolic acidosis with sodium bicarbonate, correction of electrolyte disorders. It is necessary to ensure a good diuresis. In the case of extremely severe intoxication, hemodialysis or hemoperfusion may be necessary. If these blood purification methods are not available, peritoneal dialysis or one or with forced diuresis can be used.

    Signs and symptoms of pyrazinamide overdose

    Toxicity

    There is limited information on the overdose of pyrazinamide. In case of an overdose, hepatic toxicity (acute liver damage) and hyperuricemia may occur.

    Treatment

    Treatment is mostly symptomatic. During the first hours after ingestion, induce vomiting and / or gastric lavage. 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

    During the first hours after ingestion, induce vomiting and / or gastric lavage. It may be useful to conduct hemodialysis. There is no specific antidote. Treatment is supportive and symptomatic.

    Interaction:

    - With antacids, enterosorbent agents, including Activated carbon

    These drugs can reduce the bioavailability of rifampicin, isoniazid and ethambutol. Therefore, Rifafore® should be taken at least 2 hours before or 2 hours after taking antacids, enterosorbents, including Activated carbon.

    - With glucocorticosteroids

    Corticosteroids can reduce plasma concentrations of isoniazid, due to the acceleration of its metabolism and / or renal clearance.

    - With para-aminosalicylic acid

    Para-aminosalicylic acid can increase plasma concentrations and half-life of isoniazid due to competition for acetylating enzymes.Preparations of para-aminosalicylic acid should be prescribed no earlier than 4 hours after taking rifampicin; para-aminosalicylic acid disrupts its absorption.

    - With ethanol, paracetamol and other hepatotoxic drugs

    Simultaneous administration with the drug Rifaforex may contribute to the manifestation of hepatotoxicity of rifampicin, isoniazid and pyrazinamide. Careful monitoring of patients receiving both Rifaforea and hepatotoxic drugs at the same time is necessary to detect liver damage.

    - With vaccines

    The oral live combination typhoid vaccine can be inactivated with the drug Rifafor®.

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

    Possible reduction in the effectiveness of anti-gouty drugs due to the fact that the Rifafor® pyrazinamide can reduce the excretion of uric acid.

    - With neurotoxic drugs

    With simultaneous administration with ethambutol, the neurotoxic effects of the latter (development of optic neuritis, peripheral neuritis) may be enhanced. Ethambutol - enhances the neurotoxicity of ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium salts, imipenem, methotrexate, quinine.

    - With preparations metabolized by enzymes of the cytochrome P-450 system and UDP (uridine-diphosphate) -glucuronyl transferase

    It is known that rifampicin induces and isoniazid inhibits certain enzymes of the cytochrome P-450 family (CYP450). So rifampicin is the most powerful inducer of the isoenzymes of the cytochrome P450 system, namely the subfamilies CYP3A and CYP2C, which account for more than 80% of cytochrome P450 isoenzymes. In this way, rifampicin can accelerate the metabolism of many simultaneously taken drugs that are completely or partially metabolized by these two subfamilies of cytochrome P450 isoenzymes. Furthermore, rifampicin also stimulates UDP-glucuronyl transferase, another enzyme involved in the metabolism of a number of drugs. This can lead to a decrease in the plasma concentrations of these co-administered drugs below the therapeutic values, with a decrease or even loss of their effectiveness.On the other hand, isoniazid inhibits the metabolism of certain drugs, leading to an increase in their plasma concentrations. In addition, some drugs fall under opposite influences from rifampicin and isoniazid, for example phenytoin, warfarin and theophylline with the unpredictability of the cumulative effect, which, moreover, can change over time.

    With the simultaneous use of such medications with the drug Rifafore, their dosage regimen may need to be adjusted. Drugs that are eliminated due to metabolic transformations should be used in conjunction with the drug Rifaforea only when it is possible to monitor their plasma concentrations and / or clinical and side effects, which may allow them to adequately adjust their dosing regimen. It should be noted that after the initiation of rifampicin intake, the effects of induction of enzyme systems reach a maximum within 10 days, and after the withdrawal of rifampicin, their gradual decrease occurs for 2 or more weeks.This should be taken into account when removing the drug Rifaforea, in the event that the dose of other medicines has been increased during its administration. Therefore, during treatment with the drug Rifaforea and for 2-3 weeks after its withdrawal, regular monitoring of such patients should be carried out.

    Drugs interacting with rifampicin

    Contraindicated combinations

    With mizodalam, protease inhibitors (except for ritonavir, when taken at full dose or 600 mg twice daily), voriconazole (see "Contraindications for Use").

    Unsupported combinations

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

    Combinations that require special care should be taken into account and correction of the doses of the following preparations may be required (see above "With preparations metabolized by enzymes of cytochrome P-450 and UDP (uridine-diphosphate) -glucuronyl transferase"

    Antiarrhythmic drugs group IA (disopyramide, quinidine); indirect anticoagulants (warfarin); hypoglycemic drugs for oral administration of the sulfonylurea group; azole antifungal agents (fluconazole, ketoconazole) except voriconazole, which is contraindicated; barbiturates (hexobarbiton); benzodiazepines (diazepam) and benzodiazepine-related drugs (zopiclone, zolpidem); metabolized in the liver beta-blockers (metoprolol, propranolol); blockers of "slow" calcium channels (diltiazem, nifedipine, verapamil); preparations of digitalis (digoxin, digitoxin); corticosteroids (hydrocortisone); estrogens and progestogens (with hormone replacement therapy); fluoroquinolones; thyroid hormones (levothyroxine); immunosuppressors (ciclosporin, tacrolimus, sirolimus, azathioprine); thiazolidinediones (rosiglitazone); tricyclic antidepressants (amitriptyline, nortriptyline); atovaquone; buspirone; carbamazepine; carvedilol; chloramphenicol; cimetidine; clarithromycin; clofibrate; clozapine; dapsone; doxycycline; efavirenz; enalapril; etroecoxib; exemastane; 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; tokaine; toremifene; tropospheric; zaleplon; zidovudine.

    Drugs interacting with isoniazid

    Unsuitable combinations: with carbamazepine; disulfiram (see "Special instructions")

    Combinations, which should be used with extreme caution and may require a dose adjustment of the following drugs

    Benzodiazepines; coumarin anticoagulants; glucocorticoids; halogenated inhalation anesthetics (enflurane); alfentanil; chlorosoxazone; cycloserine; ethosuximide; ketoconazole; miconazole; phenytoin (and extrapolation of phosphenytoin); stavudine; theophylline.

    Isoniazid - suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and increased toxic effect (correction of the dosage regimen of phenytoin, especially in patients with slow acetylation of isoniazid, may be required).

    When used simultaneously with enflurane isoniazid can increase the formation of inorganic fluoride metabolite, which has a nephrotoxic effect.

    Isoniazid increases the concentration of valproic acid in the blood (monitoring of valproic acid concentration is necessary, correction of the dosing regimen may be required).

    Special instructions:

    Impact on laboratory and instrumental research

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

    These tests can not be used during therapy with Rifafore® (because of the content of rifampicin in it).

    - The test with bromosulfophthalein (BSF)

    Because the rifampicin transiently competes with bilirubin and bromosulphophthalein, then to exclude false positive reactions, the BSF test should be performed in the morning before the morning intake of Rifafor®.

    - Studies with contrast material for visualization of the gallbladder

    Rifampicin because of competition for biliary excretion can disrupt biliary excretion of the contrast agent used to visualize the gallbladder. Thus, similar studies should be conducted in the morning before the morning intake of the drug Rifafor ®.

    - Determination of glucose in urine with copper sulfate

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

    - Determination of ketone bodies in the urine

    Pyrazinamide may make it difficult to detect ketone bodies in the urine.

    Interaction with food

    Refers to isoniazid

    Because of isoniazid has some inhibiting monoamine oxidase (MAO) activity, it can interact with food products containing tyramine (cheese, red wine, etc.). In addition, diaminoxidase inhibition is possible, which can cause a very pronounced reaction (eg, headache, sweating, palpitations, "hot flashes", excessive blood pressure lowering) for food containing histamine (eg, sardines, tuna, other tropical fish). Foods containing tyramine and histamine in patients receiving Rifafore® should be excluded.

    When treating with Rifaforea, it is necessary to take into account official recommendations on the use of antituberculosis drugs.

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

    A drug

    % Resistance (min - max)

    Africa

    Asia

    Europe and North America

    Average

    East

    Latin

    America

    Isoniazid

    5,3%

    (2,4-7,1%)

    9,5%

    (3,3-25,3%)

    8,2%

    (0-42,6%)

    11,4%

    (4,1-25,7)

    5,6%

    (1,1-11)

    Rifampicin

    1,9%

    (0,9-3,1%)

    2,8%

    (0,4-11,4%)

    2,3%

    (0-15,6%)

    6,3%

    (0,6-14,6)

    2,1%

    (0,3-7,3)

    Isoniazid and rifampicin (multiple medicinal resistance)

    1,5%

    (0,5-2,4%)

    2,2%

    (0-10,4%)

    2%

    (0-14,2%)

    3,8%

    (0-14,2%)

    1,5%

    (0,3-4,9)

    Ethambutol

    0,9%

    (0 -2%)

    1,4%

    (0,2-4,6)

    2%

    (0-24,8)

    3,6%

    (0-9,9)

    0,9%

    (0-2,4)

    Pyrazinamide

    No data

    Patients should be warned about the danger of interruption of treatment, alcohol consumption, and informed about the recommended methods of contraception.

    Laboratory and clinical monitoring of patients before and during treatment

    In adult patients undergoing treatment with Rifafore® for tuberculosis, prior to initiation of treatment and then regularly during treatment, the serum activity of "liver" transaminases (ALT), aspartic aminotransferase (ACT)), the concentration of bilirubin, creatinine, uric acid in the serum, make a complete general blood test (including counting the number of platelets).

    In children, carrying out these studies before treatment is not necessary, except when it is known that the child has an aggravating condition (liver or kidney damage) or if they are suspected.

    During the treatment of the patient, a medical examination must be carried out at least once a month. It should be specifically asked about the symptoms related to side effects. All patients with any abnormalities should be monitored, including if necessary laboratory tests.

    It is recommended that the oculist be observed regularly before and during treatment (see "Visual Disorders" below).

    Dysfunction of the liver (associated with rifampicin, isoniazid, pyrazinamide and ethambutol)

    Rifampicin, isoniazid, pyrazinamide and ethambutol metabolized in the liver. Rifampicin, isoniazid and pyrazinamide are associated with the development of hepatitis (see "Side effects"). The most hepatotoxic pyrazinamide. Rifampicin less than other active ingredients of this combination causes hepatocellular disorders, but it is associated with the development of cholestatic jaundice.

    When taking Rifaforea, there is often an increase in serum transaminase activity above the upper limit of the norm. Hepatic dysfunction, which can occur in the first few weeks of treatment, usually decreases and the liver function returns to the norm spontaneously, without interruption of treatment (usually by the third month of treatment). An isolated moderate increase in bilirubin and / or serum transaminase activity is not a reason for discontinuing treatment. To decide whether to continue or discontinue treatment, it is necessary to conduct repeated studies of liver function indicators and determine the trend in changing these indicators and their compliance with the clinical condition of the patient. Discontinuation of treatment Rifafor® recommended in the case of clinically significant jaundice, lack of return indicators of liver function to normal, or more than three-fold excess of the upper limit of normal for serum transaminase activity: Rifafor® should be replaced by the reception of each of its active ingredients separately (not in the fixed combination) in order to make it easier to select the necessary dosage regimes for each of the active ingredients.

    In patients with impaired liver function, careful monitoring of its function should be performed, in particular regular serum ALT activity and ACT before the start of treatment and every week or every two weeks during treatment. If signs of hepatocellular disorders occur, then Rifafore® should be discontinued (see "Side effects").

    In patients with chronic liver disease, the therapeutic benefit of Rifafore® should be compared with the possible risk. If the need for antituberculous treatment is recognized in such patients, the use of a fixed combination of Rifafore® is not recommended, since it is more appropriate to separately use each of its active ingredients (see "Side effects").

    Patients, without proven chronic liver disease, can receive conventional short-course chemotherapy regimens.

    Severe and sometimes fatal hepatitis associated with isoniazid can develop even after many months of treatment. The risk of developing hepatitis is associated with age.Associated with isoniazid hepatotoxicity (considered to be associated with its metabolite diacetylhydrazine) rarely occurs in patients before the age of 20, but it becomes more frequent with age, with the highest frequency in patients after 35 years of age and affects up to 3% of patients after the age of 50 years. Determination of the activity of transaminases in patients older than 35 years should be conducted before the beginning and at least once a month during treatment.

    Other factors that increase the risk of developing hepatitis are the daily use of alcohol, chronic liver disease, the use of intravenous drugs and a genetically determined decrease in acetylating function of the liver. Patients should be monitored for prodromal symptoms of hepatitis such as fatigue, weakness, malaise, anorexia, nausea and vomiting. If these symptoms occur or signs of liver damage are found, treatment should be stopped immediately. Continued use of Rifafore® with such patients may lead to more severe forms of liver damage (see "Possible side effects with the use of the drug").

    Alcohol

    During treatment with Rifafore®, alcohol intake should be avoided. A regular neurologic examination and special treatment for alcohol abusers are required.

    "Fast" and "slow" acetylators (due to the presence of isoniazid in the formulation)

    In the case of known acetylation phenotypes, patients with very fast or very slow acetylating ability should receive these four components separately to facilitate the selection of the dose of isoniazid.

    Hypersensitivity reactions

    In the case of severe severe hypersensitivity reactions such as thrombocytopenia, purpura, hemolytic anemia, dyspnea and similar asthmatic attacks, shock or kidney failure, Rifafore® should be immediately withdrawn. Patients who developed such reactions should never take Rifaforea in the future.

    Rifafore® should be discontinued if other hypersensitivity reactions such as fever or skin reactions occur (see "Side effects").

    Interrupted therapy or recovery of treatment after a temporary interruption (due to the presence of rifampicin in the formulation)

    Patients should be warned and monitored for a break in taking the drug, because of the possibility of developing immunological reactions that occur with intermittent therapy (less than 2-3 times per week) (see "Side effects").

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

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

    There are separate reports on the association of exacerbation of porphyria with the administration of rifampicin. Rifampicin can accelerate the metabolism of drugs taken simultaneously with it, leading to a decrease in their plasma concentrations below therapeutic and decreasing effectiveness. Medications that are eliminated by hepatic metabolism should be used in conjunction with the drug Rifaforea only if it is possible to monitor their plasma concentrations or clinical and side effects, and their dose should be carefully selected (see "Interactions with Other Drugs").

    The use of the following drugs in conjunction with the drug Rifafor ® is not recommended (see "Interactions with other drugs"):

    - because of the interaction with rifampicin: nevirapine, ritonavir (when using low doses), oral contraceptives, halothane, praziquantel, simvastatin, telithromycin and tyrosine kinase inhibitors;

    - because of the interaction with isoniazid: carbamazepine and disulfiram.

    The method of contraception (due to the presence of rifampicin in the formulation)

    Rifampicin may decrease the effectiveness of oral contraceptives. To prevent pregnancy during treatment with the drug Rifaforea and during one additional menstrual cycle after discontinuation of treatment it is necessary to use non-hormonal methods of contraception (see "Interactions with other medicinal products").

    Reddish staining of liquids (due to the presence of rifampicin in the formulation)

    Rifampicin can cause reddish staining of body fluids and secrets (urine, sweat, sputum, faeces, saliva and tears), and the patient must be warned about it in advance. It is possible to stain soft contrast lenses (see Fig."Side effects").

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

    In patients with visual impairment, Rifafore® should be used with caution.

    It is recommended that the oculist be examined (visual acuity, color vision and visual fields) before treatment and regularly during treatment, especially when using high doses of the drug.

    It was revealed that the degree of visual disturbances depends on the dose and duration of therapy (see "Side effects").

    It is necessary to ask patients questions about their vision at each visit. Progressive deterioration of visual acuity during therapy should be considered a side effect of ethambutol. If corrective glasses were used before the treatment, they should be worn during the assessment of visual acuity. During 1-2 years of therapy, a refractive error may develop, which must be corrected to obtain accurate results of the study. The study of visual acuity through the stenopathic opening eliminates the error of refraction.

    It is recommended to stop taking Rifaforea if the visual disturbances become clinically significant.Restoration of visual acuity usually occurs in weeks or months after drug withdrawal.

    Supplementary administration of pyridoxine (due to the presence of isoniazid in the formulation)

    Because the isoniazid in high doses can lead to the development of a deficiency of pyridoxine (vitamin B6), to prevent peripheral neuropathy, as well as most other dysfunctions of the nervous system, additional administration of pyridoxine may be beneficial. These side effects are dose-dependent and occur most frequently in under-nutrition patients, the elderly, patients who are "slow" acetylators, in patients with diabetes mellitus and people with alcoholism (see "Side effects"), and during pregnancy ( see "Pregnancy and the period of breastfeeding"). Pyridoxine should be applied in accordance with official recommendations.

    Patients with gout or patients with gout in the anamnesis (due to the presence of pyrazinamide and ethambutol in the formulation):

    Pyrazinamide and ethambutol should be used with caution in patients in a gout in the anamnesis. It was reported that pyrazinamide reduces urate excretion.Plasma concentrations of uric acid should be monitored regularly. If hyperuricemia occurs in combination with acute gouty arthritis during treatment, Rifafore® should be discontinued (see "Side effects").

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

    When taking isoniazid, treatment of diabetes mellitus is much more difficult (see "Side effects").

    Pyrazinamide may make it difficult to detect ketone bodies in the urine.

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

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

    High doses of isoniazid can increase the frequency of seizures in patients with epilepsy (see section "Side effects").

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

    In severe renal failure, excretion of isoniazid, pyrazinamide and ethambutol may slow down, which can lead to an increase in their plasma concentrations and contribute to the increase in their side effects.Therefore, Rifafor® is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 mL / min) (see "Contraindications for use"). Rifafore® is also not recommended for patients with moderate renal insufficiency (creatinine clearance 30-50 ml / min). In the case of acute renal failure, Rifafor® should be immediately discontinued without resuming it (see "Side effects").

    Elderly patients

    Increased risk of toxic effects. It requires careful monitoring of patients for the detection of toxic effects.

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

    Patients with hemoptysis should consider the possibility of adverse effects of pyrazinamide on clotting time or permeability of the vascular wall.

    Patients with psychoses in the anamnesis (in connection with the presence of rifampicin and isoniazid in the composition of the drug)

    Care should be taken when using the drug in such patients.

    Patients with lactose intolerance (associated with ancillary substances in the formulation of the drug Rifafor®):

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

    The need to avoid eating foods that contain tyramine and histamine (such as cheese, red wine, horse mackerel, tuna, other tropical fish) (see "Interaction with food")

    Patients receiving Rifafore® tablets should avoid taking food containing tyramine and histamine (such as cheese, red wine, horse mackerel, tuna, and other tropical fish) (see "Interaction with food").

    Effect on the ability to drive transp. cf. and fur:

    The effect of Rifafor® on the ability to drive vehicles or engage in other potentially hazardous activities is mild or moderate. Care must be taken when driving vehicles and mechanisms. In case of appearance of such side effects as confusion, disorientation in space, hallucinations, dizziness, malaise and visual disturbances (blurred vision, color blindness in red and green,loss of vision) may impair a patient's ability to drive vehicles or engage in other potentially hazardous activities.

    Form release / dosage:

    Film-coated tablets.

    Packaging:

    For 14 tablets per blister, Al. / Al.

    By 2 (4, 6, 8) blisters together with the instruction for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    After the expiration date, the drug can not be used.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001274
    Date of registration:24.11.2011
    Date of cancellation:2016-11-24
    The owner of the registration certificate:Sanofi-Aventis SA (PTI) Ltd.Sanofi-Aventis SA (PTI) Ltd. South Africa
    Manufacturer: & nbsp
    Representation: & nbspSanofi Aventis GroupSanofi Aventis Group
    Information update date: & nbsp22.03.2016
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