Rifampicin + isoniazid + ethambutol hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN+ISONIAZID+ETHAMBUTOL HYDROCHLORIDE (Rifampicin+isoniazid+ethambutol hydrochloride)

Composition:

Active substances: rifampicin, isoniazid, ethambutol hydrochloride;

1 tablet contains 150 mg of rifampicin, 75 mg of isoniazid, and 275 mg of ethambutol hydrochloride;

Excipients: microcrystalline cellulose, crospovidone, pregelatinized starch, ascorbic acid, gelatin, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry 80W56578 Brown: red iron oxide (E 172), lecithin, polyvinyl alcohol, titanium dioxide (E 171), xanthan gum, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets of brown color, with "RHE" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04AM.

Pharmacological properties.

Pharmacodynamics.

A combination drug containing 3 anti-tuberculosis components.

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

Ethambutol – a chemotherapeutic agent exerting bacteriostatic effects against Mycobacterium tuberculosis, including strains resistant to other anti-tuberculosis agents. The mechanism of tuberculostatic action is associated with inhibition of nucleic acid synthesis in bacterial cells. Primary resistance to the drug occurs in 1% of cases. Ethambutol is active against all strains of M. tuberculosis, including M. bovis and M. kansasii.

INH (Isoniazid) – an anti-tuberculosis agent, a derivative of isonicotinic acid. Isoniazid exhibits high activity against Mycobacterium tuberculosis, particularly against actively replicating forms. The drug has no effect on other common infectious pathogens. A positive treatment outcome is observed when isoniazid is combined with other anti-tuberculosis drugs. Its mechanism of action involves inhibition of mycolic acid synthesis, a key component of the bacterial cell wall. The minimal inhibitory concentration (MIC) of isoniazid against M. tuberculosis ranges from 0.025 to 0.05 mg. Resistance to isoniazid develops rapidly when it is used as monotherapy.

Pharmacokinetics.

Not studied.

Clinical characteristics.

Indications.

Tuberculosis (intensive and maintenance treatment phases – initial phase of pulmonary and extrapulmonary disease), including in combination with other antituberculosis medicinal products (including pyrazinamide, streptomycin).

Contraindications.

Hypersensitivity to the components of the drug. Toxic drug-induced hepatitis in medical history, including due to administration of hydrazine derivatives of isonicotinic acid (e.g., phthivazide, etc.); recent infectious hepatitis (within less than 1 year), jaundice (including mechanical), acute hepatic and/or renal failure, severe impairment of liver and kidney function, pronounced atherosclerosis; severe cardiopulmonary insufficiency, gout, optic neuritis; cataract; diabetic retinopathy; inflammatory eye diseases, epilepsy, predisposition to seizures; severe psychoses (including in medical history); poliomyelitis (including previously suffered); concomitant use of saquinavir/ritonavir.

Isoniazid is contraindicated in doses exceeding 10 mg/kg during pregnancy, in III-degree cardiopulmonary insufficiency, II–III stage arterial hypertension, ischemic heart disease, diseases of the nervous system, chronic renal failure, hepatitis during exacerbation, liver cirrhosis, bronchial asthma, psoriasis, exacerbation phase of eczema, hypothyroidism.

Interaction with other medicinal products and other types of interactions.

Active components of the drug are hepatotoxic agents; therefore, there is an increased risk of liver damage, and liver function should be carefully monitored (see "Special precautions for use").

Concomitant use of the drug with antacids may reduce absorption of the drug components; therefore, the drug should be taken at least 1 hour before antacids. The drug is prescribed in combination with broad-spectrum antibacterial agents, fluoroquinolones, sulfonamides, etc.

Ethambutol.

Pharmacological antagonism occurs with ethionamide, spermine, spermidine, and magnesium. Ethambutol and pyrazinamide act synergistically on uric acid excretion. Combined treatment with ethambutol and isoniazid, when administered concomitantly with cyclosporine A, leads to enhanced breakdown of the latter, increasing the risk of transplant rejection. Ethambutol interacts in blood with phentolamine and may lead to increased arterial pressure. Concomitant use of ethambutol with neurotoxic agents may enhance ethambutol's neurotoxic effects and potentiate neurotoxicity of aminoglycosides, asparaginase, ciprofloxacin, methotrexate, carbamazepine, imipenem, lithium salts, and quinine.

Ethambutol reduces the therapeutic efficacy of digoxin. Concomitant treatment with disulfiram may increase ethambutol concentration in blood serum and enhance its toxicity. Ethanol enhances the toxic effect of ethambutol on the visual organ; therefore, alcohol consumption should be avoided during treatment.

Isoniazid.

When isoniazid is prescribed to patients with slow inactivation of the drug who are simultaneously receiving para-aminosalicylic acid, tissue concentration of the drug may increase, thereby increasing the risk of adverse effects.

Isoniazid may slow down hepatic metabolism of certain medicinal products, potentially increasing their toxicity. Such drugs include carbamazepine, primidone, phenytoin, diazepam, triazolam, chlorzoxazone, and disulfiram.

Isoniazid may reduce the therapeutic effect of levodopa.

Concomitant use of isoniazid with glucocorticosteroids increases metabolism and elimination of isoniazid; with itraconazole – may result in a significant decrease in itraconazole serum concentration and absence of therapeutic effect. Concomitant use of isoniazid with ketoconazole may reduce ketoconazole serum levels; therefore, monitoring of blood concentration is necessary and dosage adjustment may be required. With acetaminophen – increases toxicity of the latter due to generation and accumulation of toxic metabolites in the liver, potentially leading to serious adverse reactions. With theophylline – increases theophylline plasma concentration (theophylline levels should be monitored and doses adjusted accordingly); with valproate – increases valproate plasma concentration, requiring dose adjustment; with stavudine – increases the risk of distal sensory neuropathy; with zalcitabine in HIV-infected patients, isoniazid clearance is doubled, thus isoniazid and zalcitabine concentrations should be monitored to ensure treatment efficacy; with vitamin B6 and glutamic acid – reduces the likelihood of isoniazid adverse effects; with diphenylhydantoin – enhances antiarrhythmic properties of diphenylhydantoin. Potential interaction between isoniazid and food products containing histamine and tyramine (e.g., hard cheese, red wine, tuna, tropical fish) is also possible: adverse reactions such as headache, increased sweating, palpitations, flushing, and arterial hypotension may develop.

Rifampicin.

Rifampicin is a potent inducer of hepatic microsomal enzymes (cytochrome P450) and may cause potentially dangerous drug interactions. It accelerates metabolism of endogenous substrates such as adrenal hormones, thyroid hormones, and vitamin D.

Concomitant use of rifampicin with drugs metabolized by this enzyme system may accelerate their metabolism and reduce their activity; therefore, maintaining their optimal therapeutic blood concentration requires dosage adjustment both at the start of rifampicin therapy and after its discontinuation.

Rifampicin accelerates metabolism of antiarrhythmic drugs (e.g., disopyramide, mexiletine, quinidine, propafenone, tocainide); beta-blockers (e.g., bisoprolol, propranolol); calcium channel blockers (e.g., diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine); cardiac glycosides (digoxin, digitoxin); antiepileptic and anticonvulsant drugs (e.g., phenytoin, carbamazepine); psychotropic drugs – antipsychotics (e.g., haloperidol, aripiprazole), tricyclic antidepressants (e.g., amitriptyline, nortriptyline), anxiolytics and hypnotics (e.g., diazepam, benzodiazepines, zopiclone, zolpidem), barbiturates; antithrombotic agents (vitamin K antagonists), indirect anticoagulants; prothrombin time should be monitored daily or as frequently as needed to determine the required anticoagulant dose; antifungal drugs (e.g., terbinafine, fluconazole, itraconazole, ketoconazole, voriconazole); antiviral drugs (e.g., saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine); antibacterial drugs (e.g., chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin); corticosteroids (for systemic use); antiestrogens (e.g., tamoxifen, toremifene, gestrinone), systemic hormonal contraceptives, estrogens, progestogens (patients using oral contraceptives should be advised to use alternative, non-hormonal contraceptive methods during rifampicin therapy); thyroid hormones (e.g., levothyroxine); clofibrate; oral antidiabetic agents (sulfonylureas and their derivatives, e.g., chlorpropamide, tolbutamide, thiazolidinediones); immunosuppressive agents (e.g., cyclosporine, sirolimus, tacrolimus); cytostatics (e.g., imatinib, erlotinib, irinotecan); losartan; methadone, narcotic analgesics; praziquantel; quinine; riluzole; selective 5-HT3 receptor antagonists (e.g., ondansetron); statins metabolized by CYP3A4 (e.g., simvastatin); theophylline; diuretics (e.g., eplerenone).

Other interactions.

Concomitant use of rifampicin with atovaquone reduces atovaquone concentration and increases rifampicin concentration in serum; with ketoconazole – reduces serum concentrations of both drugs; with enalapril – reduces blood concentration of enalaprilat, the active metabolite of enalapril (dose adjustment of enalapril may be required depending on clinical status); with probenecid and co-trimoxazole – increases rifampicin blood levels; with saquinavir/ritonavir – increases the risk of hepatotoxicity; this combination is contraindicated; with sulfasalazine – reduces plasma concentration of sulfapyridine, possibly due to disruption of intestinal bacterial flora responsible for conversion of sulfasalazine into sulfapyridine and mesalazine; with halothane, isoniazid – increases the risk of hepatotoxicity (concomitant use of rifampicin and halothane should be avoided). Severe liver damage, including fatal outcomes, have been reported in patients receiving daily rifampicin and pyrazinamide for two months; such combination should be used only with careful monitoring and only if potential benefit outweighs the risk of hepatotoxicity and fatal outcomes; with clozapine, flecainide – increases bone marrow toxicity; with para-aminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) – to ensure adequate blood concentrations, the interval between administration of these drugs should be at least 4 hours; with ciprofloxacin, clarithromycin – may increase rifampicin blood concentration; cases of lupus-like syndrome have been reported with concomitant use of rifampicin.

Laboratory and diagnostic tests.

During treatment with rifampicin, the bromsulfalein test should not be used, as rifampicin alters bromsulfalein excretion parameters, potentially leading to false interpretations of this parameter. Microbiological methods for determining serum concentrations of folic acid and vitamin B12 should also not be used.

Cross-reactivity and false-positive results in opiate screening tests using the KIMS method or quantitative immunoassay methods are possible; confirmatory tests (e.g., gas chromatography/mass spectrometry) are recommended.

Special precautions for use.

Disorders of the skin and subcutaneous tissue

Severe cutaneous adverse reactions (SCARs) have been reported in the post-marketing period in association with the use of ethambutol, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or lead to fatal outcomes. Patients should be informed about the signs and symptoms and closely monitored for skin reactions during treatment. If signs or symptoms suggestive of such reactions occur, ethambutol should be discontinued immediately and alternative treatment considered (if necessary). Ethambutol must not be re-administered in any case if a serious reaction such as SJS, TEN, or DRESS has occurred during previous treatment.

In children, skin rash may be mistakenly attributed to the underlying infection or another infectious process. Physicians should consider the possibility of an ethambutol-related reaction in children who develop rash and fever during ethambutol therapy.

Use with caution in patients with moderate to severe impairment of liver or kidney function (liver and kidney function parameters should be monitored weekly during the first two weeks and then every two weeks for an additional six weeks; the drug should be discontinued if signs of hepatotoxicity or nephrotoxicity occur), in patients with stage II–III arterial hypertension, ischemic heart disease, disorders of the nervous system, acute hepatitis, liver cirrhosis, porphyria, bronchial asthma, psoriasis, acute eczema, hypothyroidism, chronic alcoholism, elderly patients, and debilitated patients.

Alcoholic beverages should not be consumed during treatment. Alcohol increases the hepatotoxic effect and reduces the efficacy of the drug.

The risk of hepatotoxicity increases in patients aged 35 years and older, particularly in women, in slow metabolizers, in HIV-infected individuals, in patients with malnutrition, and in those with neuropathy.

The drug should be used with caution in patients with diabetes mellitus (glucosuria may occur in diabetic patients).

Pyridoxine should be administered to patients at risk of developing neuropathy or pyridoxine deficiency (patients with diabetes, chronic alcoholism, malnutrition, renal insufficiency, pregnant women, HIV-infected individuals).

Visual acuity, refraction, visual fields, intraocular pressure, and fundus should be systematically monitored before and during treatment. Ophthalmological monitoring should be performed daily in patients with renal impairment. The drug should not be administered if visual function cannot be assessed (e.g., in critically ill patients or those with psychiatric disorders).

Ophthalmological monitoring should be performed for each eye separately and for both eyes together, as visual acuity changes may be unilateral or bilateral. If visual function abnormalities occur, treatment should be discontinued to prevent optic nerve atrophy. Visual disturbances are usually reversible and resolve within several weeks, or in some cases, several months after discontinuation of treatment. In rare cases, visual changes are irreversible due to optic nerve atrophy. Patients should be instructed to report any visual changes immediately. Hydroxocobalamin or cyanocobalamin should be administered in case of visual impairment. Vision recovery may take several weeks or even months.

Treatment with the drug requires continuous monitoring of peripheral blood parameters, liver and kidney function, blood glucose, prothrombin levels, uric acid levels, and consultation with an ophthalmologist and neurologist.

Treatment should be discontinued if serum liver enzyme levels increase more than three times the upper limit of normal or if bilirubin levels rise. Treatment should be stopped immediately upon the first signs of hepatitis (malaise, fatigue, nausea, loss of appetite).

The drug may increase serum urate concentrations due to reduced renal excretion of uric acid. Use with caution in patients with elevated serum uric acid levels.

To reduce adverse effects, pyridoxine hydrochloride (orally or intramuscularly), glutamic acid, thiamine chloride or thiamine bromide (intramuscularly), or sodium ATP salt may be co-administered.

The drug should not be taken with food. Bioavailability of the drug may be reduced when administered with food.

It should be noted that metabolites of the drug may color urine, saliva, and other biological fluids orange-red.

Women of reproductive age should use reliable contraceptive methods (oral hormonal contraceptives and additional non-hormonal contraceptive methods) during treatment.

Use during pregnancy or breastfeeding.

The drug may be used during pregnancy only if, in the physician’s opinion, the potential risk to the fetus does not outweigh the benefit to the mother. Breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

Since the drug may cause reduced visual acuity and adverse reactions affecting the nervous system, it should be prescribed with caution to patients engaged in potentially hazardous activities requiring heightened attention.

Method of Administration and Dosage

For adults and children aged 15 years and older with body weight below 50 kg: 3 tablets once daily; for those with body weight above 50 kg: 4 tablets once daily. Tablets should be taken daily, once a day, in the morning on an empty stomach, with a full glass of water.

The duration of treatment is determined individually by a physician.

Children. Contraindicated in children under 15 years of age.

Overdose.

Possible symptoms: dizziness, headache, increased fatigue, drowsiness, polyneuritis, optic neuritis (blindness may occur), decreased visual acuity, blurred vision, development of neurological disorders, seizures, confusion, stupor, hallucinations (including visual), lethargy, dysarthria, slurred speech, disorientation, hyperreflexia, peripheral polyneuropathy, loss of appetite, nausea, vomiting, diarrhea, abdominal pain, respiratory depression, dyspnea, asystole, hepatomegaly, jaundice, liver function impairment, elevated plasma levels of bilirubin and liver transaminases, brown-red or orange discoloration of the skin, oral mucosa, sclera, urine, saliva, sweat, mucus, and feces proportional to the ingested dose of the drug, allergic reactions, increased body temperature, leukopenia, thrombocytopenia, acute hemolytic anemia, renal failure, periorbital or facial edema, pruritus, pulmonary edema, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, coma. Over time, respiratory distress syndrome or other adverse reactions may develop.

Treatment: There is no specific antidote. Discontinue the drug, induce vomiting or perform gastric lavage, and administer enterosorbents. Intravenous infusion of Ringer's solution, Sorbilact, or Reosorbilact should be administered, along with forced diuresis. Vitamins of group B are prescribed. Monitor and take measures to support vital functions; resuscitation procedures should be performed if necessary.

Forced diuresis, peritoneal dialysis, or hemodialysis are indicated. In life-threatening conditions, exchange transfusion is indicated.

Side effects.

Eye disorders: optic neuritis (unilateral or bilateral), manifested by impaired perception of red and green colors, narrowing of visual fields, decreased visual acuity up to complete blindness, development of central or peripheral scotoma, retinal hemorrhage, optic nerve atrophy.

Immune system disorders: anaphylactic reactions/anaphylaxis, including anaphylactic shock, angioneurotic edema, bronchospasm, interstitial pneumonitis, lymphadenopathy, vasculitis, rheumatoid syndrome.

Skin and subcutaneous tissue disorders: skin rashes (including measles-like, maculopapular dermatitis, purpura or exfoliative dermatitis), urticaria, pruritus, dermatitis, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, possible exacerbation of systemic lupus erythematosus symptoms or development of lupus-like syndrome, flushing, bullous (blistering) reaction, acne, drug-induced eosinophilia with systemic symptoms (DRESS) (see section "Special precautions").

Nervous system disorders: dizziness, headache, depression, confusion, disorientation, hallucinations, seizures, increased frequency of seizures in patients with epilepsy, ataxia, myasthenia, peripheral neuropathy, peripheral neuritis, paresthesia, paralysis, hyperreflexia, toxic encephalopathy, memory disturbances, sleep disorders, mood changes, irritability, euphoria, insomnia, intracranial hemorrhage, psychotic reactions (including toxic psychoses), ranging from minor personality changes to severe psychiatric disorders, which usually resolved upon discontinuation of the drug; hearing loss and tinnitus in patients with renal impairment.

Blood and lymphatic system disorders: neutropenia, leukopenia, thrombocytopenia, eosinophilia, anemia, including hemolytic and aplastic anemia, sideroblastic anemia, agranulocytosis, thrombocytopenic purpura, hypercoagulability, splenomegaly.

Respiratory, thoracic and mediastinal disorders: lung infiltrates with or without eosinophilia, pneumonitis.

Cardiac disorders: pericarditis, myocarditis, arterial hypertension, decreased blood pressure, palpitations, chest pain and cardiac area pain, increased myocardial ischemia in elderly patients.

Gastrointestinal disorders: loss of appetite, decreased appetite, metallic taste in mouth, heartburn, dry mouth, nausea, vomiting, diarrhea, constipation, abdominal pain/discomfort, exacerbation of peptic ulcer, acute pancreatitis, erosive gastritis, pseudomembranous colitis.

Hepatobiliary disorders: liver injury, elevated levels of liver transaminases, hepatitis, discomfort in the right hypochondrium, jaundice, fulminant hepatic failure which may lead to necrosis (especially in patients aged 35 years and older), hyperbilirubinemia, bilirubinuria.

Renal and urinary disorders: interstitial nephritis, dysuria, acute renal failure, elevated urea and creatinine levels, nephron necrosis, dysuria.

Metabolic disorders: uric acid diathesis, gout exacerbation, hyperuricemia, pyridoxine deficiency affecting the conversion of tryptophan to nicotinic acid, pellagra, acidosis, porphyria.

Endocrine disorders: gynecomastia in males, menorrhagia in females, Cushing's syndrome, menstrual cycle disturbances, adrenal insufficiency in patients with impaired adrenal function, hyperglycemia.

General disorders: increased body temperature, chills, influenza-like symptoms, weakness, edema, joint and muscle pain, malaise, tendency to bleeding and hemorrhages, herpes, lacrimation, orange-red discoloration of urine, feces, saliva, sputum, sweat, mucus, withdrawal syndrome which may occur upon discontinuation of the drug, including headache, insomnia, irritability, nervousness.

Shelf life.

3 years.

Storage conditions.

Store in a dry place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

Lupin Limited.

Manufacturer's address and location of business activity.

A-28/1, MIDC Industrial Area, Chikalthan, Aurangabad, Maharashtra 431210, India (IN).