Rifampicin 75 mg/isoniazid 50 mg/pyrazinamide 150 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN 75 MG/ISONIAZID 50 MG/PYRAZINAMIDE 150 MG (RIFAMPICIN 75 MG/ISONIAZID 50 MG/PYRAZINAMIDE 150 MG)

Composition:

Active substances: rifampicin, isoniazid, pyrazinamide;

One dispersible tablet contains 75 mg of rifampicin, 50 mg of isoniazid, and 150 mg of pyrazinamide;

Excipients: microcrystalline cellulose, crospovidone, povidone, shellac, sodium croscarmellose, aspartame (E 951), magnesium stearate, strawberry flavoring.

Medicinal form. Dispersible tablets.

Main physicochemical properties: round, biconvex, uncoated tablets of reddish-brown color with specks, having a deep score line on one side and smooth on the other side.

Pharmacotherapeutic group. Combined antituberculosis agents.

ATC code J04AM05.

Pharmacological Properties

Pharmacodynamics

Rifampicin, isoniazid, and pyrazinamide are active bactericidal antituberculosis agents. Rifampicin and isoniazid are particularly active against rapidly growing extracellular organisms. Pyrazinamide is active against intracellular organisms, especially in the acidic environment of macrophages. Rifampicin and isoniazid also exhibit bactericidal intracellular activity. Rifampicin is active against slow and intermittent growth of Mycobacterium tuberculosis (M. tuberculosis). Thus, the three active substances—rifampicin, isoniazid, and pyrazinamide—exert activity against three different bacterial populations.

Rifampicin inhibits the activity of DNA-dependent RNA polymerase in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the enzyme in mammals. Cross-resistance to rifampicin occurs only after development of resistance to other rifamycins.

Pharmacokinetics

Rifampicin

Rifampicin is rapidly absorbed from the stomach and duodenum. Maximum plasma concentration, approximately 10 µg/mL, is reached within 2–4 hours after a dose of 10 mg/kg body weight administered on an empty stomach.

In healthy volunteers, the biological half-life of rifampicin in serum averages approximately 3 hours after a 600 mg dose and increases to 5.1 hours after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2–3 hours. At doses up to 600 mg per day, the half-life does not differ in patients with renal insufficiency, so dose adjustment is not required. The half-life of rifampicin may decrease when administered concomitantly with isoniazid.

Rifampicin is rapidly excreted into bile, resulting in enterohepatic circulation. During this process, rifampicin undergoes progressive deacetylation, so that almost the entire drug in bile is in this form approximately 6 hours after administration. This metabolite retains practically full antibacterial activity. Deacetylation reduces intestinal reabsorption and facilitates elimination. Up to 30% of the administered dose is excreted in urine, with approximately half of this amount remaining unchanged. Absorption of rifampicin is reduced when the drug is taken with food.

Rifampicin is widely distributed throughout the body. It reaches effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is approximately 80% protein-bound. The majority of the unbound fraction is non-ionized, allowing free diffusion into tissues.

Isoniazid

After oral administration, isoniazid reaches peak blood concentration within 1–2 hours, declining to 50% or less within 6 hours. Administration of isoniazid with food may reduce its absorption. Isoniazid diffuses well into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excretions (saliva, sputum, and feces). The drug also crosses the placental barrier and enters breast milk at concentrations comparable to those in plasma. Between 50% and 70% of the isoniazid dose is excreted in urine within 24 hours.

Isoniazid is primarily metabolized via acetylation and dehydrogenation. The rate of acetylation is genetically determined. Approximately 50% of Black and Caucasian individuals are "slow inactivators," while most Asians are "fast inactivators."

Pyridoxine (B6) deficiency sometimes occurs in adults receiving high doses of isoniazid, likely due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.

Pyrazinamide

Pyrazinamide is almost completely absorbed from the gastrointestinal tract and rapidly distributed throughout the body, reaching peak plasma concentration within 2 hours. It is hydrolyzed to pyrazinoic acid and then metabolized to 5-hydroxypyrazinoic acid. Glomerular filtration is the main route of elimination. It is bactericidal at acidic pH and has intracellular antibacterial activity against M. tuberculosis.

Pharmacokinetic studies in healthy volunteers have shown that the three active substances in the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg have comparable bioavailability whether administered simultaneously as individual dosage forms or as the fixed-dose combination product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg.

Clinical characteristics.

Indications.

The medicinal product is indicated for the initial phase of treatment of tuberculosis in children caused by M. tuberculosis, in accordance with WHO guidelines.

Contraindications.

The medicinal product is contraindicated:

• in patients with hypersensitivity to the active substances or to any of the excipients of the medicinal product;
• in the presence of jaundice;
• during concomitant use with the combination of saquinavir/ritonavir.

Interaction with other medicinal products and other forms of interaction.

Interaction with food

Isoniazid is an inhibitor of monoamine oxidase (MAO) and diamine oxidase (DAO); therefore, it may reduce the metabolism of tyramine and histamine, leading to symptoms such as headache, increased sweating, palpitations, flushing, and arterial hypotension. Patients should be advised to avoid foods rich in tyramine and/or histamine during isoniazid therapy, such as cured meats, certain cheeses (e.g., aged cheeses), wine, beer, and certain types of fish (e.g., tuna, mackerel, salmon).

Interaction with other medicinal products

Concomitant use of the medicinal product with the combination of saquinavir/ritonavir increases the risk of hepatotoxicity. Therefore, concomitant use of the medicinal product with saquinavir/ritonavir is contraindicated.

Cytochrome P-450 enzyme interaction

Rifampicin is known to induce, while isoniazid inhibits, certain cytochrome P-450 enzymes. Overall, the net effect of the competing actions of rifampicin and isoniazid on the metabolism of medicinal products undergoing biotransformation via these pathways is unknown. Therefore, caution should be exercised when prescribing the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg together with medicinal products metabolized by cytochrome P-450. Doses of medicinal products metabolized by these enzymes may require adjustment at the initiation or after discontinuation of concomitant treatment with rifampicin/isoniazid/pyrazinamide in the form of dispersible tablets to maintain optimal therapeutic blood concentrations.

Interaction with rifampicin

Pharmacodynamic interactions

The risk of hepatotoxicity is increased when using an anesthetic.

The risk of hepatotoxicity increases when rifampicin is used concomitantly with halothane or isoniazid. Concomitant use of rifampicin and halothane should be avoided. Patients receiving rifampicin and isoniazid concomitantly should be closely monitored for hepatotoxicity.

Concomitant use of rifampicin with other antibiotics causing vitamin K-dependent coagulopathy, such as cefazolin (or other cephalosporins with an N-methyl-thiotetrazole side chain), should be avoided, as this may lead to severe coagulation disorders that can be fatal (especially with high-dose regimens).

Effect of the medicinal product on other medicinal products

Enzyme and transporter induction

The medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg is a potent inducer of enzymes and transporters involved in drug metabolism. Enzymes and transporters affected by the medicinal product include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronosyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters, including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most medicinal products are substrates for one or more of these enzymes or transporters, and these pathways may be induced by concomitant use of the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg. Thus, the medicinal product may accelerate the metabolism and reduce the activity of certain concomitantly administered medicinal products, or increase the activity of prodrugs requiring metabolic activation, and has the potential for clinically significant drug interactions with many medicinal products and across multiple medicinal product classes (see table). Dose adjustments of these medicinal products may be required at the initiation or after discontinuation of treatment with the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg to maintain their optimal therapeutic blood concentrations.

Examples of medicinal products or classes of medicinal products affected by the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg:

• antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, propafenone, tocainide);

• antiepileptics (e.g., phenytoin);

• hormone antagonists (antiestrogens, e.g., tamoxifen, toremifene, gestrinone);

• antipsychotics (e.g., haloperidol, aripiprazole);

• anticoagulants (e.g., coumarins);

• antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole);

• antivirals (e.g., saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine);

• barbiturates;

• beta-blockers (e.g., bisoprolol, propranolol);

• anxiolytics and hypnotics (e.g., diazepam, benzodiazepines, zopiclone, zolpidem);

• calcium channel blockers (e.g., diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine);

• antibacterial agents (e.g., chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin);

• corticosteroids;

• cardiac glycosides (digoxin, digitoxin);

• clofibrate;

• systemic hormonal contraceptives, including estrogens and progestogens;

• oral antidiabetic agents (e.g., chlorpropamide, tolbutamide, sulfonylureas and their derivatives, rosiglitazone);

• immunosuppressants (e.g., cyclosporine, sirolimus, tacrolimus);

• irinotecan;

• thyroid hormones (e.g., levothyroxine);

• losartan;

• analgesics (e.g., methadone, opioid analgesics);

• praziquantel;

• quinine;

• riluzole;

• selective 5-HT3 receptor antagonists (e.g., ondansetron);

• statins metabolized by CYP3A4 (e.g., simvastatin);

• theophylline;

• tricyclic antidepressants (e.g., amitriptyline, nortriptyline);

• cytostatics (e.g., imatinib);

• diuretics (e.g., eplerenone);

• enalapril: reduced exposure of the active metabolite of enalapril; dose adjustment may be required based on the patient's clinical condition;

• antiviral agents for hepatitis C treatment (e.g., daclatasvir, simeprevir, sofosbuvir, telaprevir): concomitant use of antiviral agents for hepatitis C treatment and rifampicin should be avoided;

• morphine: rifampicin may reduce plasma morphine concentrations; analgesic efficacy of morphine should be monitored during and after rifampicin treatment, and the dose adjusted accordingly;

• clopidogrel: increased exposure to active metabolites; the medicinal product Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg strongly induces CYP2C19, leading to both increased levels of the active metabolite of clopidogrel and enhanced platelet inhibition, thereby increasing the risk of bleeding; therefore, concomitant use of clopidogrel and rifampicin is not recommended.

Rifampicin treatment reduces systemic exposure to oral contraceptives. Alternative non-hormonal contraceptive methods should be recommended to patients using oral contraceptives during therapy with Rifampicin 75 mg/Isoniazid 50 mg/Pyrazinamide 150 mg. Additionally, the use of the medicinal product may complicate the management of diabetes mellitus.

Rifampicin may reduce the efficacy of ACE inhibitors (e.g., enalapril, imidapril), antiemetics (e.g., aprepitant), anticancer agents (e.g., imatinib), diuretics (e.g., eplerenone), agents used for erectile dysfunction (e.g., tadalafil), oral hypoglycemic agents (e.g., nateglinide, repaglinide), and NSAIDs (e.g., etoricoxib).

If para-aminosalicylic acid and rifampicin are included in the treatment regimen, the interval between their administration should be at least 8 hours to ensure adequate blood concentrations of both agents.

Effect of other medicinal products on rifampicin

Concomitant use of antacids may reduce the absorption of rifampicin. Rifampicin should be taken at least 1 hour before antacids.

Other medicinal interactions

Decreased concentrations of atovaquone and increased concentrations of rifampicin have been observed with concomitant use.

Interactions with isoniazid

Medicinal products that may interact with isoniazid:

Antiepileptic agents (e.g., carbamazepine, phenytoin)

The risk of developing distal sensory neuropathy is increased when isoniazid is administered to patients taking stavudine. Concomitant use of zalcitabine with isoniazid has been shown to approximately double the renal clearance of isoniazid in HIV-infected patients.

When prednisolone 20 mg was administered to 13 slow acetylators and 13 fast acetylators receiving isoniazid 10 mg/kg, plasma isoniazid concentrations decreased by 25% and 40%, respectively. The clinical significance of this effect has not been established.

The effect of acute alcohol intake (serum level of 1 g/L maintained for 12 hours) on isoniazid metabolism (300 mg daily for 2 days) was investigated in 10 healthy volunteers in a controlled crossover study. The metabolism of isoniazid and its metabolite, acetyl-isoniazid, was not altered by acute alcohol intake. However, isoniazid metabolism may be enhanced in individuals with chronic alcohol dependence, although this effect has not been quantitatively assessed.

Other interactions

Para-aminosalicylic acid may increase plasma concentrations and prolong the half-life of isoniazid by competing for acetylating enzymes.

Hepatotoxicity of isoniazid may be increased during general anesthesia.

Absorption of isoniazid is reduced by antacids.

The risk of CNS toxicity is increased when isoniazid is used concomitantly with cycloserine.

Isoniazid may reduce plasma concentrations of ketoconazole and increase concentrations of theophylline.

Pyrazinamide

Pyrazinamide is an antagonist of probenecid and sulfinpyrazone.

Laboratory and diagnostic tests

It has been demonstrated that therapeutic levels of rifampicin alter results obtained by standard microbiological methods for determining serum concentrations of folic acid and vitamin B12. Therefore, alternative quantitative methods should be considered. Transient increases in serum bromsulphthalein and bilirubin levels have also been observed. Rifampicin may interfere with biliary excretion of contrast agents used for gallbladder visualization. Therefore, these investigations should be performed before the morning dose of rifampicin.

Special precautions for use.

The special precautions for use of the medicinal product RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg are the same as those for the individual use of rifampicin, isoniazid, and pyrazinamide. Each of these active substances is associated with disturbances in liver function. The medicinal product RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg should be administered under the supervision of a pulmonologist or other qualified physician.

For all patients with tuberculosis, a complete assessment of liver function should be performed before initiating treatment with this medicinal product.

In adult patients undergoing anti-tuberculosis treatment with this product, baseline levels of liver enzymes, bilirubin, creatinine in blood, and a complete blood count, including platelet count (or estimation), should be determined.

Patients should be examined at least once a month during therapy and questioned about symptoms related to adverse reactions. All patients with abnormal test results should undergo further monitoring, including laboratory tests, if necessary.

However, since there is an increased risk of isoniazid-related hepatitis in individuals over 35 years of age, transaminase levels should be measured at the start of treatment and at least once a month during therapy in this age group. Other factors associated with an increased risk of hepatitis include daily alcohol consumption, chronic liver disease, intravenous drug use, and belonging to African or Latin American ethnic groups.

Paradoxical drug reaction

After initial improvement during therapy with RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg, symptoms may worsen again. Clinical or radiological worsening of existing tuberculosis lesions or development of new lesions has been observed in patients. These reactions have been reported during the first few weeks or months of anti-tuberculosis treatment. Such reactions usually do not indicate treatment failure.

The cause of this paradoxical reaction is not yet known, but it may be due to an enhanced immune response. In case of suspected paradoxical reaction, symptomatic therapy to suppress excessive immune response should be initiated if necessary. Furthermore, continuation of the planned combined anti-tuberculosis therapy is recommended.

Patients should be advised to seek immediate medical attention if symptoms worsen. Symptoms that may occur are usually specific to the affected tissues. General symptoms may include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness.

If the patient has no history of liver disease and normal liver function before treatment

If the patient has no signs of liver disease and normal liver function tests before treatment, repeat liver function tests are required only if fever, vomiting, jaundice, or other clinical deterioration occurs.

The medicinal product RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg should be administered to patients with impaired liver function only if absolutely necessary, with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum glutamic-pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT), should be performed before the start of therapy and then every 2–4 weeks during treatment.

If signs of hepatocellular injury or clinically significant changes in liver function tests occur, the medicinal product RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg should be discontinued. Consideration should be given to alternative forms of anti-tuberculosis therapy and alternative regimens. Immediate consultation with a tuberculosis treatment specialist is required. If the drug is restarted after normalization of liver function, liver function should be monitored daily.

Severe systemic hypersensitivity reactions, including fatal cases such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been observed during anti-tuberculosis therapy.

The use of RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg should be discontinued if an alternative etiology for signs and symptoms cannot be established.

Rifampicin

Caution should be exercised in patients with renal insufficiency when the dose exceeds 600 mg per day.

Particular caution is recommended when prescribing regimens containing both isoniazid and rifampicin to patients with impaired liver function, elderly patients, malnourished patients, and possibly children under two years of age.

In some cases, hyperbilirubinemia may occur due to competition between rifampicin and bilirubin for hepatobiliary excretion at the cellular level, which may appear in the first days of treatment. Isolated reports of mild increases in bilirubin and/or transaminases alone are not an indication to discontinue treatment; rather, decisions should be based on repeat testing, monitoring trends in levels, and considering them in conjunction with the patient’s clinical status.

Due to the potential for immunological reactions, including anaphylaxis, associated with intermittent rifampicin therapy (less than 2–3 times per week), patients should be closely monitored. Patients should be warned against interrupting the dosing schedule, as such reactions may occur.

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis, which may be life-threatening or fatal, have been reported with unknown frequency in association with the use of this product.

Patients should be informed about signs and symptoms and carefully monitored for skin reactions.

Early signs of hypersensitivity, such as fever, lymphadenopathy, or biological abnormalities (including eosinophilia, liver function abnormalities), may be present even in the absence of visible rash. If such signs or symptoms occur, the patient should seek immediate medical advice.

If signs and symptoms suggestive of these reactions appear, the drug should be discontinued immediately and alternative treatment considered (if needed).

Most of these reactions occurred between 2 days and 2 months after initiation of treatment; the time to onset may vary depending on the condition.

Rifampicin has enzyme-inducing properties that may enhance the metabolism of endogenous substrates, including adrenal hormones, thyroid hormones, and vitamin D. Individual reports have linked porphyria exacerbation with rifampicin use.

Rifampicin may cause discoloration (yellow, orange, red, brown) of teeth, urine, sweat, sputum, and tears, which should be explained to the patient. The drug may permanently stain soft contact lenses.

Rifampicin is a well-documented potent inducer of drug-metabolizing enzymes and transporters and may therefore decrease or increase exposure, safety, and efficacy of concomitant medications. Potential drug interactions should therefore be considered whenever starting or stopping rifampicin therapy.

Rifampicin may cause vitamin K-dependent coagulopathy and severe bleeding. Monitoring for the development of coagulopathy is recommended in patients at increased risk of bleeding. The need for additional vitamin K supplementation (in cases of vitamin K deficiency, hypoprothrombinemia) should be considered.

Isoniazid

Isoniazid use should be carefully monitored in patients with pre-existing chronic liver disease. Severe, and sometimes fatal, hepatitis associated with isoniazid therapy may develop even after several months of treatment. The risk of hepatitis is age-dependent. Therefore, patients should be monitored for prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. If these symptoms appear or if signs indicating liver injury occur, isoniazid should be discontinued immediately, as continued use in such cases has been reported to lead to more severe liver injury.

Cases of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, some with fatal outcomes, have been reported during isoniazid use.

Patients should be informed about signs and symptoms and carefully monitored for skin reactions. If signs or symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis develop (e.g., progressive skin rash, often with blistering or mucosal involvement), patients should be advised to seek immediate medical attention. Isoniazid should be permanently discontinued if an alternative etiology for signs and symptoms cannot be established.

Treatment should be administered with caution to elderly patients or malnourished patients, who may require additional vitamin B6 supplementation during isoniazid therapy.

Isoniazid use should be carefully monitored in patients who are slow acetylators, have a history of epilepsy, psychosis, peripheral neuropathy, diabetes mellitus, alcohol dependence, HIV infection, or porphyria.

Pyrazinamide

The product should be used with caution in patients with a history of gout. If hyperuricemia is accompanied by acute gouty arthritis, the patient should be switched to a treatment regimen that does not contain pyrazinamide.

The potential negative impact of pyrazinamide on blood clotting time or vascular integrity should be considered in patients with hemoptysis.

Excipients: This medicinal product contains aspartame, which is a source of phenylalanine. This should be taken into account for patients with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy

Rifampicin

At high doses, rifampicin has shown teratogenic effects in animals. There are no adequate and well-controlled studies on the effects of rifampicin in pregnant women. Rifampicin crosses the placental barrier and is found in umbilical cord blood, but its effect on the fetus, either as monotherapy or in combination with other anti-tuberculosis drugs, is unknown. Administration of rifampicin in the last weeks of pregnancy increases the risk of bleeding in newborns and postpartum women, which may be treated with vitamin K.

Isoniazid

Isoniazid has been reported to have embryocardial effects in rats and rabbits when administered orally during pregnancy, although congenital anomalies related to isoniazid use were not observed in reproductive studies in mammals (mice, rats, rabbits).

The product should be used in pregnant women or women of childbearing age only if the potential benefit outweighs the risk.

Lactation period

Rifampicin, isoniazid, and pyrazinamide are excreted in breast milk. Therefore, women receiving RIFAMPICIN 75 mg/ISONIAZID 50 mg/PYRAZINAMIDE 150 mg should not breastfeed, except when the expected benefit to the mother outweighs the potential risk to the infant.

In infants who are breastfed by mothers taking isoniazid, there is a theoretical risk of seizures and neuropathy (related to vitamin B6 deficiency); therefore, they should be monitored for early signs of these effects, and prophylactic treatment with pyridoxine for both mother and infant should be considered.

Ability to affect reaction speed when driving vehicles or operating machinery.

Isoniazid use has been associated with dizziness, visual disturbances, and psychotic reactions. Patients should be informed about the possible effects, and if such adverse reactions occur, they should not drive vehicles or operate machinery or engage in any activity where these symptoms could endanger themselves or others.

Method of administration and dosage.

For oral use.

The recommended daily dosage of the drug tablets according to body weight is shown in the table below:

Body weight	Number of tablets
5-7 kg	1
8-14 kg	2
15-20 kg	3

For children with body weight above 20 kg, medicinal products with higher dosages should be used.

The required number of tablets should be dissolved in approximately 50 ml of water, and the entire mixture should be swallowed. The mixture (tablets dispersed in water) should be administered within 10 minutes. After administration, an additional amount of water should be consumed immediately.

The drug should be taken on an empty stomach (at least 1 hour before or 2 hours after meals). If the drug is taken with food to improve gastrointestinal tolerability, impaired absorption of the drug may occur.

In cases where dose reduction or discontinuation of one of the active substances in the drug is required, individual medicinal products containing rifampicin, isoniazid, or pyrazinamide should be used.

Renal impairment

Patients with renal insufficiency (creatinine clearance < 30 ml/min) may require dose reduction. In such cases, individual preparations of rifampicin, isoniazid, and pyrazinamide should be prescribed.

Hepatic impairment

Limited data indicate that the pharmacokinetics of rifampicin and isoniazid are altered in patients with hepatic insufficiency. Therefore, patients with liver dysfunction should be closely monitored for signs of toxicity. The drug is contraindicated in patients with severe liver disease.

Children

The drug is not administered to children with body weight less than 5 kg.

Overdose

There is limited information on overdose with the combination of rifampicin, isoniazid, and pyrazinamide.

Signs and symptoms

Rifampicin

Symptoms: nausea, vomiting, abdominal pain, pruritus, headache, and increased fatigue may occur shortly after ingestion of a large dose; loss of consciousness in the presence of severe liver disease, elevated plasma bilirubin and liver transaminases; orange-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces proportional to the dose ingested; periorbital or facial edema in children.

Some fatal cases have been reported, characterized by hypotension, sinus tachycardia, ventricular arrhythmia, seizures, and cardiac arrest.

The minimal lethal or toxic dose has not been established. However, non-fatal cases of acute overdose in adults have been reported at doses ranging from 9 to 12 g of rifampicin. Fatal severe overdoses in adults have been reported at doses ranging from 14 to 60 g. Some reports of fatal and non-fatal cases mention concomitant alcohol presence in the body or chronic alcohol abuse.

Non-critical overdoses have been reported in children aged 1 to 4 years after ingestion of one (100 mg/kg) or two doses.

Isoniazid

Signs and symptoms of overdose occur within 30 minutes to 3 hours after ingestion and include nausea, vomiting, dizziness, speech disturbances, visual disturbances, and hallucinations (including vivid colors and strange images).

With significant isoniazid overdose, respiratory arrest and CNS depression may occur, rapidly progressing from stupor to deep coma, accompanied by severe seizures. Typical laboratory findings include severe metabolic acidosis, ketonuria, and hyperglycemia.

Pyrazinamide

Data on pyrazinamide overdose are insufficient. Hepatotoxicity and hyperuricemia may occur.

Treatment

Induced emesis, gastric lavage, and administration of activated charcoal may be effective if performed within several hours after drug ingestion. Antiemetic agents may be required to control severe nausea and vomiting.

Intensive supportive measures should be implemented, including maintenance of airway patency and symptomatic treatment as symptoms arise.

Isoniazid

In suspected acute isoniazid overdose, even in asymptomatic patients, intravenous administration of pyridoxine (vitamin B6) should be considered. In cases of seizures unresponsive to pyridoxine (vitamin B6), anticonvulsant therapy should be initiated.

Sodium bicarbonate should be administered to control metabolic acidosis. Hemodialysis is recommended in refractory cases; if hemodialysis is not available, peritoneal dialysis combined with forced diuresis may be used.

Side effects.

Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (≤ 1/10,000), frequency not known (cannot be estimated based on available data).

Rifampicin

Reactions occurring with daily or intermittent dosing regimens include:

Body systems	Frequency	Adverse reactions
Infections and infestations	frequency unknown	pseudomembranous colitis, influenza-like symptoms
Blood and lymphatic system disorders	common	thrombocytopenia with or without purpura (more frequent with intermittent therapy, reversible if drug is discontinued as soon as purpura appears)
	uncommon	leukopenia
	frequency unknown	disseminated intravascular coagulation, eosinophilia, agranulocytosis, hemolytic anemia, vitamin K-dependent coagulation disorders
Immune system disorders	frequency unknown	anaphylactic reaction
Endocrine disorders	frequency unknown	adrenal insufficiency in patients with adrenal dysfunction
Metabolism and nutrition disorders	frequency unknown	decreased appetite
Psychiatric disorders	frequency unknown	psychotic disorder
Nervous system disorders	common	headache, dizziness
	frequency unknown	there have been reports of cerebral hemorrhage and fatal outcomes when rifampicin therapy was continued or resumed after the development of purpura
Eye disorders	frequency unknown	change in tear color
Vascular disorders	frequency unknown	shock, inflammation, vasculitis, bleeding
Respiratory, thoracic and mediastinal disorders	frequency unknown	dyspnea, wheezing, discoloration of sputum
Gastrointestinal disorders	common	nausea, vomiting
	uncommon	diarrhea
	frequency unknown	gastrointestinal disturbances, abdominal discomfort, tooth discoloration which may be irreversible
Hepatobiliary disorders	frequency unknown	hepatitis, hyperbilirubinemia
Skin and subcutaneous tissue disorders	frequency unknown	multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, skin reactions, pruritus, urticaria, allergic dermatitis, pemphigoid (bullous) reaction, change in sweat color
Musculoskeletal and connective tissue disorders	frequency unknown	muscle weakness, myopathy, bone pain
Renal and urinary disorders	frequency unknown	acute kidney injury, usually due to renal tubular necrosis or interstitial nephritis, chromaturia
Pregnancy, puerperium and perinatal conditions	frequency unknown	postpartum hemorrhage, fetomaternal hemorrhage
Reproductive system and breast disorders	frequency unknown	menstrual cycle disturbances
Congenital, familial and genetic disorders	frequency unknown	porphyria
General disorders and administration site conditions	very common	fever, chills
	common	paradoxical reaction to drugs (recurrence or appearance of new symptoms of tuberculosis, clinical and radiological signs in a patient who previously showed improvement under appropriate antituberculosis treatment, known as a paradoxical reaction, diagnosed after excluding poor patient compliance, drug resistance, or adverse reactions to antituberculosis therapy, secondary bacterial/fungal infections)*
	frequency unknown	edema
Investigations	common	increased blood bilirubin levels, increased aspartate aminotransferase levels, increased alanine aminotransferase levels
	frequency unknown	decreased blood pressure, increased blood creatinine levels, increased liver enzyme levels

* Frequency of paradoxical drug reactions: the lower reported frequency was 9.2% (53/573) (data from October 2007 to March 2010), and the higher frequency was 25% (19/76) (data between 2000 and 2010).

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

28 tablets in a strip, 3 strips in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and location of operations.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.