Macox 300

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MACOX 150, MACOX 300 (MACOX 150, MACOX 300)

Composition:

Active substance: rifampicin;

1 capsule contains rifampicin 150 mg or 300 mg;

Excipients: microcrystalline cellulose, povidone K-30, corn starch, sodium lauryl sulfate, talc, magnesium stearate;

Capsule shell for 150 mg capsules: gelatin, carmoisine (E 122), Ponceau 4R (E 124), Sunset Yellow FCF (E 110), titanium dioxide (E 171), sodium lauryl sulfate, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216);

Capsule shell for 300 mg capsules: gelatin, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), colloidal anhydrous silicon dioxide, sodium lauryl sulfate, glycerin, titanium dioxide (E 171), Ponceau 4R (E 124), carmoisine (E 122).

Pharmaceutical form. Capsules.

Main physicochemical properties:

150 mg capsules: hard gelatin capsules No. 2 with bright red cap and body, containing brick-red powder;

300 mg capsules: hard gelatin capsules No. 0 with bright red cap and body, containing brick-red powder.

Pharmacotherapeutic group.

Antituberculosis agents. Antibiotics. ATC code J04AB02.

Pharmacological Properties.

Pharmacodynamics.

Rifampicin is a semisynthetic antibiotic of the rifamycin group and a first-line antituberculosis agent. It exerts a bactericidal effect, the mechanism of which is due to inhibition of DNA-dependent RNA polymerase activity by forming complexes with it, leading to reduced microbial RNA synthesis.

Rifampicin is a broad-spectrum antibiotic with the highest activity against Mycobacterium tuberculosis.

The drug is active against various types of atypical mycobacteria (except M. fortuitum), Gram-positive cocci (staphylococci, streptococci), Bacillus anthracis, clostridia, etc. Gram-negative cocci – N. meningitidis and N. gonorrhoeae (including β-lactamase-producing strains) – are sensitive but rapidly develop resistance. It is active against H. influenzae (including strains resistant to ampicillin and chloramphenicol), H. ducreyi, B. pertussis, B. anthracis, L. monocytogenes, F. tularensis, Legionella pneumophila, Rickettsia prowazekii, and Mycobacterium leprae. Rifampicin has virucidal activity against the rabies virus and suppresses the development of rabies encephalitis.

Members of the Enterobacteriaceae family and non-fermenting Gram-negative bacteria (Pseudomonas spp., Acinetobacter spp., Stenotrophomonas spp., etc.) are insensitive. It has no effect on anaerobic microorganisms or fungi.

Resistance to rifampicin develops rapidly. Cross-resistance to other antituberculosis agents has not been observed (except for other rifamycins).

Pharmacokinetics.

Rifampicin is well absorbed in the gastrointestinal tract; bioavailability when taken on an empty stomach is 95%. Bioavailability decreases when taken with food. It achieves effective concentrations in sputum, saliva, nasal secretions, lungs, pleural and peritoneal exudates, kidneys, and liver. It penetrates well into cells. It crosses the blood-brain barrier and reaches effective concentrations in cerebrospinal fluid during tuberculous meningitis. It crosses the placenta and is excreted in breast milk. It binds to plasma proteins by 60–90% and is lipid-soluble. Maximum blood concentration is observed 2 hours after administration on an empty stomach and 4 hours after food intake. Therapeutic drug concentration in the body is maintained for 8–12 hours (for highly sensitive microorganisms – up to 24 hours). Rifampicin can accumulate in lung tissue and maintain prolonged concentrations within cavities. It is metabolized in the liver, forming an active metabolite. The elimination half-life is 3–5 hours. It is excreted from the body mainly via bile and urine, and in small amounts via feces.

Clinical characteristics.

Indications.

In combination therapy:

• tuberculosis of various localizations, tuberculous meningitis, as well as atypical mycobacterioses;
• infectious-inflammatory diseases of non-tuberculous origin caused by pathogens sensitive to the drug (including severe forms of staphylococcal infection, leprosy, legionellosis, brucellosis);
• asymptomatic carriage of N. meningitidis for elimination of meningococci from the nasopharynx and prevention of meningococcal meningitis.

Contraindications.

Hypersensitivity to rifampicin, other rifamycins, or any component of the drug; severe impairment of liver or kidney function; jaundice (including mechanical jaundice); recent history (within less than 1 year) of infectious hepatitis; severe cardiopulmonary insufficiency; concomitant use of saquinavir/ritonavir.

Interaction with other medicinal products and other types of interactions.

Rifampicin is a potent inducer of hepatic microsomal enzymes (cytochrome P450) and may cause potentially dangerous drug interactions. Concomitant administration of rifampicin with drugs metabolized by this enzyme system may accelerate their metabolism and reduce their activity; therefore, maintenance of their optimal therapeutic blood concentrations requires dosage adjustment of these medicinal products upon initiation and discontinuation of rifampicin therapy.

Rifampicin accelerates the metabolism of:

• antiarrhythmic agents (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, anticonvulsant agents (e.g., phenytoin, carbamazepine);
• psychotropic agents – 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; monitoring of prothrombin time daily or as frequently as necessary to determine the required anticoagulant dose is recommended;
• antifungal agents (e.g., terbinafine, fluconazole, itraconazole, ketoconazole, voriconazole);
• antiviral agents (e.g., saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine);
• antibacterial agents (e.g., chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin);
• glucocorticoids (for systemic use);
• antiestrogens (e.g., tamoxifen, toremifene, gestrinone), systemic hormonal contraceptives, estrogens, progestogens; female 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.

With concomitant use of rifampicin and:

• atovaquone – decreased serum concentration of atovaquone and increased serum concentration of rifampicin;
• ketoconazole – decreased serum concentrations of both drugs;
• enalapril – reduced blood concentration of enalaprilat, the active metabolite of enalapril. Depending on the clinical condition, enalapril dosage adjustment may be necessary;
• antacids – possible reduction in rifampicin absorption. Rifampicin should be taken at least 1 hour before antacids;
• probenecid and co-trimoxazole – increased blood levels of rifampicin;
• saquinavir/ritonavir – increased risk of hepatotoxicity. This combination is contraindicated;
• sulfasalazine – reduced plasma concentration of sulfapyridine, possibly due to disruption of intestinal bacterial flora responsible for conversion of sulfasalazine to sulfapyridine and mesalazine;
• halothane, isoniazid – increased risk of hepatotoxicity. Concomitant use of rifampicin and halothane should be avoided. In patients receiving both rifampicin and isoniazid, liver function should be closely monitored;
• pyrazinamide – severe liver damage, including fatal outcomes, have been reported in patients receiving daily rifampicin and pyrazinamide for 2 months; this combination should only be used with careful monitoring and if the potential benefit outweighs the risk of hepatotoxicity and mortality;
• clozapine, flecainide – increased toxic effects on bone marrow;
• para-aminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) – to ensure adequate blood concentrations of these drugs, the interval between their administration should be at least 4 hours;
• ciprofloxacin, clarithromycin – possible increase in 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 bromsulphalein test should not be used, as rifampicin alters the excretion parameters of bromsulphalein, potentially leading to misinterpretation of test results. Microbiological methods for determining serum concentrations of folic acid and vitamin B12 should also be avoided.

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

Special precautions for use.

Monotherapy of tuberculosis with rifampicin is often associated with the development of pathogen resistance to the antibiotic; therefore, it should be combined with other antituberculosis agents. When treating nontuberculous infections, rapid development of microbial resistance is possible; this process can be prevented by combining rifampicin with other chemotherapeutic agents.

In case of recurrence, the drug should not be prescribed without prior bacteriological testing.

Rifampicin should not be prescribed for the treatment of nonspecific pulmonary lesions suspected of being tuberculosis until a definitive diagnosis has been established.

In gonorrhea, unlike penicillin, rifampicin does not mask syphilis in cases of mixed infection; serological tests for syphilis remain positive.

During prolonged use, systematic monthly monitoring of liver function and peripheral blood parameters is recommended.

The drug should be used with caution in elderly patients due to possible age-related changes in liver function.

Patients with mild to moderate hepatic impairment may receive rifampicin only in extreme cases and under constant medical supervision. In such patients, monitoring should be performed weekly during the first two weeks and then every two weeks for an additional six weeks. If signs of hepatotoxicity occur, the drug should be discontinued.

The risk of hepatotoxicity also increases during alcohol consumption throughout the treatment period.

In some patients, an increase in bilirubin may occur during the first days of rifampicin therapy. Rifampicin induces enzymes that accelerate the metabolism of endogenous substrates such as adrenal hormones, thyroid hormones, and vitamin D.

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

Use with caution in debilitated patients, patients who abuse alcohol, and in porphyria.

Use during pregnancy or breastfeeding.

Use during pregnancy is possible only in exceptional cases and on life-saving indications when the expected benefit to the woman outweighs the potential risk to the fetus. Administration of rifampicin in the last weeks of pregnancy increases the risk of bleeding in newborns and mothers in the postpartum period.

Rifampicin passes into breast milk. If it is necessary to use the drug, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

During treatment with rifampicin, disturbances in motor coordination and visual disturbances may occur; therefore, if such reactions develop, patients should refrain from driving or operating complex machinery.

Dosage and Administration.

Rifampicin should be administered orally 30 minutes before or 2 hours after a meal, taken with sufficient amount of water.

Tuberculosis: in adults, the dose is 8–12 mg/kg body weight per day. For patients with body weight less than 50 kg – 450 mg/day; for those with body weight of 50 kg and above – 600 mg/day. In children aged 6 to 12 years, the dose is 10–20 mg/kg body weight per day; the maximum daily dose should not exceed 600 mg.

The duration of antituberculosis therapy is individual and determined by the therapeutic response, and may last 1 year or longer. To prevent the development of mycobacterial resistance to rifampicin, the drug should generally be administered in combination with other first- and second-line antituberculosis agents at their usual doses.

Non-tuberculous infectious and inflammatory diseases caused by pathogens sensitive to the drug – brucellosis, legionellosis, severe forms of staphylococcal infection (in combination with another appropriate antibiotic to prevent emergence of resistant strains): in adults, the dose is 900–1200 mg daily in 2–3 divided doses; the maximum daily dose is 1200 mg. The drug should be continued for an additional 2–3 days after disappearance of disease symptoms.

Leprosy: the drug (in combination with immunostimulating agents) is administered orally at a dose of 600 mg daily in 1–2 doses for 3–6 months (repeated courses with a 1-month interval are possible). According to another regimen (during combined antileprosy therapy), the drug is administered at a daily dose of 450 mg, divided into 3 doses, for 2–3 weeks, with 2–3 month intervals, over a period of 1–2 years.

Carriage of N. meningitidis: rifampicin should be administered for 4 days. The daily dose for adults is 600 mg; for children – 10–12 mg/kg body weight.

Hepatic impairment: the daily dose should not exceed 8 mg/kg in patients with impaired liver function.

Use in elderly patients: in elderly patients, renal excretion of rifampicin decreases proportionally to the decline in physiological kidney function, resulting in compensatory increase in hepatic excretion of the drug. Rifampicin should be used with caution in this age group, especially if signs of impaired liver function are present.

Children.

The drug in this pharmaceutical form is not recommended for children under 6 years of age.

Overdose.

Symptoms: nausea, vomiting, diarrhea, abdominal pain, increased fatigue, drowsiness, hepatomegaly, jaundice, increased levels of bilirubin and liver transaminases in blood plasma; brown-red or orange discoloration of the skin, oral mucosa, sclera, urine, saliva, sweat, mucus, and feces proportional to the administered dose; allergic reactions, fever, dyspnea, leukopenia, thrombocytopenia, acute hemolytic anemia, renal failure, periorbital or facial edema, pruritus, confusion, pulmonary edema, seizures.

Treatment: discontinue the drug. Symptomatic therapy. In severe cases – forced diuresis. There is no specific antidote.

Side effects.

Gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, decreased appetite, anorexia, erosive gastritis, pseudomembranous colitis, discomfort.

Hepatobiliary system: increased serum liver transaminase activity, hyperbilirubinemia, hepatitis, discomfort in the right hypochondrium.

Skin: flushing, pruritus, rash, urticaria, exanthema, exfoliative dermatitis, pemphigoid (bullous) reaction, erythema multiforme including Stevens-Johnson syndrome, Lyell's syndrome, and vasculitis.

Immune system: hypersensitivity reactions, including angioneurotic edema, bronchospasm, anaphylactic shock, anaphylaxis.

Other: arthralgia, fever, herpes, lacrimation.

Blood system: leukopenia, neutropenia, hemolytic anemia, thrombocytopenia with/without purpura (more frequently during intermittent therapy), eosinophilia; very rarely – agranulocytosis, disseminated intravascular coagulation syndrome. Rifampicin therapy should be discontinued at the first signs of purpura, as there have been reports of cerebral hemorrhage and fatal outcomes when rifampicin treatment was continued or resumed after the onset of purpura.

Nervous system: headache, dizziness, decreased visual acuity, ataxia, disorientation, psychosis.

Endocrine system: menstrual cycle disturbances, adrenal insufficiency in patients with impaired adrenal function.

Urinary system: nephron necrosis, interstitial nephritis, acute renal failure (reversible), hyperuricemia.

Other: orange-red discoloration of urine, feces, saliva, sputum, tears, sweat, mucus; induction of porphyria, myasthenia, myopathy, gout exacerbation, dyspnea and wheezing, intracerebral hemorrhage, decreased arterial pressure.

In case of irregular intake or resumption of treatment after an interruption, influenza-like symptoms may occur (headache, dizziness, episodes of fever, chills, arthralgia).

Due to the presence of excipients, allergic reactions including delayed-type reactions may develop.

Shelf life. 2 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 10 blisters in a cardboard box.

10 capsules in a strip; 10 strips in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

MACLEOD'S PHARMACEUTICALS LIMITED.

Manufacturer's address and location of business activity.

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