INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN (RIFAMPICIN)

Composition:

Active ingredient: rifampicin;

1 capsule contains 150 mg of rifampicin (calculated as 100% dry substance);

Excipients: magnesium carbonate light, lactose monohydrate, calcium stearate.

The capsule cap and body contain colorants: Yellow West FCF (E 110), Ponceau 4R (E 124), and titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard capsules with orange-red cap and body, containing powder or mass in the form of partially or completely formed pellets ranging from pale red to reddish-brown with white specks.

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 RNA synthesis in microorganisms.

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, and clostridia. Gram-negative cocci – N. meningitidis and N. gonorrhoeae (including β-lactamase-producing strains) – are initially susceptible but rapidly develop resistance. Rifampicin 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 not susceptible. The drug 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 after administration on an empty stomach is 95%. Bioavailability decreases when administered 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. Rifampicin is 60–90% bound to plasma proteins and is lipid-soluble. Maximum plasma concentration is reached within 2 hours after administration on an empty stomach and within 4 hours after food intake. Therapeutic drug concentrations in the body are maintained for 8–12 hours (for highly susceptible 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. Rifampicin is primarily excreted from the body via bile and urine, with a small amount eliminated in feces.

Clinical characteristics.

Indications.

In combination therapy:

tuberculosis of various localizations, tuberculous meningitis, as well as atypical mycobacterioses;
infectious-inflammatory diseases of non-tuberculous etiology 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 other component of the drug;
severe impairment of liver or kidney function;
jaundice;
recent history (within less than 1 year) of infectious hepatitis;
severe cardiorespiratory 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 that are also metabolized by this enzyme system may accelerate their metabolism and reduce their activity; therefore, maintenance of their optimal therapeutic blood concentrations requires adjustment of the dosage 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: prothrombin time should be monitored daily or as frequently as necessary to determine the required anticoagulant dose;
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);
corticosteroids (for systemic use);
antiestrogens (e.g., tamoxifen, toremifene, gestrinone), systemic hormonal contraceptives, estrogens, progestogens; alternative, non-hormonal contraceptive methods should be recommended to patients taking oral contraceptives 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);
cytostatic agents (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 concentration of rifampicin;
ketoconazole – reduced serum concentrations of both drugs;
enalapril – reduced blood concentration of enalaprilat, the active metabolite of enalapril. Depending on the clinical condition, dose adjustment of enalapril 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. Patients receiving both rifampicin and isoniazid should be closely monitored for liver function;
pyrazinamide – severe liver damage, including fatal cases, have been reported in patients receiving daily rifampicin and pyrazinamide for 2 months; this combination should only be used with careful monitoring and only if potential benefit outweighs the risk of hepatotoxicity and fatal outcome;
clozapine, flecainide – increased bone marrow toxicity;
para-aminosalicylic acid preparations containing bentonite (aluminum hydro-silicate) – to ensure adequate blood concentrations of these drugs, the interval between 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, bromsulfalein test should not be used, as rifampicin alters the excretion parameters of bromsulfalein, which may lead 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 may occur in opiate screening tests using the KIMS method or quantitative immunoassay methods; confirmatory tests (e.g., gas chromatography/mass spectrometry) are recommended.

Special precautions.

Rifampicin therapy requires careful medical supervision.

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

Monotherapy of tuberculosis with rifampicin frequently leads to the development of resistant strains of mycobacteria. Therefore, rifampicin should be administered concomitantly with isoniazid, ethambutol, pyrazinamide, and other antituberculosis agents.

Rifampicin is preferably administered daily rather than intermittently to reduce the risk of severe adverse reactions. Daily administration is better tolerated than intermittent therapy.

Prior to initiating treatment, liver enzyme levels, bilirubin, creatinine, and complete blood count including platelet count should be determined. During prolonged therapy, periodic (preferably monthly) monitoring of blood parameters and liver and kidney function is required.

In some patients, hyperbilirubinemia may occur during the first days of treatment due to competition between rifampicin and bilirubin for hepatic excretion.

If a flu-like syndrome develops, uncomplicated by thrombocytopenia, hemolytic anemia, bronchospasm, dyspnea, shock, or renal failure, in patients receiving intermittent therapy, consider switching to daily administration. In such cases, the dose should be gradually increased: 150 mg on the first day, reaching the required therapeutic dose within 3–4 days.

Rifampicin should be prescribed with particular caution, only when absolutely necessary and under strict medical supervision, in patients with liver disease. Severe hepatotoxic reactions, sometimes fatal, have been reported in patients with impaired liver function or in those with normal liver function who were concurrently receiving other hepatotoxic drugs. Such patients should receive lower doses of rifampicin and undergo careful monitoring of liver function: prior to treatment initiation, weekly during the first two weeks, and then every two weeks thereafter. Rifampicin must be discontinued immediately upon signs of hepatocellular injury. Rifampicin therapy should also be discontinued if clinically significant abnormalities in liver function tests occur.

When rifampicin is re-administered after normalization of liver function, daily monitoring of liver function is required.

Mild liver function abnormalities are usually transient and do not require discontinuation of the drug. Administration of ademetionine (SAMe), methionine, pyridoxine, and vitamin B12 may be considered.

Particular caution is advised when combining rifampicin and isoniazid in patients with impaired liver function, elderly patients, and those suffering from malnutrition.

Alcohol consumption during treatment or use in patients with a history of alcoholism increases the risk of hepatotoxicity.

Deviation from the prescribed regimen, whether intentional or accidental interruption of dosing, or intermittent therapy (less than 2–3 times per week) increases the risk of serious hypersensitivity reactions and other adverse effects (anaphylactic shock, flu-like syndrome, hemolytic anemia, acute renal failure, severe skin reactions, gastrointestinal disturbances). Patients should be informed about the consequences of interrupting treatment.

When resuming treatment, consider switching to daily administration, starting with a low dose (150 mg/day) and gradually increasing to the required therapeutic dose. During this transition period, renal and hematopoietic functions should be closely monitored. The drug should be discontinued immediately at the first signs of renal failure, thrombocytopenic purpura, or hemolytic anemia. Subsequent use of the drug is contraindicated.

Antibacterial therapy, especially in severe diseases in elderly patients, debilitated patients, and children, may lead to antibiotic-associated diarrhea and colitis, including pseudomembranous colitis. Therefore, in case of diarrhea during or after rifampicin treatment, these conditions, including pseudomembranous colitis, must be ruled out. Without appropriate treatment, toxic megacolon, peritonitis, and shock may develop.

Prolonged use of antibacterial agents may lead to overgrowth of non-susceptible microorganisms and fungi, resulting in superinfection, requiring appropriate interventions.

Women of reproductive age should use reliable contraceptive methods during rifampicin therapy, as rifampicin reduces the efficacy of hormonal contraceptives (non-hormonal contraceptive methods are recommended as an additional measure).

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

Rifampicin has enzyme-inducing properties (including delta-aminolevulinic acid synthetase), which may enhance the metabolism of endogenous substrates, including adrenal hormones, thyroid hormones, and vitamin D. Isolated reports have linked rifampicin therapy to porphyria exacerbations.

In some cases, decreased circulating vitamin D metabolites have been observed, accompanied by reduced calcium and phosphate levels and elevated serum parathyroid hormone levels.

During rifampicin therapy, skin, sputum, sweat, feces, tears, and urine may turn orange-red. Permanent staining of soft contact lenses is possible.

During treatment, the following should not be used:

– Bromsulphthalein test, as rifampicin competitively interferes with its excretion;

– Microbiological methods for determining serum folate and vitamin B12 concentrations;

– Immunological methods, including KIMS method, for screening opiate tests.

The drug contains the excipient lactose monohydrate; therefore, it is contraindicated in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Use during pregnancy is possible only in exceptional cases and when strictly indicated, if the expected benefit to the mother outweighs the potential risk to the fetus. Rifampicin administration in the last weeks of pregnancy increases the risk of hemorrhage in newborns and mothers in the postpartum period.

Rifampicin passes into breast milk. If treatment is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when operating vehicles or machinery.

During rifampicin therapy, patients should refrain from driving vehicles or operating machinery, as impaired coordination, reduced concentration, and visual disturbances may occur.

Dosage and Administration

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

Tuberculosis:

Adults: 8–12 mg/kg body weight once daily. For patients with body weight below 50 kg – 450 mg/day; for patients with body weight of 50 kg and above – 600 mg/day.

Children aged 6 to 12 years: 10–20 mg/kg body weight once daily; maximum daily dose should not exceed 600 mg.

The duration of antituberculosis therapy is individual, determined by 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 standard 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):

Adults: 900–1200 mg daily in 2–3 divided doses; maximum daily dose – 1200 mg. The drug should be continued for an additional 2–3 days after disappearance of disease symptoms.

Leprosy: the drug (in combination with immunostimulants) should be administered orally at 600 mg daily in 1–2 doses for 3–6 months (repeated courses with 1-month intervals 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.

N. meningitidis carriage: Rifampicin should be administered for 4 days. Daily dose for adults – 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: renal excretion of rifampicin decreases proportionally to the decline in physiological kidney function in elderly patients, leading to compensatory increase in hepatic excretion of the drug. Rifampicin should be used with caution in this age group, especially in the presence of signs of impaired liver function.

Children.

This medicinal product in the given pharmaceutical form should not be administered to children under 6 years of age.

Overdose.

Symptoms: nausea, vomiting, abdominal pain, headache, increased fatigue, increasing drowsiness, allergic reactions, fever, dyspnea, cyanosis, leukopenia, thrombocytopenia, acute hemolytic anemia, renal failure, skin reactions, pruritus, which may occur shortly after drug intake.

Transient increases in bilirubin levels and liver transaminases, hepatomegaly, jaundice, and loss of consciousness in severe cases of liver dysfunction may occur. A characteristic reddish discoloration of the skin, urine, sweat, saliva, tears, and feces may appear, the intensity of which is proportional to the amount of drug ingested.

Cases of facial or periorbital edema, usually in children, have been reported.

Arterial hypotension, sinus tachycardia, ventricular arrhythmia, seizures, and cardiac arrest have been observed in some fatal cases.

Treatment: discontinue the drug, gastric lavage within the first 2–3 hours, administration of activated charcoal, and symptomatic therapy. In severe cases – forced diuresis, hemodialysis may be considered, along with intensive supportive care and monitoring of hematological, renal, and hepatic functions until the patient's condition stabilizes. There is no specific antidote.

Adverse Reactions

Gastrointestinal tract. Nausea, vomiting, anorexia, diarrhea, heartburn, dyspepsia, discomfort, spasms/pain in the abdominal area, flatulence, esophagitis, pseudomembranous enterocolitis, erosive gastritis, decreased appetite; with prolonged use, dysbacteriosis may develop.

Hepatobiliary system. Transient elevation of hepatic transaminases, alkaline phosphatase, and plasma bilirubin levels; jaundice with signs of hepatocellular damage, hepatitis, potentially fatal severe manifestations of hepatotoxicity (e.g., in shock-like syndrome), usually in patients with impaired liver function or in those with normal liver function who are concurrently taking other hepatotoxic drugs. Baseline and periodic monitoring of liver function is recommended for all patients undergoing long-term rifampicin therapy.

Hematopoietic system. Transient leukopenia, neutropenia, thrombocytopenia with or without purpura (more frequently during intermittent high-dose therapy or after resuming interrupted treatment, especially when combined with ethambutol), eosinophilia, decreased hemoglobin, hemolytic anemia, agranulocytosis, erythrocytic aplasia, methemoglobinemia, hemolysis, disseminated intravascular coagulation syndrome, hemorrhages. Rifampicin therapy should be discontinued at the first signs of purpura, as cases of cerebral hemorrhage (including intracranial hemorrhage) and fatal outcomes have been reported when rifampicin therapy was continued or resumed after the onset of purpura.

Nervous system. Headache, dizziness, paresthesia, weakness, asthenia, confusion, drowsiness, increased fatigue, ataxia, behavioral changes, decreased concentration, impaired motor coordination, disorientation, myopathies, muscle weakness, limb pain, generalized numbness.

Psychiatric disorders. Psychoses.

Immune system. When the dosing schedule is not followed or treatment is resumed after a temporary interruption, or with intermittent treatment regimens, flu-like syndrome may occur (petechiae, myalgia, arthralgia, episodes of fever, chills, nausea, vomiting, malaise).

Cases have been reported of dyspnea, bronchospasm, anaphylactic reactions including anaphylactic shock, and other hypersensitivity reactions, including pruritus, urticaria, Quincke's edema (angioedema), skin hyperemia, rash (including exanthema), pemphigoid reactions, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis (including leukocytoclastic vasculitis), stomatitis, glossitis, conjunctivitis.

Urinary system. Renal function impairment (transient increases in blood urea nitrogen, hyperuricemia). Hemoglobinuria, hematuria, interstitial nephritis, glomerulonephritis, acute tubular necrosis, renal failure, including acute renal failure. These reactions may represent manifestations of hypersensitivity reactions, typically occurring with irregular drug intake or upon resumption of treatment after interruption, particularly with intermittent regimens, and are usually reversible upon discontinuation of rifampicin and appropriate treatment.

Other. Decreased arterial pressure (associated with hypersensitivity reactions), hot flushes, facial and limb edema, adrenal insufficiency in patients with impaired adrenal gland function, menstrual cycle disturbances (breakthrough bleeding, bloody discharge, amenorrhea, prolonged menstrual cycle), visual disturbances, orange-red discoloration of skin, urine, feces, saliva, sputum, sweat, mucus, induction of porphyria, gout exacerbation, lacrimation, herpes, wheezing.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 capsules in a blister pack, 2 blisters per carton; 90 capsules in a container, 1 container per carton; 1000 capsules in a container.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical-Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Mиру Street, Kyiv, 03134, Ukraine.