Rifampicin-Binergia (Lyophilisate) Instructions for Use

ATC Code

J04AB02 (Rifampicin)

Active Substance

Rifampicin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antibiotic of the rifamycin group. Antituberculosis drug

Pharmacotherapeutic Group

Antibiotic-rifamycin

Pharmacological Action

A broad-spectrum semisynthetic antibiotic, a first-line antituberculosis drug. In low concentrations, it exerts a bactericidal effect on Mycobacterium tuberculosis, Brucella spp., Chlamydia trachomatis, Legionella pneumophila, Rickettsia typhi, Mycobacterium leprae; in high concentrations – on some gram-negative microorganisms.

It is characterized by high activity against Staphylococcus spp. (including penicillinase-producing and many methicillin-resistant strains), Streptococcus spp., Clostridium spp., Bacillus anthracis; gram-negative cocci: Neisseria meningitidis, Neisseria gonorrhoeae. It acts on gram-positive bacteria in high concentrations.

It is active against both intracellularly and extracellularly located microorganisms. It inhibits the DNA-dependent RNA polymerase of microorganisms. With monotherapy, the selection of rifampicin-resistant bacteria occurs relatively quickly. Cross-resistance with other antibiotics (except for other rifamycins) does not develop.

Pharmacokinetics

With intravenous administration, the therapeutic concentration is maintained for 8-12 hours. Plasma protein binding is 84-91%.

It is rapidly distributed throughout organs and tissues (the highest concentration is in the liver and kidneys), penetrates into bone tissue, the concentration in saliva is 20% of the plasma concentration. The apparent V_d is 1.6 L/kg in adults and 1.1 L/kg in children.

It penetrates the blood-brain barrier only in case of inflammation of the meninges. It penetrates the placenta (the concentration in the fetal plasma is 33% of the concentration in the maternal plasma) and is excreted in breast milk (breastfed infants receive no more than 1% of the therapeutic dose of the drug).

It is metabolized in the liver to form a pharmacologically active metabolite – 25-O-desacetylrifampicin. It is an autoinducer – it accelerates its own metabolism in the liver, resulting in a systemic clearance of 6 L/h after the first dose, increasing to 9 L/h after repeated administration.

It is excreted mainly with bile, 80% as a metabolite; by the kidneys – 20%. After taking 150-900 mg of the drug, the amount of rifampicin excreted by the kidneys unchanged depends on the dose taken and is 4-20%.

In patients with impaired renal excretory function, T_1/2 is prolonged only in cases where the dose of rifampicin exceeds 600 mg. It is removed by peritoneal dialysis and hemodialysis.

In patients with impaired liver function, an increase in the concentration of rifampicin in the plasma and a prolongation of T_1/2 are noted.

Indications

• Tuberculosis (all forms) – as part of combination therapy;
• Leprosy (in combination with dapsone – multibacillary types of the disease);
• Infectious diseases caused by microorganisms sensitive to rifampicin (in cases of resistance to other antibiotics and as part of combined antimicrobial therapy; after excluding the diagnosis of tuberculosis and leprosy);
• Brucellosis – as part of combination therapy with antibiotics of the tetracycline group (doxycycline);
• Meningococcal meningitis (prevention in persons in close contact with patients with meningococcal meningitis; in carriers of Neisseria meningitidis).

ICD codes

Dosage Regimen

Lyophilisate

Rifampicin is administered parenterally – intravenously by drip. The infusion rate is 60-80 drops per minute.

Intravenous administration of the drug is recommended for acutely progressive and widespread forms of destructive pulmonary tuberculosis, severe purulent-septic processes, when it is necessary to quickly create high concentrations of the drug in the blood and at the site of infection, in cases where oral administration of the drug is difficult or poorly tolerated by patients.

Preparation of solutions for intravenous infusion

For a dosage of 300 mg: dilute the lyophilisate by adding 5 ml of water for injections to the vial with the drug, shake the vial to ensure complete dissolution of the contents of the vial. Mix the resulting solution with 250 ml of 5% dextrose solution.

For a dosage of 450 mg: dilute the lyophilisate by adding 7.5 ml of water for injections to the vial with the drug, shake the vial to ensure complete dissolution of the contents of the vial. Mix the resulting solution with 375 ml of 5% dextrose solution.

For a dosage of 600 mg: dilute the lyophilisate by adding 10 ml of water for injections to the vial with the drug, shake the vial to ensure complete dissolution of the contents of the vial. Mix the resulting solution with 500 ml of 5% dextrose solution.

During the dissolution of the drug in water for injections, a large number of bubbles form, which disappear when the drug is completely dissolved. The contents of the vial dissolve completely within 5 minutes.

If it is necessary to administer a lower dose of rifampicin, the required number of milliliters is taken from vials with the dissolved drug (10 ml = 600 mg of rifampicin, 7.5 ml = 450 mg, 5 ml = 300 mg of rifampicin, etc.) and mixed with 5% dextrose solution.

For intravenous administration, the daily dose for adults is 450 mg, for severe, rapidly progressive forms – 600 mg, administered in one dose. The duration of intravenous use depends on the tolerability of the drug and is 1 month or more (with subsequent transition to oral administration). The total duration of use for tuberculosis is determined by the effectiveness of treatment and can be up to 1 year.

For infections of non-tuberculous etiology, the daily dose of rifampicin is 0.3-0.9 g (maximum – 1.2 g). The daily dose is divided into 2-3 administrations. The duration of treatment is set individually, depends on effectiveness and can be 7-10 days. Intravenous administration should be discontinued as soon as oral administration becomes possible.

For the treatment of tuberculosis, Rifampicin is combined with at least one other antituberculosis drug (isoniazid, pyrazinamide, ethambutol, streptomycin). Adults with body weight less than 50 kg – 450 mg/day; 50 kg and more – 600 mg/day. Children and newborns – 10-20 mg/kg/day, maximum daily dose – 600 mg.

For tuberculous meningitis, disseminated tuberculosis, spinal lesions with neurological manifestations, for the combination of tuberculosis with HIV infection, the total duration of treatment is 9 months, the drug is used daily, the first 2 months in combination with isoniazid, pyrazinamide and ethambutol (or streptomycin), 7 months – in combination with isoniazid.

In case of pulmonary tuberculosis and detection of mycobacteria in sputum, one of the following 3 schemes is used (all lasting 6 months)

1. First 2 months – as above; 4 months – daily, in combination with isoniazid.
2. First 2 months – as above; 4 months – in combination with isoniazid, 2-3 times per week.
3. Throughout the course – use in combination with isoniazid, pyrazinamide and ethambutol (or streptomycin) 3 times per week. In cases where antituberculosis drugs are used 2-3 times a week (as well as in case of exacerbations of the disease or ineffectiveness of therapy), administration should be carried out under the supervision of medical personnel.

For the treatment of multibacillary types of leprosy (lepromatous, borderline, lepromatous and borderline)adults – 600 mg once a month in combination with dapsone (100 mg once daily) and clofazimine (50 mg once daily + 300 mg once a month); children – 10 mg/kg once a month in combination with dapsone (1-2 mg/kg/day) and clofazimine (50 mg every other day + 200 mg once a month). The minimum duration of treatment is 2 years.

For the treatment of paucibacillary types of leprosy (tuberculoid and borderline tuberculoid)adults – 600 mg once a month, in combination with dapsone – 100 mg (1-2 mg/kg) once daily; children – 10 mg/kg once a month, in combination with dapsone – 1-2 mg/kg/day. The duration of treatment is 6 months.

For the treatment of infectious diseases caused by sensitive microorganisms, it is prescribed in combination with other antimicrobial drugs. The daily dose for adults is 0.6-1.2 g; for children and newborns – 10-12 mg/kg. Frequency of administration – 2 times a day.

For the treatment of brucellosis – 900 mg/day once, in the morning on an empty stomach, in combination with doxycycline; average duration of treatment is 45 days.

For the prevention of meningococcal meningitis – 2 times a day every 12 hours for 2 days. Single doses for adults – 600 mg; for children – 10 mg/kg; for newborns – 5 mg/kg.

For patients with impaired renal excretory function and preserved liver function, dose adjustment is required only when it exceeds 600 mg/day.

Adverse Reactions

Side effects are presented with the following frequency assessment: very common – 1/10 prescriptions (≥ 10 %); common – 1/100 prescriptions (≥ 1 % and <10 %); uncommon – 1/1000 prescriptions (≥ 0.1 % and <1 %); rare – 1/10000 prescriptions (≥ 0.01 % and <0.1 %); very rare – 1/10000 prescriptions (≤ 0.01%).

From the digestive system common – loss of appetite, abdominal pain, nausea, vomiting, flatulence and diarrhea; rare – acute pancreatitis; very rare – pseudomembranous colitis.

From the liver and biliary tract common or very common – increased activity of “liver” transaminases, alkaline phosphatase, gamma-glutamyl peptidase, less commonly bilirubin; in very rare cases (especially in patients with pre-existing liver dysfunction, alcoholism, elderly, with simultaneous use of other hepatotoxic antituberculosis drugs): jaundice and hepatomegaly, which in most cases are transient.

From the blood system rare – eosinophilia, leukopenia, granulocytopenia, thrombocytopenia, thrombocytopenic purpura, hypoprothrombinemia and hemolytic anemia; very rare – disseminated coagulopathy.

From the immune system: common – hypersensitivity reactions (fever, exudative multiforme erythema, exanthematous nosopod-like erythema, pruritus, urticaria); rare – lupus-like symptoms such as fever, weakness, muscle and ligament pain, appearance of antinuclear antibodies; very rare (with combination therapy): severe allergic skin reactions such as toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, pemphigus vulgaris; rare – shallow breathing, asthmoid reactions, pulmonary edema and shock.

Flu-like syndrome (only with intermittent therapy or irregular use of rifampicin, more frequent the longer the intervals between drug use): fever, chills, exanthema, nausea, vomiting, muscle and joint pain, headache and weakness. It develops 3-6 months after the start of intermittent therapy. Symptoms appear 1-2 hours after drug administration and last up to 8 hours, and in some cases longer. In almost all cases, the flu-like syndrome disappears when intermittent treatment is replaced by daily use of rifampicin. In this case, the daily dose of the drug is gradually increased from 50-150 mg on the first day by 50-150 mg per day until the required dose is reached. Corticosteroids can be used.

From the endocrine system rare – menstrual disorders.

From the nervous system rare – myopathy; very rare – headache, ataxia, impaired concentration, increased fatigue, muscle weakness, limb pain, numbness.

From the organ of vision rare – visual impairment, loss of vision, optic neuritis.

From the respiratory system very rare – acute respiratory distress syndrome and pneumonitis.

From the urinary system very rare – acute renal failure, nephronecrosis, interstitial nephritis.

From the skin very rare – burning sensation of the skin.

Contraindications

• Hypersensitivity to the components of the drug;
• Jaundice;
• Recent (less than 1 year) infectious hepatitis;
• Chronic renal failure;
• Severe cardiopulmonary failure;
• Children under 1 year of age.

Use in Pregnancy and Lactation

Therapy during pregnancy (especially in the first trimester) is possible only for “vital” indications. During pregnancy, it is used only if the intended benefit to the mother outweighs the potential risk to the fetus.

When prescribed in the last weeks of pregnancy, postpartum bleeding in the mother and bleeding in the newborn may be observed. In this case, vitamin K is prescribed.

During lactation, the drug is contraindicated.

Use in Renal Impairment

For patients with impaired renal excretory function and preserved liver function, dose adjustment is required only when it exceeds 600 mg/day.

Pediatric Use

Contraindicated for use in children under 1 year of age.

Special Precautions

During treatment, the skin, sputum, sweat, feces, tear fluid, and urine acquire an orange-red color. It may permanently stain soft contact lenses.

Intravenous infusion is carried out under blood pressure control; with prolonged administration, phlebitis may develop.

To prevent the development of microbial resistance, the drug should be used in combination with other antimicrobial drugs.

In case of development of a flu-like syndrome, not complicated by thrombocytopenia, hemolytic anemia, bronchospasm, shortness of breath, shock and renal failure, in patients receiving the drug on an intermittent schedule, the possibility of switching to daily intake should be considered. In these cases, the dose is increased slowly: on the first day, 75-150 mg is prescribed, and the required therapeutic dose is reached in 3-4 days. If the above serious complications are noted, Rifampicin is discontinued. Kidney function should be monitored; additional prescription of glucocorticosteroids is possible.

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

In case of prophylactic use in meningococcal carriers, strict monitoring of patients is necessary in order to timely identify symptoms of the disease in case of resistance to rifampicin.

With long-term use, systematic monitoring of the peripheral blood picture and liver function is indicated. During treatment, microbiological methods for determining folic acid and vitamin B₁₂ in blood serum should not be used.

Effect on the ability to drive vehicles, mechanisms

There are no data confirming the effect of rifampicin on the ability to engage in potentially hazardous activities requiring increased attention.

Overdose

Symptoms pulmonary edema, lethargy, confusion, convulsions.

Treatment symptomatic; gastric lavage, activated charcoal; forced diuresis.

Drug Interactions

It reduces the activity of oral anticoagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis preparations, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tocainide), glucocorticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, azathioprine, beta-blockers, “slow” calcium channel blockers, enalapril, cimetidine (Rifampicin induces some liver enzyme systems, accelerates metabolism).

Antacids, opiates, anticholinergic drugs and ketoconazole reduce (in case of simultaneous oral administration) the bioavailability of rifampicin.

Isoniazid and/or pyrazinamide increase the frequency and severity of liver function disorders to a greater extent than when prescribing rifampicin alone, in patients with pre-existing liver disease.

Para-aminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) should be prescribed no earlier than 4 hours after taking the drug, as absorption may be impaired.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.