Rifabutin-Ferein - instructions for use, dose, side effects, contraindications

Housing: titanium dioxide (E 171) - 0.5000%, dyes: iron oxide red (E 172) - 1.0000%, crimson [Ponso 4R] (Е 124) - 1.5967%, blue patented V (Е 131) - 0.0073%, brilliant black BN (E 151) - 0.0415%; water - 14.50%, gelatin - 82.35%.

Cap: titanium dioxide (E 171) - 0.5000%, dyes: iron oxide red (E 172) - 1.0000%, crimson [Ponso 4R] (Е 124) - 1.5967%, blue patented V (Е 131) - 0.0073%, brilliant black BN (E 151) - 0.0415%; water - 14.50%, gelatin - 82.35%.

Description:Hard gelatin capsules number 0. Body and cap capsules of dark brown color. The contents of capsules are a powder of violet color with white impregnations.

Pharmacotherapeutic group:Antibiotic-rifamycin.

ATX: & nbsp

J.04.A.B Antibiotics

J.04.A.B.04 Rifabutin

Pharmacodynamics:

Semisynthetic broad-spectrum antibiotic. It is active against extracellular and intracellularly located microorganisms. It is a selective inhibitor of DNA-dependent RNA polymerase; bactericidin. Highly active in relation to Mycobacterium spp. (Mycobacterium tuberculosis, Mycobacterium avium intracellulare complex (MAC) and other atypical mycobacteria); many gram-positive and gram-negative bacteria. Rifabutin shows activity against 25-40% of strains Mycobacterium tuberculosis, atypical mycobacteria, resistant to rifampicin and other antibacterial drugs, indicating an incomplete cross-resistance between these drugs. The rate of development of resistance to rifabutin is lower than to rifampicin.

It is used in combination with other antibacterial drugs, in monotherapy - resistance develops rapidly. Rifabutin activity in vivo with experimental tuberculosis 10 times or more exceeds the activity of rifampicin, which corresponds to the data in vitro.

Pharmacokinetics:

Quickly absorbed from the gastrointestinal tract. The maximum concentration in the blood plasma (Cmah) is achieved 2-4 hours after ingestion.The concentration of the drug in the plasma is maintained above the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis up to 30 hours from the date of admission. With a single admission of 300, 450 and 600 mg of the drug, the pharmacokinetics of rifabutin is linear in nature, with Cmah is determined in the range of 0.4-0.7 μg / ml.

Rifabutin penetrates very actively into cells. The ratio of its intra- and extracellular concentrations ranged from 9 in human neutrophils to 15 in monocytes. High intracellular concentrations are probably key to maintaining rifabutin activity against intracellular pathogens, such as mycobacteria. Rifabutin and its metabolites are excreted mainly by the kidneys. Among the 5 known metabolites of rifabutin, the major ones are 25-deacetyltrifabutin and 31-hydroxythrifabutin. The first for antibacterial activity is comparable to rifabutin. The half-life of rifabutin is about 35-40 hours.

Indications:Treatment of infections caused by sensitive microorganisms (Mycobacterium tuberculosis, MAC complex, other atypical mycobacteria such as Mycobacterium xenopi), including in patients with immunodeficiency: treatment of pulmonary tuberculosis, both newly diagnosed and resistant chronic; prevention of infections,caused by a complex of MAC in patients with immunodepression, with a CD4 count <200 in μl; treatment of disseminated Mycobacterium avium infection in patients with HIV infection.

Rifabutin is prescribed in combination with other antituberculosis drugs.

Contraindications:Hypersensitivity to rifabutin, other components of the drug and rifamycins. Pregnancy, lactation, children's age (experience of clinical use in children is absent).

Carefully:Severe renal insufficiency, hepatic insufficiency, viral hepatitis, severe atherosclerosis.

Pregnancy and lactation:The drug is contraindicated for use during pregnancy and lactation. If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Dosing and Administration:

Inside, 1 time per day, regardless of food intake.

Tuberculosis of the lung: 150 mg / day for 6-9 months or for at least 6 months after receiving negative results of culture analysis. In patients with multidrug-resistant tuberculosis, the dose of the drug is 300-450 mg / day up to 6 months after receiving negative results of culture analysis. Prevention of M4C infections in patients with immunosuppression - 300 mg / day.In combination with other drugs: with non-tuberculous mycobacterial infection - 450-600 mg / day, up to 6 months from the time of receiving negative seeding. If the drug is used in combination with clarithromycin, then after the first month of treatment, its daily dose should be reduced to 300 mg. Dose adjustments in elderly patients are not required.

When the creatinine clearance is below 30 ml / min, the dose is reduced by 50%. With moderate violations of the liver and / or kidneys do not require dose adjustment.

Side effects:

From the digestive system: nausea, vomiting, taste change, dyspepsia, belching, flatulence, diarrhea, abdominal pain, increased activity of "liver" transaminases, alkaline phosphatase, jaundice, hepatitis, pseudomembranous colitis.

From the hematopoiesis: leukopenia, including neutropenia, thrombocyte singing, anemia, hemolysis.

From the side of the musculoskeletal system: arthralgia, myalgia, myositis.

From the nervous system: insomnia.

From the respiratory system: dyspnea.

Allergic reactions: fever, rash, eosinophilia, bronchospasm, anaphylactic shock, uveitis.

Other: asthenia, chest pain, fever, flu-like syndrome, coloration of urine in orange, discoloration of the skin.

Overdose:

Symptoms: increased dose-related side effects.

Treatment: gastric lavage, symptomatic therapy, the appointment of diuretics.

Interaction:

Treatment with rifabutin is accompanied by the induction of hepatic enzymes belonging to the cytochrome P 450 subfamily CYP3A. The main metabolite of rifabutin (25-deacetyltrifabutin; LM 565) also has this effect. Induction of metabolism under the influence of rifabutin can lead to a decrease in plasma concentrations of other drugs that are metabolized by CYP450 isoenzymes. It was shown that induction of enzymes is completed within 5 days after initiation of rifabutin treatment and is dose independent when used in the range of 300 to 600 mg. Drugs that competitively inhibit the activity of CYP450 OA may increase the plasma concentration of rifabutin. It is unlikely to develop clinically significant interactions with ethambutol, theophylline, sulfonamides, pyrazinamide, fluconazole, zalcitabine. Clarithromycin increases the concentration of the drug in plasma (with a simultaneous reception with clarithromycin, the daily dose of rifabutin is reduced to 300 mg). Rifabutin reduces the concentration of zidovudine in plasma.

Use of rifabutin in combination with pyrazinamide, isoniazid and prothionamide shown pronounced synergism due to microbiological level. Oral contraceptives may be ineffective when taken concomitantly with rifabutin. Rifabutin can cause an acceleration of the metabolism of sex hormones, which can be the cause of intermenstrual bleeding or inefficiency of hormonal contraception. The mechanism of interaction is based on the ability of rifabutin to induce hepatic enzymes, which metabolize sex hormones. Table 1 summarizes information on the interaction of drugs with rifabutin. The clinical significance of these interactions and the need for dose adjustment should be evaluated taking into account the characteristics of the patient, the severity of the disease, the spectrum of drugs used and the possible impact on the risk / benefit ratio.

Table 1. Studies of the interaction of rifabutin

Concomitant therapy	The effect on the pharmacokinetics of rifabutin	The effect of rifabutin on the pharmacokinetics of a concomitant drug	Comments
ANTI-VIRUS MEANS
Delavirdine	nd	The increase in clearance by 5 times and a significant decrease in the average plasma concentration at the end of the dosing interval (from 18 ± 15 to 1.0 ± 0.7 μM)	The study was conducted in HIV-infected patients. Rifabutin it is not recommended to appoint patients receiving dela-viridin mesylate at a dose of 400 mg every 8 hours.
Didanosine	No significant changes	Absence of significant changes in the equilibrium state
Indinavir	Increase AUC	Decrease AUC
Saquinavir	nd	Decrease AUC
Ritonavir	Increase AUC and CmOh	nd	In combination with ritonavir, the risk of side effects, including uveitis, may increase. If the patient receiving rifabutin, requires a protease inhibitor, then the possibility of using non-ritonavir and another drug of this group should be discussed
Zidovudine	No significant changes	Decrease in Cmah and AUC	A large controlled study showed that these changes have no clinical significance
Amprenavir	Increase AUC	nd	Simultaneous use of amprenavir and rifabutin leads to an increase in AUC rifabutin by 200% and to an increase in the side effects of rifabutin.
Fosamprenavir	Increase AUC	nd	Fosamprenavir in the body is converted into amprenavir, which is metabolized predominantly in the liver with the participation of the CYP isoenzyme ZA4. The simultaneous use of fosamprenavir and rifabutin leads to an increase in plasma rifabutin concentration of 200% (AUC) and an increase in the number of unwanted reactions associated with rifabutin. It is recommended to reduce the dose of rifabutin by at least 50% with simultaneous administration with fosamprenavir, and at least 75% with fosamprenavir in combination with ritonavir. Careful medical follow-up is necessary, further reduction of the dose may be required.
Lopinavir / ritonavir	With the simultaneous use of rifabutin and lopinavir / ritonavir for 10 Days of Cmax and AUC of rifabutin (the drug itself and the active 25-0- deacetyl metabolite) are increased by 3.5 and 5.7 times, respectively	nd	It is recommended to reduce the dose of rifabutin by 75% (that is, taking 150 mg every other day or three times a week) when used with lopinavirum / ritonavir. It may be necessary to reduce the dose of rifabutin.
Tipranavir / ritonavir	Tipranavir (used with a low dose of ritonavir) increases the concentration of rifabutin in the plasma by no more than 3 times, and the concentration of 25-0-dezacil-rifabutin (active metabolite) is not more than 20 times	Increases the minimum concentration of tipranavir by 16%	A reduction in the usual dose of rifabutin (300 mg) is recommended, at least 75.0% (eg, 150 mg every other day or three times a week). It may be necessary to reduce the dose of rifabutin. Patients receiving rifabutin together with tipranovir / ritonavir, should be carefully monitored for possible adverse events associated with rifabutin therapy.
Anti-fouling agents
Fluconazole	Increase AUC	The absence of significant changes in the concentrations in the plasma in the equilibrium state	With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients receiving concurrently rifabutin and fluconazole, should be carefully observed (see section "Special instructions").
Itraconazole	nd	Decrease in Cmah and AUC	The description of one case indicates the possibility of pharmacokinetic interaction, which is accompanied by an increase in the concentration of rifabutin in the blood plasma and the risk of development of uveitis.
Voriconazole	Increase AUC and CmOh	Reduction of CmOh and AUC	If necessary the combined use of voriconazole and rifabutin should carefully evaluate the intended benefit and potential risk of combination therapy and monitor it in a peripheral blood picture, as well as other possible undesirable effects of rifabutin (eg, uveitis).
Posaconazole	nd	Reduces Cmax and AUC by 57% and 51%, respectively	The combined use of posaconazole and rifabutin should be avoided if the benefits of sharing do not exceed its risk for patients. Patients receiving rifabutin together with pozanazole should be carefully observed in relation to possible adverse events associated with rifabutin therapy.
ANTIPNEVMOCCULAR MEANS (pneumonia caused by Pneumocystis carinii)
Dapson	nd	Decrease AUC	The study was conducted in HIV-infected patients (fast and slow acetylators).
Sulfamethoxazole / trimethoprim	Lack of meaningful changes Cmah and AUC	Decrease AUC	In another study, only a decrease AUC and Smokes of trimethoprim (but not sulfamethoxazole) by 14 and 6%, respectively; these changes are regarded as clinically insignificant.
ANTIMICOBACTERIAL MEANS (Mycobacterium avium intracellular complex)
Azithromycin	nd	nd	The results are analyzed. Preliminary data indicate a lack of interaction.
Clarithromycin	Increase AUC	Decrease AUC	The study was conducted in HIV-infected patients. In combination with clarithromycin, dose adjustment of rifabutin is required (see section "Dosage and Administration").
Anti-tuberculosis
Ethambutol	nd	No significant changes AUC and CmOh
Isoniazid	nd	No change in pharmacokinetics
Pyrazinamide	nd	nd	The results are analyzed
OTHERS
Methadone	nd	Lack of significant effect	Rifabutin had no significant effect on Cmah or AUC methadone. The pharmacokinetics of rifabutin were not evaluated.
Tacrolimus	nd	nd	Rifabutin reduces the minimum concentration of tacrolimus in the blood.
Theophylline	nd	No significant changes AUC and CmOh

nd - n / a AUC - the area under the concentration-time curve

FROMmah - the maximum content in blood plasma.

Special instructions:During the treatment period, it is necessary to periodically monitor the number of leukocytes, platelets in peripheral blood, the activity of "liver" enzymes. As the prevention of anemia, folic acid is effective.

When rifabutin is used in combination with clarithromycin (or other macrolides) and / or fluconazole (and related substances), patients should be closely monitored for the risk of developing uveitis. With the development of uveitis, consultation of an ophthalmologist, temporary withdrawal of the drug is indicated.

May impart a reddish-orange color to urine, skin and secreted fluids. Patients taking the drug should not wear contact lenses because of the possibility of their coloring in orange.

The use of rifabutin as monotherapy for the prevention of Mycobacterium avium disease in tuberculosis patients can lead to the development of cross-resistance to rifabutin and rifampicin.

Rifabutin should be combined with anti-tuberculosis drugs that do not belong to the rifamycin group.

Oral contraceptives may be ineffective, other contraceptive methods should be used.

With prolonged use of the drug may develop pseudomembranous colitis. Symptoms: watery diarrhea with an unpleasant odor; rarely - with an admixture of blood (in case of development of erosive - hemorrhagic changes in the intestinal mucosa); cramping pains in the lower abdomen, mainly in the projection of the large intestine, after defecation; fever (with a rise in body temperature to 38 ° C), dehydration and electrolyte disorders are a sign of a severe course of the disease. Toxic megacolon and perforation of the colon are rare but serious complications requiring surgical intervention.

Actions: abolition of antibiotics that caused the disease, except for cases of their appointment for life indications, etiotropic therapy aimed at eliminating Clostridium difficile (vancomycin, metronidazole). Correction of metabolic disturbances and water - electrolyte balance, bacterial therapy, in cases of development of severe complications - surgical treatment.

Effect on the ability to drive transp. cf. and fur:

Given the possible side effects of the drug, care should be taken when

the management of vehicles and the implementation of potentially hazardous

activities.

Form release / dosage:Capsules 150 mg.

Packaging:

10 capsules per circuit cell packaging made of polyvinylchloride film and flexible packaging on the basis of aluminum foil.

For 10, 20, 30, 50, 100 capsules in cans of polymeric with screw caps. The bank, 1, 2, 3, 5, 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Packing for hospitals

For 50, 100, 200, 300, 500 contour mesh packages together with an equal number of instructions for use in a cardboard box.

For 500, 1000 capsules in cans of polymeric with lids. By 4, 6, 10, 12 cans together with an equal number of instructions for use in a cardboard box.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:On prescription.

Terms of leave from pharmacies:On prescription

Registration number:LP-002792

Date of registration:29.12.2014

Date of cancellation:2019-12-29

The owner of the registration certificate:BRYNTSALOV-A, CJSC BRYNTSALOV-A, CJSC Russia

Manufacturer: & nbsp

BRYNTSALOV-A, CJSC Russia

Information update date: & nbsp02.05.2016

Illustrated instructions

Instructions

Rifabutin-Ferein® (Rifabutin-Ferein®)