Mikobutin - instructions for use, dose, side effects, contraindications

Rifabutin is a semisynthetic antibiotic from the group of rifamycins.The mechanism of action is associated with inhibition of the synthesis of amino acids by inhibiting the DNA-dependent RNA polymerase. Rifabutin is active against Mycobacterium tuberculosis, both sensitive and resistant to rifampicin strains. Its activity against microorganisms resistant to rifampicin is explained by its ability to suppress the incorporation of thymidine into the DNA of Mycobacterium tuberculosis. Besides, rifabutin is active against non-tuberculosis (atypical) bacteria, including Mycobacterium avium intracellulare complex (MAC).

The spectrum of rifabutin activity includes gram-positive and gram-negative bacteria.

Pharmacokinetics:

Rifabutin is rapidly absorbed, and the maximum concentration of the drug in the blood plasma (C_max) is reached approximately in 2-4 hours after intake. The plasma level of the drug is maintained above the minimum inhibitory concentration (MIC) for M. tuberculosis until 30 hours from the time of admission. As shown in healthy volunteers, with a single admission of 300, 450 and 600 mg of the drug, the rifabutin pharmacokinetics is linear, with Cmax being determined in the range 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 levels 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:

Mycobutin is indicated for the treatment of infections caused by Mycobacterium M. tuberculosis, the MAC complex, and other atypical mycobacteria, such as M. xenopi (including those with immunodeficiency). Mycobutin is indicated for

- treatment of pulmonary tuberculosis: both newly diagnosed and resistant chronic;

- prevention of infections caused by the MAC complex in patients with immunodepression with CD4 cell count ≤ 200 in μL;

- treatment of disseminated M. avium infection in patients with AIDS.

Contraindications:

Mycobutin is contraindicated in patients with hypersensitivity to rifabutin or other rifamycins (for example, rifampicin) in the anamnesis.

Due to the lack of clinical experience in pregnant women, nursing mothers and children, Mikobutin should not be used in these groups of patients.

Carefully:Hepatic failure, renal insufficiency.

Dosing and Administration:

Mycobutin is administered orally once a day, regardless of food intake.

- Tuberculosis of the lung: 150 mg / day (1 capsule) for 6-9 months or within 6 months after receiving negative test results. In patients with chronically resistant tuberculosis, the dose is increased to 300-450 mg / day (2-3 capsules).

- Non-tuberculous mycobacterial infection: 450-600 mg (3-4 capsules) up to 6 months after receiving negative cultures. If mycobutin is used in combination with clarithromycin (eg in the treatment of IAS), then after the first month of treatment, its dose should be reduced to 300 mg (see Special Cautions and Special Precautions, and Interactions with Other Drugs and Other Interactions) .

- Prevention of MAC infection in patients with immunosuppression: 300 mg (two capsules).

Correction of dose in the elderly is not required.

Side effects:

The most common side effects, located in frequency in descending order, are associated with:

- gastrointestinal system, such as nausea, vomiting, increased levels of hepatic enzymes, jaundice;

- blood and lymphatic system, such as leukopenia, thrombocytopenia and anemia;

- musculoskeletal system: arthralgia and myalgia.

There may also be fever, rashes and, rarely, other reactions of increased individual sensitivity, such as eosinophilia, bronchospasm, shock, reversible uveitis. A limited number of cases of skin discoloration are described.

Overdose:

In case of overdosage, gastric lavage is used, symptomatic therapy is used and diuretics are prescribed.

Interaction:

Treatment with rifabutin was accompanied by induction of hepatic enzymes belonging to the subfamily CYP450 OA. 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 levels of other drugs (which are metabolized by CYP450 isoenzymes). It has been shown that induction of enzymes terminates within 5 days after initiation of rifabutin treatment and is dose independent when used in the range of 300 up to 600 mg. Drugs that competitively inhibit the activity of CYP450 OA can increase the circulating levels of rifabutin. In Table.1 summarizes the information on the interaction of other 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. Although rifabutin and rifampicin have a similar structure, their physicochemical properties (in particular the degree of ionization and the distribution coefficient) indicate significant differences in the distribution and ability to induce isoenzymes CYP450: By inducing activity against enzymes rifabutin significantly inferior to rifampicin. The available data indicate that the inducing properties of rifabutin are 2-3 times weaker. Therefore, if changes in the circulating levels of the drug may affect the response of the patient to treatment, the clinical significance of the possible interaction with rifabutin should be lower than with rifampicin.

when using rifampicin.

Table 1. Studies of the interaction of rifabutin

Concomitant therapy	The effect on pharmacokinetics rifabutin			Effect rifabutin on pharmacokinetics simultaneously appointed preparation	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 interval dosing (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 delavirdine mesylate at a dose of 400 mg every 8 hours.
Didanosine	Absence of significant changes			Absence of significant changes in the equilibrium state
Indinavir	Increase AUC			Decreased AUC
Saquinavir	nd			Decreased AUC
Ritonavir	Increase in AUC and Cmax			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	Absence of significant changes			Reduction of C max and AUC	A large controlled study showed that these changes are not clinically important
Anti-fouling agents
Fluconazole	Increase AUC		Absence of significant changes concentrations in plasma in equilibrium condition		Cm.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 serum levels of rifabutin and a risk of uveitis development.
ANTIPNEVMOCCULAR MEANS (pneumonia caused by Pneumocystis carinii)
Dapson	nd		Decrease AUC		The study was conducted in HIV-infected (fast and slow acetylators).
Sulfamethoxazole / trimethoprim	Lack of meaningful changes Cmah and AUC	Decrease AUC			In another study, only a decrease AUC and Cmof 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 and section Special instructions).
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 levels of tacrolimus in the blood.
Theophylline	nd	No significant changes AUC and CmOh

* nd - no data AUC is the area under the concentration-time curve.

FROMmah - the maximum content in the blood plasma

Special instructions:

In accordance with the generally accepted principles of the treatment of mycobacterial infections, Mycobutin should always be given in combination with other anti-tuberculosis drugs that do not belong to the rifamycin family. Mycobutin can give a reddish-orange color of urine, skin and secreted fluids.

Patients taking Mycobutin should not wear contact lenses. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the dose should be reduced by 50%. With mild or moderate renal dysfunction, a dose reduction is not required.

During treatment it is recommended to periodically monitor the number of leukocytes and platelets and the activity of hepatic enzymes.

If Mikobutin is used in combination with clarithromycin to treat MAS infection, it is recommended that the dose of rifabutin be reduced, taking into account the increase in its plasma concentration. When using Mycobutin in combination with clarithromycin (or other macrolides) and / or fluconazole (and related substances), patients should be closely monitored for the risk of developing uveitis. If uveitis is suspected, the patient should be referred for advice to the ophthalmologist and, if necessary, for a time to stop treatment with Mycobutin.

Protease inhibitors are substrates or inhibitors of CYP450-mediated metabolism. Considering the presence of a pronounced interaction between protease inhibitors and rifabutin, the question of their combined use should be considered taking into account the characteristics of the patient and the spectrum of the drugs used (see Interactions with other drugs and other forms of interaction). Oral contraceptives: due to insufficient data on the use of oral contraceptives, use of other methods of contraception.

Malabsorption.Changing the pH of the contents of the stomach with the progression of HIV infection led to a violation of absorption of certain drugs in HIV-infected (eg, rifampicin, isoniazid). The results of the analysis of rifabutin content in blood plasma of AIDS patients of different severity (depending on the number of CD4 + cells) indicate that its absorption does not change with the progression of HIV infection.

Effect on the ability to drive transp. cf. and fur:There are no reports on the impact on the ability to drive and use technical equipment.

Form release / dosage:

Capsules 150 mg.

Packaging:

10 capsules per blister; 3 blisters together with instructions for use in a cardboard box.

15 capsules per blister; 2 blisters together with instructions for use in a cardboard box.

Storage conditions:At a temperature of no higher than 30 ° C. Keep out of the reach of children!

Shelf life:2 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013636 / 01

Date of registration:18.09.2008

Expiration Date:Unlimited

The owner of the registration certificate:Pfizer Italy Sr.L.Pfizer Italy Sr.L. Italy

Manufacturer: & nbsp

PFIZER ITALIA, S.r.L. Italy

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp23.04.2018

Illustrated instructions

Instructions

Mycobutin (Mycobutin)