Rapamun - instructions for use, dosage, side effects, contraindications

Active substanceSirolimusSirolimus

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Rapamun

solution inwards

Wyeth Whitehall Export GmbH Austria

Rapamun®

pills inwards

Pfizer Inc. USA

Dosage form: & nbspfilm coated tablets

Composition:

Each tablet, coated with a shell, contains:

Placebo-core tablet compressed: lactose monohydrate - 86.4 mg; Macrogol-8000 - 28.8 mg; magnesium stearate - 0.600 mg; talc - 4.20 mg;

Shellac layer: macrogol-20000 - 0.300 mg; glyceryl monooleate (60%) 0.150 mg; pharmaceutical glaze (shellac solution No. 4) - 5.62 mg (in terms of dry matter - 1.956 mg); calcium sulfate - 10.7 mg;

Layer of inert filler: cellulose microcrystalline - 7.32 mg; sucrose 97.6 mg; titanium dioxide - 0.100 mg;

Active filler layer: sirolimus nanosystems dispersed 150 mg / g (sirolimus 100 % (active substance) - 1.02 mg; poloxamer-188 - 0.51 mg; sucrose - 99.20 mg; cellulose microcrystalline - 0.714 mg; povidone-K29-32 - 0.510 mg;

alpha-tocopherol acetate - 0.051 mg;

Sheath colored: sucrose - 19.0 mg;

titanium dioxide - 0.923 mg; povidone-K29-32 - 0.077 mg;

Polishing: wax karnauba - 0.079 mg;

Marking: red ink - opaque S-1-15095 [shellac solution ~ 45% (contains 20% esters) in ethanol, iron dye red oxide (E172), isopropanol, butanol, propylene glycol, aqueous ammonia, simethicone] - 0.200 mg.

Description:

Tablets are triangular in white, coated with a coat, marked red "RAPAMUNE 1 mg & quot ;.

Pharmacotherapeutic group:immunosuppressive agent

ATX: & nbsp

L.04.A.A Selective immunosuppressants

L.04.A.A.10 Sirolimus

Pharmacodynamics:

Sirolimus inhibits T-lymphocyte activation by blocking the calcium-mediated, and calcium-independent intracellular signal transduction. Data from the studies indicate that the mechanism of action of sirolimus differs from the mechanism of action of cyclosporine, tacrolimus and other immunosuppressants. According to experimental data, sirolimus binds to a specific cytosolic protein - immunophilin (FK-binding protein-12 - FKPB-12), complex

FKPB-12-sirolimus suppresses the activation of the kinase of the "target of rapamycin in mammals" (mTOR-mammalian Target of Rapamycin) and is of fundamental importance for the development of the cell cycle. Inhibition mTOR leads to blockade of several specific ways in which the signal is transmitted. Ultimately, the activation of lymphocytes, leading to immunodepression, is inhibited.

Pharmacokinetics:

Most of the information presented in this section is derived from the experience of using a solution for oral administration. Information relating directly to the dosage form in the form of coated tablets is located in the "Tablets" part.

Solution for oral administration

After oral administration sirolimus quickly absorbed; with the maximum concentration (Cmax) being reached approximately one hour after a single dose by healthy volunteers, and approximately two hours after repeated administration by patients in a stable clinical state after allogeneic kidney transplantation. Systemic bioavailability of sirolimus with simultaneous admission with cyclosporine is approximately 14%. At the subsequent reception the average concentration of sirolimus in blood increases approximately in 3 times. The half-life (T1 / 2) with repeated oral administration of the drug to patients in a stable clinical state after kidney transplantation was 62 + 16 hours, and average equilibrium concentrations were reached after 5-7 days. The coefficient reflecting the ratio of blood concentration to plasma concentration (C / I) is 36. This indicates that sirolimus largely accumulates in the blood cells.

Sirolimus is a substrate both for the isoenzyme of the cytochrome P450 IIIA4 system (CYP3A4) and for the P-glycoprotein (P-gp). Sirolimus is extensively metabolized by O-demethylation and / or hydroxylation.In the blood, seven major metabolites are determined, including hydroxyl, dimethyl, and hydroxydimethyl derivatives. However, in human blood sirolimus is the main component of the drug, which more than 90% determines the immunosuppressive effect of the drug Rapamun®. After a single intake of [| 4C] -sirolimus by healthy volunteers, the bulk (91.1%) of the drug labeled with a radioisotope was excreted through the intestine, and only a small part (2.2%) through the kidneys.

In dialysis children (with a decrease in the glomerular filtration rate by 30-50%) 5-11 years and 12-18 years, it was noted that the average, normalized body weight, the ratio of clearance to filtration (CL / F) is higher in the younger age group group (580 ml / h / kg), compared with the older age group (450 ml / h / kg), whereas in adults the corresponding value is 287 ml / h / kg. Within the limits of each age group the variability of this indicator is noted in wide limits.

In patients with mild to moderate hepatic impairment (class A or B according to the Child-Pugh classification), mean values of the area under the concentration-time curve (AUC) and T1 / 2 of sirolimus were increased by 61 and 43, respectively %, and the average value of CL / F was reduced by 33% compared with healthy subjects.In patients with severe hepatic impairment (Child-Pugh class C), mean values of AUC and T1 / 2 sirolimus were increased by 210% and 170%, respectively, and the mean CL / F was reduced by 67% compared with healthy subjects. A longer ti / 2 sirolimus as a result of a disturbed liver function led to a slower achievement of its equilibrium state in the body.

In the group of patients with different renal function, from normal to completely absent (hemodialysis patients), the pharmacokinetic parameters of sirolimus were similar.

Clinical studies of sirolimus did not include a sufficient number of patients over the age of 65, so it is impossible to assess whether there is a difference in response to the drug in elderly patients and young patients.

Pills

In healthy volunteers, the average bioavailability of sirolimus after a single dose in the form of tablets is approximately 27% higher than the corresponding value after taking the solution; the average Stach is 35% lower, and the average time to reach the maximum concentration (Tmax) is 82% higher. After achieving the equilibrium state of sirolimus in recipients of renal transplants, the difference in bioavailability was less pronounced.In a randomized study involving 477 patients, the therapeutic equivalence of the two dosage forms was demonstrated. When transferring patients from oral solution to tablets, it is recommended to apply the previous dose and monitor the minimum concentration of sirolimus in the blood after 1 to 2 weeks to ensure that it remains within the recommended range.

24 healthy volunteers who received the Rapamun * tablet along with high-fat food were observed to increase Cmax, Tmax and AUC, respectively, by 65, 32 and 23%. To minimize fluctuations, the Rapamun tablets should always be taken with or without food. Do not consume grapefruit juice, which affects the metabolism of sirolimus mediated by the isoenzyme CYP3A4.

The concentration of sirolimus when taking the drug Rapapur in the form of tablets is once proportional to the dose in the range of 5 to 40 mg.

Initial therapy (2-3 months after transplantation): in the majority of patients in whom treatment with Rapamun in the form of tablets starts with a saturating dose (6 mg) followed by a transition to a maintenance dose of 2 mg once a day,the minimal concentrations of sirolimus in the blood quickly reach equilibrium concentrations corresponding to a given interval (from 4 to 12 ng / ml according to the chromatographic analysis).

According to monitoring of all patients during the period of obtaining cyclosporine as a concomitant therapy, the average concentration of sirolimus in the blood (chromatographic method) was 8.6 ± 3.0 ng / ml with a daily dose of 2.1 ± 0.70 mg. Supportive therapy: 3-12 months after ciclosporin abolition, the minimum blood sirolimus concentration (chromatographic method) was 19 ± 4.1 ng / ml with daily doses of 8.2 ± 4.2 mg. Thus, the dose of sirolimus was approximately 4 times higher than the calculated dose.

Indications:

Rapamun® is designed to prevent graft rejection in adult patients with low or moderate immunological risk after kidney transplantation. It is recommended to use Rapamun '* initially in combination with glucocorticosteroids and a microemulsion of cyclosporine during the first 2-3 months after transplantation. Therapy with Rapamun® can be continued as maintenance therapy with glucocorticosteroids only if ciclosporin will be gradually canceled.

Contraindications:

Hypersensitivity to sirolimus, its derivatives or other components of the drug.

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption, sugarase / isomaltase deficiency, fructose intolerance.

Children under 18 years of age (insufficient experience of use, there are only limited data, see section "Pharmacokinetics"),

Carefully:

Caution should be exercised while using sirolimus and drugs that affect kidney function.

Pregnancy and lactation:YesThere are no reports of using Rapamun® in pregnant women. During pregnancy, Rapamun® should only be used when the intended benefit to the mother exceeds the possible risk to the fetus.

Effective contraception should be started before treatment with the drug Rapamun and continue during the treatment period, and also within 12 weeks after its termination.

There is no data on the intake of sirolimus in breast milk. Given the potential risk to the child, during treatment with Rapamun®, breastfeeding should be discontinued.

Dosing and Administration:

Rapamun® is for oral use only.

It is not recommended to break the integrity of the tablets before swallowing them because the bioavailability of the drug after crushing, chewing or breaking the tablets has not been studied.

Patients who are not able to take the drug Rapamun® in the form of tablets should receive it in the form of a solution for oral administration.

Rapamun® should be taken continuously either concurrently with a meal or between meals.

Therapy should be carried out in a specially equipped place and under the supervision of a transplant physician.

It is recommended to take the drug Rapamun® 4 hours after taking the microemulsion of cyclosporine.

Adults

Initial therapy (within 2-3 months after transplantation): in the usual mode of administration, as soon as possible after transplantation, the oral dose of Rapamun®, equal to 6 mg, is administered once, followed by a dose of 2 mg once a day. Subsequently, the dose of Rapamun® is selected individually in such a way that the minimum blood concentrations are from 4 to 12 ng / ml (chromatographic method). Treatment with the drug Rapamun continues against the background of a simultaneous gradual reduction in the dose of glucocorticosteroids and a microemulsion of cyclosporine.

During the first 2-3 months after transplantation, minimum concentrations of cyclosporine should be maintained between 150 and 400 ng / ml (immune method for determining the concentration).

Supportive therapy: 4-8 weeks after the start of treatment with cyclosporine, its dose should be gradually reduced until the drug is completely discontinued, and the dose of Rapamun® should be adjusted so that the minimum blood concentrations range from 12 to 20 ng / ml (chromatographic method). Rapamun should be taken with glucocorticosteroids. Patients in whom cyclosporine withdrawal was unsuccessful or impossible, the duration of joint therapy with cyclosporine and Rapamun® should not exceed 3 months. In clinically justified situations, such patients should abolish Rapamun® and prescribe an alternative mode of immunodepression.

The elimination of cyclosporine has not been studied in patients with acute rejection of a grade III transplant according to the classification Bnaff 93 or in patients with vascular rejection developed prior to the abolition of cyclosporine. Also, the elimination of cyclosporine has not been studied in patients,who are on dialysis or who have plasma creatinine> 4.5 mg / dL, Negroid race, with repeated kidney transplantation, multiple organ transplantation, or in patients with high titers of panel-reactive antibodies. These are not sufficient for the use of sirolimus in patients of the Negroid race .

Elderly patients (over 65 years of age):

Experience with Rapamun® in patients over 65 years is not enough to determine if there are differences in response to therapy between patients of this age group and younger ones. In 35 patients older than 65 years after kidney transplantation, the minimum concentrations of sirolimus did not differ from the corresponding concentrations in 822 patients from 18 to 65 years. The results obtained with the use of the drug Rapamun¹Inside in 12 patients over the age of 65 years after kidney transplantation also corresponded to the results obtained for adult patients (n = 167) aged 18 to 65 years.

Use in patients with impaired renal function: There is no need to change the dose in patients with impaired renal function.

Use in patients with impaired liver function: in severe hepatic insufficiency, the maintenance dose of the drug Rapamun® is recommended to be reduced approximately twice due to the delayed clearance of the drug. Shock dose should not be changed.

After changing the dose or taking a shock dose of the drug Rapamun ⁸ in patients with severe hepatic insufficiency, in connection with the delay in achieving the equilibrium state, the control of the drug concentration in the blood should be performed every 5-7 days until 3 consecutive determinations of the sirolimus concentration confirm the achievement of a stable level.

Monitoring of therapeutic drug concentration: the

Most patients who received 2 mg of Rapamun 4 hours after cyclosporine, the minimum blood sirolimus concentrations corresponded to a prescribed range of 4 to 12 ng / ml (according to chromatographic analysis). Optimal therapy requires monitoring of the therapeutic drug concentration in all patients. The concentration of sirolimus in the blood should be monitored particularly carefully in the following groups of patients: (1) patients with impaired hepatic function; (2) during the period of simultaneous use of inducers or inhibitors of the isoenzyme CYP3A4 and P-gp, and also after the termination of their reception (see.section "Interaction with other medicinal products"); and / or (3) in the case of a sharp dose reduction or ciclosporin withdrawal, since for these groups of patients the dose correction is most likely to be required.

In order to minimize fluctuations in the concentration of sirolimus, Rapamun® should be taken at regular intervals with respect to cyclosporine, namely 4 hours after the administration of cyclosporine. In the optimal case, the choice of Rapamun® dose should be based on a more than one measurement of the minimum concentration performed no earlier than 5 days after the last dose change. After the beginning of treatment with a solution of the drug Rapamun®, the patient can continue therapy with Rapamun® in tablets, while maintaining the exact dose. After transferring the patient to another dosage form or other dosing regimen, it is recommended to measure the minimum concentration of sirolimus within 1 to 2 weeks.

After ciclosporin withdrawal it is recommended to maintain a minimum concentration of sirolimus in the blood at a level of 12-20 ng / ml (chromatographic method). Cyclosporin inhibits the metabolism of sirolimus, so if the dose of Rapamun will not be increased, the concentrations of sirolimus after cyclosporine withdrawal will decrease. On average, the dose of Rapamun should be 4 times higher, taking into account the lack of pharmacokinetic interaction (2-fold increase) and increased need for immunosuppression in the absence of cyclosporine (2-fold increase). The rate of increase in the dose of the drug Rapamun® should correspond to the rate of excretion of cyclosporine after its withdrawal.

If dosage adjustment is necessary with maintenance therapy (after cyclosporine cancellation), it can be performed in most patients using the following formula: a new dose of Rapamun® = current dose x (desired concentration / current concentration). The shock dose should be used in addition to the maintenance dose, if it is required to significantly increase the minimum concentration of sirolimus: the impact dose of the drug Rapamun® = 3 x (the new maintenance dose is the current maintenance dose). The maximum daily dose of Rapamoun® should not exceed 40 mg. If the calculated daily dose exceeds 40 mg due to the impact dose, the shock dose should be taken longer than 2 days.Determination of the minimum concentration of sirolimus should be carried out at least 3-4 days after the application of the impact dose.

The calculation of the 24-hour minimum concentration of sirolimus is based on the results of chromatographic methods. Various approaches have been used to measure the concentrations of sirolimus in the blood. Currently, the concentrations of sirolimus in the blood are measured by both chromatographic and immunoenzymatic methods. The concentration values obtained by these methods are not interchangeable. Using andMgunoenzyme systems should always follow the manufacturer's recommendations in order to correlate the obtained values with those obtained by standard chromatographic methods. All concentrations of sirolimus given in this document were measured by chromatography or converted to the corresponding equivalent values. To determine the desired minimum concentration of sirolimus, adjustments should be made in accordance with the methods used. Monitoring of therapeutic drug concentrations should not be the only guideline in selecting a dose of sirolimus.Particular attention should be given to clinical symptoms, histological findings and laboratory data.

Side effects:

The following table shows the side effects observed in patients treated with Rapamun in combination with cyclosporine and corticosteroids.

In general, the side effects associated with the use of the drug Rapamun, depended on him doses/ and concentrationwalkie-talkie.

Organs and Systems	Very Frequent > 1/10	Frequent> 1/100 and <1/10	Infrequent > 1/1 000 and <1/100	Rare> 1/10 000 and <1/1 000	Very rare <1/10 000	The frequency is unknown (nc may be installed on basis of available data)
Violations from	trombone persecution,	hemolytic-	pancytopenia,
hand and	anemia,	in the remission syndrome,	thrombotic
lymphatic	leukopenia	neutropenia	thrombocytopenic
systems			aI'm purple
Cardiological	tachycardia	pericardial
violations		effusion
Violations from	abdominal pain,	stomatitis, ascites,
hand	diarrhea, constipation.	pancreatitis
gastric	nausea
intestinal tract

Systemic disorders and complications at the site of administration

edema.

peripheral edema, pyrexia.pain of different locations, delayed healing of wounds

Immune system disorders

reactions

hypersensitivity and, including

anaphylactoid / ana

phialectic

reaction,

angioedema

edema

Infections and invasions

pneumonia, fungal, viral and bacterial infections, downtime of herpes, urinary tract infections

sepsis, pyelonephritis, ichthyohalovirus infection, and herpes zoster

infections caused by mycobacteria, including tuberculosis, viral infection Epstein-Barr

enterocolitis,

caused by

Clostridium

difficile

Disorders of nutrition and metabolism

giokalemia,

hypophosphatemia,

hyperlipidemia

(including

hypercholesterol

July),

Hyperglycemia, gyertriglyceridemia, fluid retention, diabetes mellitus

Disturbances from the musculoskeletal system and connective tissue

arthralgia

osteonecrosis

Tumors

benign, malignant and nonspecific (including cysts and polyps)

squamous cell carcinoma of the skin, basal cell carcinoma of the skin

lymphoma,

postransplantation

The

lymphoproliferative 1schizophrenia, melanoma

Disturbances from the nervous system	headache				syndrome rear reversible encephalopa rotting
Kidneys and urinary tract system	proteinuria		notfrotichsky cider, focal segmental glomerulosclerosis
Dysfunction of the podovyh organs and breast	disorders of menstrual blood, including amenorrhea and menorrhagia	ovarian cysts
Respiratory, thoracic and mediastinal disorders		pulmonary embolism, pneumonitis, pleural effusion, epistaxis	1СгоЧНОС bleeding	alveolar th proteinase lungs
Disturbances from the skin and subcutaneous tissues	rash, acne		exfoliative dermatitis	allergic skin vasculitis
Vascular disorders	lymphocele. rise arterial pressures	thrombosis, including deep vein thrombosis	Stasis of lymph

Immunodepression increases the risk of developing lymphoma and other malignant tumors of the skin (see section "Special instructions").

Published data on the hepatoxicity of the drug Rapamun. "The risk of hepatotoxicity may increase as the minimum concentration of sirolimus in the blood rises. There are reports of rare cases of liver necrosis with a fatal outcome when the minimum concentration of sirolimus in the blood is exceeded.

Cases of interstitial lung diseases (including pneumonitis and, infrequently, bronchiolitis obliterans with organizing pneumonia and pulmonary fibrosis), in some cases fatal with an unidentified pathogen, in patients receiving immunosuppressive therapy, including Rapamun®, were noted. In some cases, the abolition of the Rapamun drug * or a reduced dose led to the elimination of the interstitial pulmonary process. The risk of the disease may increase, but as the minimum concentration of sirolimus in the blood rises. The cases of delayed healing of wounds after transplantation, including divergence of fascia, postoperative hernia and anastomosis rupture are described.

In some patients, against the background of treatment with the drug Rapamun *, reversible a violation of the functional activity of sperm.

In patients with delayed graft function, the administration of sirolimus may slow the recovery of kidney function.

In a subgroup of patients with initially reduced glomerular filtration rate (<40 ml / min), as well as in patients after kidney transplantation when transferred from therapy with inhibitors calcinus corn on sirolimus the incidence of serious adverse events with Rapamun was higher (including pneumonia, acute graft rejection, graft death, and death).

Cases of ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported. Patients with ovarian cysts, accompanied by clinical symptoms, are subject to additional examination. The incidence of cysts may be higher during premenomyusis than in postmenopausal women. In some cases, these violations were resolved after the abolition of therapy with the drug Rapamun *.

There have been reports of cases of nephropathy, the associated EBC virus and progressive multifocal leukoencephalopathy associated with JC virus, in patients receiving immunosuppressants, including Rapamun. "Since the ego data obtained in the post-marketing period, there is no precise information on the frequency of these reactions.

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Overdose:

Currently, information on cases of overdose is minimal. One patient who took 150 mg of the drug Rapamun®, had atrial fibrillation.In general, the manifestations of an overdose coincide with the dose-related side effects associated with the pharmacological action of the drug listed in the "Side effect" section. In case of overdose, symptomatic treatment is recommended. Given the low solubility of sirolimus in water and the high level of binding to erythrocytes and proteins, it is suggested that Rapamun® can not be removed in significant amounts from the body by dialysis.

Interaction:

In the wall of the intestine and liver sirolimus is subjected to extensive metabolism under the action of the CYP3A4 isoenzyme. Besides, sirolimus is a substrate for localized in the small intestine P-gp, which removes many drugs. Therefore, substances that act on these proteins, can affect the absorption of sirolimus and its subsequent elimination. Inhibitors of the isoenzyme CYP3A4 and P-gp (ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) reduce the metabolism of sirolimus, which leads to an increase in its concentration. Inductors of the isoenzyme CYP3A4 and P-gp (rifampicin or rifabutin) increase the metabolism of sirolimus, reducing its concentration.It is not recommended to apply sirolimus simultaneously with powerful inducers or inhibitors of the isoenzyme CYP3A4 and P-gp.

Ciclosporin (substrate and inhibitor isoenzyme CYP3A4 and P-gp):

cyclosporine significantly increases the rate and degree of absorption of sirolimus. The simultaneous use of the Rapamun drug at a dose of 5 mg, followed by 5 mg in 2 hours and 10 mg after 4 hours after the application of 300 mg of the cyclosporin microemulsion led to an increase in the AIC sirolimus to approximately 183%, 141% and 80%, respectively. The effect of the action of cyclosporine was manifested in the increase of Stax and tmax sirolimus. If sirolimus was taken 2 hours before the application of the cyclosporine microemulsion, no effect on AUC and Staph of Sirolimus was noted. In healthy volunteers who received a single dose of sirolimus simultaneously with cyclosporine (microemulsion) or at a 4 hour interval, the pharmacokinetics of cyclosporine did not change. It is recommended to use Rapamun® 4 hours after taking a cyclosporine microemulsion.

Rifampicin (inductor of isoenzyme CYP3A4 and P-gp): repeated intake of rifampicin (600 mg once a day for 14 days) reduced the concentration of sirolimus in the blood after a single dose of 20 mg of the drug Rapamun "in the form of a solution for oral administration. Rifampicin increased the clearance of sirolimus by approximately 5.5 times and reduced the AUC of sirolimus and Stach, by approximately 82 and 71 %, respectively. It is not recommended to apply sirolimus at the same time with

rifampicin.

Ketoconazole (CYP3A4 isoenzyme inhibitor and P-gp): Repeated reception of ketoconazole is significantly alter the rate and extent of absorption of impact sirolimus: evidenced 4,4-, 1,4- and 10.9 fold increase, respectively, Cmax, tmax and AUC. It is not recommended to apply sirolimus concomitantly with ketoconazole.

Voriconazole (an inhibitor of isozyme CYP3A4): while applying healthy volunteers sirolimus (2 mg dose) and voriconazole (oral 400 mg every 12 hours on the first day followed by 100 mg every 12 hours for 8 days) was observed in average 7-fold Increase of C max and 11-fold increase in AUC of sirolimus. It is not recommended to apply sirolimus concomitantly with voriconazole. Diltiazem (Substrate and inhibitor of isozyme CYP3A4 and P-gp): while receiving 10 mg Rapamuna "in the form of oral solution and 120 mg of diltiazem significantly increased bioavailability of sirolimus Cmax, tmax and AUC increased sirolimus, respectively, 1.4, 1. , 3 and 1.6 times. Sirolimus did not change the pharmacokinetics of diltiazem and its metabolites - deacetylldithiasem and desmethyldithiazem. When using diltiazem it is necessary to monitor the concentration of sirolimus in the blood and, if necessary, adjust the dose of the drug. Verapamil (inhibitor of isoenzyme CYP3A4): when using multiple doses of verapamil and sirolimus in the form of a solution for oral administration, the rate and degree of absorption of both compounds varied significantly. Cmax, T1 / 2, Tmax and AUC of sirolimus in whole blood increased, respectively, in 2,3, 1,1 and 2,2 times. The values of Cmax, and AUC S - (-) verapamil in the blood plasma increased 1.5 times, and tmax decreased by 24%. It is necessary to control the concentration of sirolimus and, if necessary, reduce the doses of both drugs.

Erythromycin (inhibitor of the isoenzyme CYP3A4): when repeated doses of erythromycin and sirolimus were used in the form of a solution for oral ingestion, the rate and degree of absorption of both compounds increased significantly. Cmax, tmax and AUC of sirolimus in whole blood increased, respectively, in 4.4, 1.4 and 4.2 times. Cmax, tmax and AUC of erythromycin in the blood plasma increased, respectively, in 1.6, 1.3 and 1.7-fold. It is necessary to monitor the concentration of sirolimus and, if necessary, reduce the doses of both drugs.

Oral contraceptives: there was no clinically significant

pharmacokinetic interaction between sirolimus and 0.3 mg norgestrel / 0.03 mg ethinylestradiol. Although the results of the study of the interaction of a single dose of the drug Rapamun and oral contraceptive indicate a lack of pharmacokinetic interaction, long-term treatment with the drug Rapamun can not exclude possible changes in pharmacokinetics that may affect the effectiveness of oral contraceptives.

Other Possible Interactions: Moderate and weak inhibitors of the CYP3A4 isoenzyme may reduce the metabolism of sirolimus and increase the concentration of sirolimus in the blood (eg, slow calcium channel blockers: nicardipine;

antifungal agents: clotrimazole, fluconazole, itraconazole, voriconazole; antibiotics: troleandomycin, telithromycin, clarithromycin; and other substances: bromocriptine, cimetidine, danazol, protease inhibitors: ritonavir, andandinavir, boceprevir and telaprevir).

Inductors of CYP3A4 isofermeptide can accelerate the metabolism of sirolimus and reduce the concentration of sirolimus in the blood (for example,medicinal herb St. John's wort - Hypericum perforatum; anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although in vitro sirolimus inhibits the activity of isozymes of microsomal cytochrome P450 in the human (isozymes CYP2C9, CYP2C19, CYP2D6, CYP3A4 / 5), inhibition of the activity of these isoenzymes in vivo is unlikely, since this sirolimus concentration should be significantly higher than in patients receiving the drug at therapeutic doses. P-gp inhibitors can reduce the release of sirolimus from intestinal cells and help increase its concentration in the blood.

Grapefruit juice reduces metabolism mediated isoenzyme CYP3A4, and potentially enhances the return transport from enterocytes into the lumen of the small intestine, mediated by P-gp and therefore it should not be consumed during reception Rapamun ® formulation.

Pharmacokinetic interaction can be observed with gastrointestinal prokinetic agents such as cisapride, metoclopramide.

There was no clinically significant pharmacokinetic interaction of sirolimus with acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim / sulfamethoxazole.

With the simultaneous use of Rapamun® with calcineurin inhibitors, an increased risk of hemolytic-uremic syndrome / thrombotic thrombocytopenic purpura / thrombotic microangiopathy induced by calcineurin inhibitors is possible.

Special instructions:TO There is currently insufficient data on the use of the drug Rapamun in patients with high immunological risk, so its use in such patients is not recommended. There is a research experience on the use of sirolimus in conjunction with the following drugs: tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil, glucocorticosteroids and cytotoxic antibodies. Combinations ofRapamun's preparation with other immunosuppressive drugs has not been studied enough.

Since the half-life of sirolimus is long, frequent dose adjustments of the drug Rapamun^to. based not on the equilibrium concentration of the drug, may lead to an overdose of the drug or the use of a too small dose. The use of sirolimus, mycophenolate mofetil and glucocorticosteroids in combination with antibodies to interleukin (IL) -2 receptors is not recommended for kidney transplant transplantation de novo.

Immunosuppressants can affect the effectiveness of vaccination. During treatment with immunosuppressants, including Rapamun^Mr., vaccination may be less effective. During the period of treatment with Rapamun¹* Live vaccines should be avoided.

In patients with impaired liver function, the level of the minimum concentration of sirolimus in the blood should be carefully monitored. Given the elongated 11/2 drug in this category of patients after changing the dose or taking a shock dose of the drug Rapamun *, the control of the concentration of the drug in the blood should be carried out until it reaches a stable level (see the section "Method of administration and dose"), Patients with severe hepatic insufficiency are recommended to reduce the maintenance dose half, which is determined by a decrease in clearance.

Reduced resistance to infections and a predisposition to the development of lymphoma and other malignant diseases, especially of the skin, can be a consequence of the inhibition of the immune system.

It is necessary to take precautions,common for patients with an increased risk of skin cancer: limit exposure to sunlight and ultraviolet radiation with protective clothing and the use of creams with a high sunscreen effect.

AT result excessive suppression of the immune system may increase susceptibility to infections, including infections caused by opportunistic pathogens, the possible consequences of which, sepsis and death, are noted in the section "Side effect."

Among these conditions, nephropathy associated with VC virus and progressive multifocal leukoencephalopathy associated with JC virus. These infections are often associated with high immunosurevine load and can lead to severe or lethal conditions. Doctors should keep this in mind when conducting differential diagnosis in patients with reduced immunity and impaired renal function or neurological symptoms. Since the safety and efficacy of the drug Rapamoon®, as an immunosuppressive therapy for patients with hepatic and pulmonary transplants, is not established, the drug is not recommended for use in these patient groups.

In a clinical trial, the use of sirolimus in combination with tacrolimus in patients with transplanted de novo liver in some cases was associated with increased mortality and loss of the graft. Many of these patients showed signs of an infectious process shortly before the death.

In the same study, as well as in another study involving patients with transplanted de novo liver application of sirolimus together with cyclosporine or tacrolimus was accompanied by an increase in the frequency of hepatic artery thrombosis, in most cases leading to graft loss or death. Cases of hepatic artery thrombosis were observed within 30 days after transplantation.

Reported a violation or slowdown of wound healing in patients on the background of taking the drug Ppamun, especially often in patients whose body mass index exceeds 30 kg / m² (lymphocele, divergence of the edges of the wound).

There are reports of discrepancies in the edges of bronchial anastomosis in patients with grafted de novo lungs, in most cases with a fatal outcome, with the use of sirolimus in the composition of immunosuppressive therapy.

Patients treated with Rapamun are reported to have fluid retention, in particular peripheral edema, lymphatic stasis, pleural effusion and exudative pericarditis (including hemodynamically significant effusions in children and adults).

When applying sirolimus, allergic reactions were noted, such as anaphylactic / anaphylactoid reactions, exfoliating dermatitis, angioedema and vasculitis.

Rapamun '¹ in the form of coated tablets, contains sucrose and lactose. Before using the drug, patients who have a history of malnutrition of sucrose, lactase and isomaltase, fructose intolerance, glucose malabsorption and galactose, galactose intolerance (eg, galactosemia) should evaluate the risk / benefit ratio and, if necessary, replace Rapamun * tablets with Rapamun * solution for oral administration.

In rare cases, the combined use of sirolimus and angiotensin-converting enzyme (A11F) inhibitors led to the development of angioedema.

LSR-002186 / 09-130515

There are reports of cases of pneumonia caused by Pneumocystis carinii in patients who did not receive antimicrobial prophylaxis.In this regard, during the first 12 months after transplantation, antimicrobial prophylaxis directed against Pneumocystis carinii.

Within 3 months after transplantation, prophylaxis of tsigosgalovirus infection is advisable.

The use of the drug Rapamun "in patients after kidney transplantation was accompanied by an increase in the concentration of cholesterol and triglycerides in the serum, in some cases requiring

drug correction. Patients receiving Rapamun need control in order to identify possible hyperlipidemia. In the event that hyperlipidemia is established, appropriate measures should be taken, including dieting, exercise and taking medications that lower the concentration of cholesterol. Before the use of immunosuppressants, including Rapamun®, and when deciding whether to continue treatment with Rapamun® with patients with severe persistent hyperlipidemia, it is necessary to assess the risk-benefit ratio of this type of therapy.

In patients with delayed graft function, the use of sirolimus may delay the restoration of kidney function.

A good tolerability of the drug Rapamun in combination with inhibitors of HMG-CoA reductase and / or fibrogami has been noted. During the treatment with Rapamun, "in combination with HMG-CoA reductase inhibitors or fibrates, patients should be monitored for the possible development of rhabdomyolysis and other side effects described in the instructions for the medical use of these medicines.

LSR-002186 / 09-130515

When sharing the drug Rapamun® and cyclosporine, it is necessary to monitor the patient's condition for rhabdomyolysis and renal dysfunction. It should be borne in mind that for patients with elevated serum creatinine concentration, correction of the immunosuppressant regimen will be required. You must observe caution with simultaneous use with other drugs that adversely affect the function of the kidneys.

Patients treated with Rapamun¹¹ and cyclosporine for more than 3 months, higher serum creatinine concentrations and a lower level of glomerular filtration were observed, compared with the control group patients who received ciclosporin and placebo or ciclosporin and azathioprip. Patients who successfully discontinued cyclosporine had a lower serum creatinine concentration and a higher level of glomerular filtration, as well as a lower incidence of malignant tumors compared to patients who continued to receive ciclosporin. Until additional clinical data are obtained, the combined use of cyclosporine and the Rapamun drug as maintenance therapy is not recommended.

In patients with delayed graft function, Rapamun "can delay the recovery of renal function.

In addition, renal function should be carefully monitored while using Rapamun and tacrolimus.In patients with elevated serum creatinine concentrations, the immunosuppressive therapy should be adjusted accordingly, including abolition

therapy with the drug Rapamun and / or cyclosporin, and / or tacrolimus.

LSR-002186 / 09-130515

Safety and efficacy of the use of the drug Rapamun^to at primary application without calcineurin inhibitors has not been studied in patients with a transplanted kidney.In two multicenter clinical trials in patients with transplanted de novo kidney, receiving treatment with the drug Rapamun®, mycophenolate mofetil, glucocorticosteroids and receptor antagonists IL-2, a significantly higher incidence of acute graft rejection and a higher incidence of deaths than patients receiving calcineurin inhibitors, mycophenolate mofetil, glucocorticosteroids and receptor antagonists IL-2. From the point of view of the effect of renal function, there was no apparent improvement in the initial therapy with Ranamun "¹ without the simultaneous use of calcineurin inhibitors. It should be borne in mind that one of two studies used a reduced course of daclizumab.

It is recommended to periodically check the level of excretion of proteins in the urine. In clinical studies, there was an increase in the concentration of protein in the urine after the transfer of patients with calcineurin to the drug Rapamun^th. Usually, this increase was noted within 6-24 months after the change in therapy compared to patients who continued therapy with calcineurin inhibitors.Nephrotic syndrome was detected in 2% of patients in clinical trials. The safety and efficacy of transferring patients from calcineurin inhibitors to the Rapamun drug * have not been established. The simultaneous use of the drug Rapamun^to with calcineurin inhibitors may increase the risk of calcineurin-induced hemolytic uremic syndrome / thrombotic thrombocytopenic purpura.

Joint use of sirolimus with strong inhibitors CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inductors CYP3A4 (eg, rifampicin, rifabutin) is not recommended.

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

Influence pi ability to manage transport and work with mechanisms

Studies to study the impact on the ability to drive vehicles and the use of mechanisms were not carried out.

Form release / dosage:

Coated tablets, 1 mg.

Packaging:

For 10 tablets in a planar cell package (blister) [laminated film (PVC / PE / Aclar®) / aluminum foil].

For 3 or 10 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002186/09

Date of registration:23.03.2009

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PFIZER, Inc. USA

WYETH PHARMACEUTICALS COMPANY Puerto Rico

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

Information update date: & nbsp05.08.2015

Illustrated instructions

Instructions

Rapamun® (Rapamune)