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

Active substanceSirolimusSirolimus

Similar drugsTo uncover

Rapamun

solution inwards

Wyeth Whitehall Export GmbH Austria

Rapamun®

pills inwards

Pfizer Inc. USA

Dosage form: & nbsporal solution

Composition:

Active substance: sirolimus 1 mg / ml;

Excipients: polysorbate 80, fozal 50 PG (phosphatidylcholine, propylene glycol, mono- and diglycerides, ethanol, soy fatty acids, ascorbyl palmitate).

Description:

Solution from pale yellow to yellow without visible mechanical impurities

Pharmacotherapeutic group:immunosuppressive agent

ATX: & nbsp

L.04.A.A Selective immunosuppressants

L.04.A.A.10 Sirolimus

Pharmacodynamics:

Sirolimus inhibits activation of T-lymphocytes by blocking calcium-mediated and calcium-independent intracellular signaling. 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 special cytosolic whitecom immunophilin, FK-binding protein-12 (FKPB-12), and complex FKPB- 12-sirolimus inhibits the activation of the enzyme kinase, which is the target for Rapamycin in mammals (mTOR-mammalian Target of Rapamycin) and is of fundamental importance for the development of the cell cycle. Inhibition mTOR leads to the blocking of several specific paths by which the signal is transmitted. Ultimately, the activation of lymphocytes, leading to immunosuppression, is inhibited.

The maintenance regimen of sirolimus, without cyclosporine, has been studied in patients with a low and moderate immunological risk of graft loss. The study involved patients with an allogeneic kidney transplant of the deceased or kidney of a living donor. In addition, recipients with transplanted grafts in which previous grafts survived for at least 6 months after transplantation were included in the study. Cyclosporin did not abolish patients who underwent acute graft rejection of the 3rd degree on a scale Banff, or who was on dialysis, or with a serum creatinine content of> 400 μmol / L, or with renal insufficiency that did not allow the withdrawal ciclosporin. Patients with high immunological risk of graft loss have not been adequately studied in this study, which does not allow us to recommend this treatment regimen for this group of patients.

Pharmacokinetics:

After oral administration, Rapamun (sirolimus) is rapidly absorbed; the peak concentration is achieved approximately one hour after a single intake by healthy people and approximately two hours after repeated oral administration by patients in a stable state after allogeneic kidney transplantation. Systemic bioavailability of Rapamun when administered concomitantly with cyclosporine is approximately 14%. At the subsequent reception the average concentration of sirolimus in blood increases approximately in 3 times.

The half-life with repeated oral administration of the drug to patients in a stable 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 system IIIA4 (CYP3A4), and for P-glycoprotein. 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 determines the immunosuppressive effect of Rapamun by more than 90%. After a single admission [¹⁴C] -sirolimus by healthy volunteers, the major part (91.1%) of the drug labeled with a radioisotope was found in the feces, and only a small part (2.2%) was excreted in the urine.

In children on dialysis (with a decrease in the glomerular filtration rate by 30-50%) 5-11 years and 12 to 18 years, it was noted that the average, normalized by weight of the body, the ratio of clearance to filtration (CL / F) higher in the younger age 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 impaired liver function from mild to moderate severity (grade A or B on a scale Child-Pugh) mean values AUC and T_1/2sirolimus were increased, respectively, by 61 and 43%, and the mean CL / F decreased by 33% compared with healthy subjects.In patients with severe hepatic impairment, no assessment of the pharmacokinetics of sirolimus was performed.

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

Indications:

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

Contraindications:

Hypersensitivity to sirolimus or other components of the drug.

Children's age (not enough experience of use, there are only limited data, see the section "Pharmacokinetics").

Pregnancy and lactation:

Data on the use of Rapamun in pregnant women are absent. The results of experimental studies indicate the presence of reproductive toxicity.During pregnancy, Rapamun should be used only when the expected benefit clearly outweighs the possible danger to the fetus.

Effective contraceptive measures must begin before the treatment with Rapamun and continue them during the treatment period, and also within 12 weeks after discontinuation.

It is not known whether sirolimus with breast milk. Given the potential risk to the baby, breastfeeding should be discontinued during Rapamun's treatment.

Dosing and Administration:

Rapamun is intended only for oral administration.

Therapy should be performed under the supervision of a qualified transplant physician.

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 Rapamun dose is individually selected in such a way that the minimum concentrations in whole blood are 4 to 12 ng / ml (chromatographic analysis). Treatment with Rapamun continues against the background of a simultaneous gradual decrease in the dose of glucocorticoids 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 starting treatment with cyclosporine, the dose should be gradually reduced until the drug is completely discontinued and the Rapamun dose is selected so that the minimum concentrations in whole blood are 12 to 20 ng / ml (chromatographic analysis). 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 be more than 3 months. In clinically justified situations, such patients should abolish Rapamun and prescribe an alternative regimen of immunosuppression.

Data for the use of sirolimus in patients of the Negroid race is not enough.

Elderly patients (over 65 years of age):

The experience of using Rapamun in patients older than 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 appointment of Rapamun tablets to 12 patients over the age of 65 years after kidney transplantation also corresponded to those obtained for adult patients (n = 167) aged 18 to 65 years.

Use in patients with impaired liver and kidney function: cm.

section "Special instructions".

Monitoring of therapeutic drug concentration:

In most patients who received 2 mg of Rapamun 4 hours after cyclosporine, the minimum concentrations of sirolimus in whole blood corresponded to a prescribed range of 4 to 12 ng / ml (chromatographic method).

Optimal therapy requires monitoring of the therapeutic drug concentration in all patients. The concentration of sirolimus in whole blood should be monitored particularly carefully in the following groups of patients: (1) in patients with impaired liver function; (2) during the simultaneous administration of inducers or inhibitors of the cytochrome system CYP3A4, and also after the end of their admission (see the section "Drug and other types of interactions"); and / or (3) in the case of a dramatic reduction in dosage or the elimination of cyclosporine, since for these patient groups the dose modification is most likely to be required.

In order to minimize fluctuations in the concentration of sirolimus, Rapamun should be taken at constant intervals with respect to cyclosporine, namely 4 hours after the administration of cyclosporine. Rapamun should be taken continuously either concurrently with food intake or between meals. (see section "Pharmacokinetics"). In the optimal case, the choice of the Rapamun dosage should be based on a more than one measurement of the minimum concentration performed no earlier than 5 days after the last dose change. Patients can be transferred to tablets after treatment with a solution for oral administration based on an accurate recalculation of the amount of the drug "mg per mg". After transferring the patient to another dosage form or other dosing regimen, it is recommended to measure the minimum concentration of sirolimus within 1-2 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 (according to chromatographic analysis). Cyclosporin inhibits the metabolism of sirolimus, so if the Rapamun dosage is not increased, the concentration of sirolimus after cyclosporine withdrawal will decrease. On average, the dose of Rapamun should be 4 times higher, taking into account the absence 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 Rapamun should correspond to the rate of ciclosporin withdrawal.

If it is necessary to adjust the dose with maintenance therapy (after cyclosporine cancellation), it can be performed in most patients using the following formula: a new dose of Rapamunum = 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 Rapamun shock dose = 3 x (the new maintenance dose is the current maintenance dose).

The maximum daily dose of Rapamun should not exceed 40 mg.If the calculated daily dose exceeds 40 mg because of the impact dose, the shock dose should be divided by 2 days. Monitoring of the minimum concentration of sirolimus is recommended for at least 3-4 days after the administration of the impact dose.

Recommended levels of minimum daily concentrations of sirolimus were obtained using chromatographic methods. In clinical practice, both chromatographic and immunoenzymatic techniques are used to determine the concentration of sirolimus in whole blood. The results of these methods are not interchangeable. The dose adjustment should be carried out in accordance with the method used to determine the minimum concentrations of sirolimus.

Monitoring of therapeutic drug concentrations should not be the only guideline in selecting a dose of sirolimus. It should also take into account clinical symptoms, the results of histological studies and laboratory data.

Cyclosporine, like some other substances of medicinal and non-drug origin, can influence the action of sirolimus, for more details, see the section "Drug and other types of interactions."

Side effects:

Most often (> 10% of patients) observed side effects such as thrombocytopenia, anemia, hypokalemia, hypophosphatemia, urinary tract infections, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, abdominal pain, lymphocele, peripheral edema, arthralgia, acne, diarrhea and increased levels lactate dehydrogenase.

The frequency of any side effect may increase with an increase in the minimum concentration of sirolimus in the blood

The table below shows side effects identified during clinical trials, as well as those registered after the drug was released to the market. The listed side effects are subdivided according to the organ and frequency of manifestation and are presented in the table in order of decreasing severity of the disease. This list includes only those side effects that, at least, presumably may have a causal relationship with Rapamoon therapy.

Most patients received immunosuppressive therapy, which included the use of Rapamun in combination with other immunosuppressors.

System of organs	very frequent	frequent (> 1/100 to <	not frequent	rare (> 1/10000
	(> 10%)	1/10)	(> 1/1000 to <	up to <1/1000)
			1/1000)
Infections and invasions	Infections	Sepsis
	genito-urinary	pneumonia
	tract	pyelonephritis, herpes simplex fungal, viral and bacterial infections (caused by mycobacteria, Epstein-Barr virus, cytomegalovirus and virus shingles)
Tumors		Skin cancer	Lymphoma
benign,			/ posttransplan-
malignant and			tational
nonspecific			lymphoproliferate
(including cysts and polyps)			obvious violations
Hematopoietic and	Thrombocytopenia	Thrombohemolytic	Pancytopenia
lymphatic	anemia	thrombocytopenic
system		purpura/
		hemolytic-
		uremic syndrome

		leukopenia neutropenia
Hepatobiliary disorders		An increase in the level of hepatic transaminases (ALT and ACT)
The immune system				Hyperensitivity- Awareness, including anaphylactoid- / anaphylactic reactions, angioedema, exfoliative dermatitis, allergic vasculitis
Metabolism	Hypercholesterolemia, hypertriglyceridemia (hyperlipidemia) hypokalemia, hypophosphatemia, hyperglycemia
Cordially vascular violations	Lymphocele	Tachycardia Deep vein thrombosis	Exudative pericarditis (including hemodynamically significant effusions in children and adults) Pulmonary embolism	Stasis of lymph
Respiratory system		Pneumonitis. nose bleed	Pulmonary bleeding
Gastro- intestinal violations	Abdominal pain, diarrhea	Stomatitis	Pancreatitis
Skin and subcutaneous tissue	Acne	Rash

Musculoskeletal system	Arthralgia	Osteonecrosis
Genitourinary system		Proteinuria	Nephrotic syndrome
Organism as a whole	peripheral edema	Delayed wound healing, swelling, enhancement temperatures above 38 ° С
Laboratory Tests	increase in the level of lactate dehydrogenase	increase in ALT and ACT

Immunodepression increases the risk of developing lymphoma and other malignant tumors, especially those that occur with skin lesions (see section "Special instructions").

There are reports of hepatotoxicity of 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.

There were cases of interstitial lung diseases (including pneumonitis and, infrequently,obliterans bronchiolitis and pulmonary fibrosis), in some cases with a fatal outcome in an unidentified pathogen, in patients receiving immunosuppressive therapy, including Rapamun. In some cases, the abolition of Rapamun or a reduction in the dose led to the elimination of the interstitial pulmonary process. The risk of the disease may increase as the minimum concentration of sirolimus in the blood rises.

The cases of complicated wound healing after transplantation, including divergence of fascia and rupture of anastomosis, are described.

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

Overdose:

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

Interaction:

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

Ciclosporin (substrate for CYP3A4): Cyclosporin A significantly increases the rate and degree of absorption of sirolimus. Simultaneous reception of Rapamun in a dose of 5 mg, then 5 mg in 2 hours and 10 mg in 4 hours after the appointment of 300 mg of a microemulsion of cyclosporine A led to an increase AUC sirolimus will bring about 80%,

respectively.The effect of the action of cyclosporin A appeared in the increase Сmах and T_max sirolimus. If sirolimus was taken 2 hours prior to administration of the cyclosporin A microemulsion, no effect was observed on AUC and Cmax sirolimus. In healthy volunteers who received a single dose of sirolimus simultaneously with cyclosporine (microemulsion) or at a 4-hour interval, the pharmacokinetics of cyclosporin A did not change. It is recommended to appoint Rapamun 4 hours after taking a cyclosporine microemulsion.

Rifampicin (inducer CYP3A4): Multiple administration of rifampicin reduced the concentration of sirolimus in the blood after a single dose of 10 mg

Rapamun, solution for oral administration. Rifampicin increased the clearance of sirolimus by approximately 5.5 times and reduced AUC sirolimus and Cmax, approximately 82 and 71%, respectively. It is not recommended to appoint sirolimus simultaneously with rifampicin.

Ketoconazole (inhibitor CYP3A4): The repeated administration of ketoconazole significantly altered the rate, the degree of absorption and the effect of sirolimus: as indicated by a 4,4-, 1,4- and 10,9-fold increase, respectively, Cmax, Tmax and AUC. It is not recommended to appoint sirolimus concomitantly with ketoconazole.

^ Voriconazole (inhibitor CYP3A4): When combined in healthy volunteers, sirolimus (2 mg once) and voriconazole (400 mg intravenously every 12 hours on the first day, then 100 mg every 12 hours for 8 days), an average 7-fold increase in Cmax and 11-fold increase AUC sirolimus. It is not recommended to appoint sirolimus concomitantly with voriconazole.

Diltiazem (inhibitor CYP3A4): With the simultaneous administration of 10 mg of Rapamun in the form of a solution for oral administration and 120 mg of diltiazem, the bioavailability of sirolimus significantly changed. Cmax, Tmax and AUC sirolimus increased, respectively, in 1.4, 1.3 and 1.6 times. Sirolimus did not change the pharmacokinetics of diltiazem and its metabolites-

deacetyl-dithiasem and desmethyldiltiazem. When appointing diltiazem it is necessary to control the concentration of sirolimus in the blood and, if necessary, adjust the dose of the drug.

Verapamil (inhibitor CYP3A4): With the appointment of multiple doses of verapamil and sirolimus in the form of a solution for oral administration, the rate and degree of absorption of both drugs varied significantly. Cmax, Tmax and AUC sirolimus in whole blood increased, respectively, in 2,3, 1,1 and 2,2 times. Cmax value, and AUC S - (-) verapamil in plasma increased by 1.5 times, and Tmax was reduced by 24%. It is necessary to control the concentrations of sirolimus and, if necessary, to reduce the doses of both drugs accordingly.

Erythromycin (inhibitor CYP3A4): With the appointment of multiple doses of erythromycin and sirolimus in the form of a solution for oral administration, the rate and degree of absorption of both compounds increased significantly. Cmax, Tmaxand AUC sirolimus in whole blood increased, respectively, 4.4, 1.4 and 4.2 times. Cmax, Tmax and AUC erythromycin in the plasma increased, respectively, in 1.6, 1.3 and 1.7-fold. Need to monitor

concentration of sirolimus and, if necessary, reduce the doses of both drugs accordingly.

Oral contraceptives: There were no clinically significant pharmacokinetic interactions 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 Rapamun with an oral contraceptive indicate a lack of pharmacokinetic interaction, long-term treatment with Rapamun can not exclude possible changes in pharmacokinetics that may affect the effectiveness of oral contraceptives.

Other possible interactions: Moderate and weak inhibitors CYP3A4 can reduce the metabolism of sirolimus and increase the concentration of sirolimus in the blood (for example, blockers of slow calcium channels:

nicardipine; antifungal agents: clotrimazole, fluconazole; antibiotics: troleandomycin; and other drugs: bromocriptine, cimetidine, danazol, protease inhibitors).

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

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

Grapefruit juice affects CYP3A4 mediated metabolism and, therefore, it should not be consumed while taking Rapamun.

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 / thrombocytopenic thrombotic purpura / thrombotic microangiopathy induced by calcineurin inhibitors is possible.

Special instructions:

To date, there is insufficient data on the use of Rapamun in patients with high immunological risk (see the section "Pharmacodynamics").

There is a research experience in the appointment of sirolimus in conjunction with the following drugs: cyclosporine, azathioprine, mycophenolate mofetil, glucocorticosteroids and cytotoxic antibodies. Combinations of Rapamun with other immunosuppressive drugs have not been adequately studied.

The administration of sirolimus, mycophenolate mofetil and glucocorticosteroids in combination with antibodies to 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, vaccination may be less effective. During the treatment with Rapamun, live vaccines should be avoided.

Pharmacokinetics Rapamun in the body of patients with severe impairment of liver function has not been studied. In patients with impaired liver function, the level of the minimum concentration of sirolimus in the blood should be carefully monitored.

There is no need to change the dosage in patients with impaired renal function (see section "Pharmacokinetics").

As a result of excessive inhibition of the immune system, it is possible to increase susceptibility to infections, including infections caused by conditionally pathogenic microorganisms, the possible consequences of which, sepsis and death, are noted in the section "Side effect."

Since the safety and effectiveness of Rapamun, as an immunosuppressive therapy for patients with hepatic and pulmonarytransplant is not established, the drug is not recommended for use in these patient groups.

In two clinical trials 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 death of the graft or death.

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

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 immunosuppressive therapy.

When applying sirolimus, there have been cases of hypersensitivity reactions, such as anaphylactic / anaphylactoid reactions, exfoliative dermatitis, angioedema and vasculitis due to hypersensitivity.

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.

In rare cases, the combined use of sirolimus and ACE inhibitors led to the development of angioedema.

There are reports of cases of pneumonia caused by Pneumocystis carinii in patients who did not receive antimicrobial prophylaxis. In this regard, in

During the first 12 months after transplantation, antimicrobial prophylaxis directed against Pneumocystis carinii.

Within 3 months after transplantation, the prevention of cytomegalovirus infection is advisable.

The use of Rapamun in patients after kidney transplantation was accompanied by an increase in the level of cholesterol and triglycerides in the serum, in some cases requiring medication correction. Patients receiving Rapamun need control in order to identify possible hyperlipidemia. If hyperlipidemia is established, appropriate measures should be taken, including dieting, exercise and taking medications that lower cholesterol levels.Before the appointment of immunosuppressants, including Rapamun, and when deciding whether to continue treatment with Rapamun patients with severe persistent hyperlipidemia, it is necessary to assess the relationship between the risk and benefit of this type of therapy.

Good tolerability of Rapamun in combination with HMG-CoA reductase inhibitors and / or fibrates has been noted. During the period of treatment with Rapamun in combiination with inhibitors of HMG-CoA reductase 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 drugs.

With the joint appointment of Rapamun and cyclosporine, it is necessary to monitor kidney function. It should be borne in mind that for patients with elevated serum creatinine levels, correction of the immunosuppressant regimen will be required. Care must be taken when concomitantly with other drugs that adversely affect kidney function.

Patients treated with Rapamun and cyclosporine for more than 3 months had higher serum creatinine concentrations and

a lower level of glomerular filtration, compared with patients in the control group who received ciclosporin and placebo or ciclosporin and azathioprine. Patients after successful cyclosporine withdrawal had a lower serum creatinine level and a higher level of glomerular filtration compared to patients who continued to receive ciclosporin. Until additional clinical data are obtained, the joint administration of cyclosporine and Rapamun is not recommended as maintenance therapy.

The safety and efficacy of transferring patients from calcineurin inhibitors to Rapamoun has not been studied.

^ It is recommended to periodically monitor the concentration of protein in the urine.

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

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

Form release / dosage:

Solution for oral administration 1 mg / ml. For 60 or 150 ml of the drug in bottles of dark glass.

Packaging: For 60 or 150 ml of the drug in bottles of dark glass. 1 bottle per set with 1 syringe adapter is placed in a cardboard box that is bundled with 30 yellow plastic syringes-dispensers and caps to the syringes, 1 case for the syringe together with the instruction for use is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C.

Keep out of the reach of children.

When stored in a refrigerator in the bottle with a solution, there may be a slight cloudiness. If this happens, leave the drug for a while at room temperature, then gently shake. The presence of turbidity does not affect the quality of the drug.

Shelf life:

2 years in the original packaging.

30 days after opening the vial. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013700 / 01

Date of registration:02.04.2009

The owner of the registration certificate:Wyeth Whitehall Export GmbHWyeth Whitehall Export GmbH Austria

Manufacturer: & nbsp

WYETH PHARMACEUTICALS, Inc. USA

Information update date: & nbsp05.08.2015

Illustrated instructions

Instructions

breeding instruction

Rapamun (Rapamune)