Rapamune 1 mg 100 pcs. (Sirolimus/Rapamycin)

Name: Rapamune 1 mg 100 pcs. (Sirolimus/Rapamycin)
SKU: A627811
Availability: InStock

€892.86

SKU: A627811 Categories: Immune system, Medicine

Rapamune® is indicated for the prevention of graft rejection in adult patients at low or moderate immunological risk after kidney transplantation. It is recommended to use Rapamune® initially in combination with glucocorticosteroids and cyclosporine microemulsion during the first 2-3 months after transplantation. Therapy with Rapamune® can be continued as maintenance therapy in conjunction with glucocorticosteroids only if cyclosporine is gradually discontinued.
Rapamune® is indicated for the treatment of patients with lymphangioleiomyomatosis.

Instructions

Rapamune® is for oral administration only.

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

Patients who are unable to take Rapamune® in tablet form should receive it as an oral solution.

Rapamune® must be taken continuously, either at the same time as meals or between meals.

Prevention of organ rejection during kidney transplantation

Rapamune® should be prescribed only by physicians experienced in immunosuppressive therapy and the treatment of organ transplant patients. Therapy should be carried out in specially equipped facilities equipped with appropriate laboratory and auxiliary medical resources. The physician responsible for maintenance therapy must have complete information necessary to monitor the patient.

It is recommended to take Rapamune® 4 hours after taking cyclosporine microemulsion.

Adults

Initial therapy (within 2-3 months after transplantation): In the usual dosing regimen, as soon as possible after transplantation, a single loading dose of Rapamune® is administered orally equal to 6 mg, followed by a dose of 2 mg once a day. Subsequently, the dose of Rapamune® is selected individually so that the minimum blood concentrations range from 4 to 12 ng/ml (chromatographic method). Treatment with Rapamune® is continued with a simultaneous gradual reduction in the dose of glucocorticosteroids and cyclosporine microemulsion.

During the first 2-3 months after transplantation, it is recommended to maintain minimum concentrations of cyclosporine within the range of 150-400 ng/ml (immune method for determining concentrations).

Maintenance therapy: 4-8 weeks after starting treatment with cyclosporine, its dose should be gradually reduced until the drug is completely discontinued, and the dose of Rapamune® should be selected so that minimum blood concentrations range from 12 to 20 ng/ml (chromatographic method). Rapamune® should be taken together with glucocorticosteroids. For patients in whom discontinuation of cyclosporine was unsuccessful or impossible, the duration of combined therapy with cyclosporine and Rapamune® should not be more than 3 months. In clinically justified situations, such patients should discontinue Rapamune® and be prescribed an alternative immunosuppressive regimen.

Discontinuation of cyclosporine has not been studied in patients with acute grade III graft rejection according to the Bnaff 93 classification or in patients with vascular rejection that developed before discontinuation of cyclosporine. Also, cyclosporine withdrawal has not been studied in patients on dialysis or with plasma creatinine > 4.5 mg/dL, in patients of black race, in renal renal transplantation, in multiple organ transplantation, or in patients with high titers of panel-reactive antibodies. There is insufficient data for the use of sirolimus in black patients. Elderly patients (over 65 years):

There is insufficient experience with Rapamune® in patients over 65 years of age to determine whether there are differences in response to therapy between patients in this age group and younger patients. In 35 patients over 65 years of age after kidney transplantation, trough concentrations of sirolimus did not differ from the corresponding concentrations in 822 patients from 18 to 65 years of age. The results obtained with the use of Rapamune® orally in 12 patients over the age of 65 years after kidney transplantation were also consistent with the results obtained in 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 liver failure, the maintenance dose of Rapamune® is recommended to be reduced by approximately half due to the slow clearance of the drug. The loading dose should not be changed.

After changing the dose or taking a loading dose of the drug Rapamune® in patients with severe liver failure, due to the slowdown in achieving an equilibrium state, monitoring the drug concentration in the blood should be carried out every 5-7 days until 3 consecutive determinations of the concentration of sirolimus confirm that a stable level has been achieved .

Use in patients with lymphangioleiomyomatosis

The initial dose of Rapamune® for patients with lymphangioleiomyomatosis is 2 mg per day. The minimum concentration of sirolimus in whole blood is measured on days 10-20, followed by dose adjustment to maintain the concentration in the range of 5-15 ng/ml.

For most patients, dose adjustments can be made based on the following formula: new dose of Rapamune® = current dose x (desired concentration/current concentration). Frequent dose adjustments of Rapamune not based on steady-state drug concentrations may result in overdose or underdose due to the long half-life of sirolimus.

After adjusting the maintenance dose of Rapamune®, the patient must take this dose for at least 7 to 14 days before the next dose adjustment is made based on monitoring of drug concentrations in the blood. Once a stable dose is achieved, blood concentrations of the drug should be monitored at least every three months.

Monitoring of therapeutic drug concentrations: in the majority of patients receiving 2 mg of Rapamune® 4 hours after cyclosporine, the minimum concentrations of sirolimus in the blood corresponded to the specified interval from 4 to 12 ng/ml (according to chromatographic analysis).

Optimal therapy requires monitoring of therapeutic drug concentrations in all patients. Sirolimus blood concentrations should be monitored particularly carefully in the following patient groups: (1)

patients with impaired liver function; (2) during the simultaneous use of inducers or inhibitors of the CYP3A4 and P-gp isoenzymes, as well as after the end of their use (see section “Interaction with other drugs”); and/or (3)

in case of a sharp dose reduction or discontinuation of cyclosporine, since these groups of patients are most likely to require dose adjustment.

In order to minimize fluctuations in sirolimus concentrations, Rapamune® should be taken at regular intervals relative to cyclosporine, namely 4 hours after taking cyclosporine. Optimally, dose adjustment of Rapamune® should be based on more than one trough concentration measurement performed no earlier than 5 days after the last dose change. After starting treatment with Rapamune® solution, the patient can continue therapy with Rapamune® tablets while maintaining the exact dose. After switching a patient to a different dosage form or dosage regimen, it is recommended to measure sirolimus trough concentrations over a period of 1 to 2 weeks.

After discontinuation of cyclosporine, it is recommended to maintain the minimum concentration of sirolimus in the blood at a level of 12-20 ng/ml (chromatographic method). Cyclosporine inhibits the metabolism of sirolimus, so unless the dose of Rapamune® is increased, sirolimus concentrations will decrease after discontinuation of cyclosporine. On average, the dose of Rapamune® should be 4 times higher, taking into account the lack of pharmacokinetic interaction (2-fold increase) and the increased need for immunosuppression in the absence of cyclosporine (2-fold increase). The rate of increase in the dose of Rapamune® should correspond to the rate of elimination of cyclosporine after its discontinuation.

If dose adjustment is necessary during maintenance therapy (after discontinuation of cyclosporine), it can be done in most patients using the following formula: new dose of Rapamune® = current dose x (desired concentration/current concentration). A loading dose should be used in addition to the maintenance dose if a significant increase in the trough concentration of sirolimus is required: Rapamune® loading dose = 3 x (new maintenance dose – current maintenance dose). The maximum daily dose of Rapamune® should not exceed 40 mg. If the calculated daily dose exceeds 40 mg due to the loading dose, the loading dose should be taken for longer than 2 days. Determination of the minimum concentration of sirolimus should be carried out at least 3-4 days after administration of the loading dose.

Calculation of the 24-hour minimum concentration of sirolimus is based on the results of chromatographic methods. Various approaches have been used to measure sirolimus blood concentrations. Currently, blood concentrations of sirolimus are measured by both chromatographic and enzyme immunoassay methods. The concentration values obtained by these methods are not interchangeable. When using enzyme immunoassay systems, the manufacturer’s recommendations should always be followed to correlate the values obtained with those obtained by standard chromatographic methods. All sirolimus concentrations given in this document were measured by chromatographic methods or converted to appropriate equivalent values. To determine the desired trough concentration of sirolimus, adjustments should be made according to the methods used. Monitoring therapeutic drug concentrations should not be the sole guideline for dose selection of sirolimus. Particular attention should be paid to clinical symptoms, histological examination results and laboratory data.

Composition

Each film-coated tablet contains:

Placebo tablet core 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;

Inert filler layer: microcrystalline cellulose (type PH-101) – 7.32 mg; sucrose – 97.6 mg; titanium dioxide – 0.100 mg;

Active filler layer: sirolimus nanosystem dispersed 150 mg/g (sirolimus 100% (active substance) – 1, mg; poloxamer-188 – 0.5 mg; sucrose – 97.25 mg; microcrystalline cellulose (type PH-101) – 0 .7 mg; povidone-K29-32 – 0.5 mg; alpha-tocopherol acetate – 0.05 mg;

Colored shell: sucrose – 19.0 mg;

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

Polishing: carnauba wax – 0.079 mg;

Red ink – opacode S-1-15095 [shellac solution ~ 45% (contains 20% esters) in ethanol, red iron oxide dye (E172), isopropyl alcohol, butanol, propylene glycol, aqueous ammonia, simethicone] – 0.200 mg.

Contraindications

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

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

Children under 18 years of age (insufficient experience with use, only limited data available, see section “Pharmacokinetics”).

Carefully

Caution should be exercised when sirolimus is used concomitantly with drugs that affect renal function.

Use during pregnancy and breastfeeding

There are no data on the use of Rapamune® in pregnant women. During pregnancy, Rapamune® should be used only in cases where the expected benefit to the mother outweighs the possible risk to the fetus.

Effective contraception must be started before treatment with Rapamune® and continued during treatment, as well as for 12 weeks after its end.

There is no data on the passage of sirolimus into breast milk. Given the potential risk to the baby, breastfeeding should be discontinued during treatment with Rapamune®.

Special instructions

To date, there is not enough data on the use of Rapamune® in patients with high immunological risk, so its use in such patients is not recommended. There is research experience with the use of sirolimus in combination with the following drugs: tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil, glucocorticosteroids and cytotoxic antibodies. Combinations of Rapamune® with other immunosuppressive drugs have not been sufficiently studied.

Because sirolimus has a long half-life, frequent dose adjustments of Rapamune not based on steady-state drug concentrations may result in drug overdose or too low a dose. The use of sirolimus, mycophenolate mofetil and glucocorticosteroids in combination with antibodies to interleukin (IL)-2 receptors is not recommended for de novo renal transplantation.

Immunosuppressants may affect the effectiveness of vaccination. During treatment with immunosuppressants, including Rapamune®, vaccinations may be less effective. During treatment with Rapamune®, the use of live vaccines should be avoided.

In patients with impaired liver function, sirolimus trough concentrations in the blood should be carefully monitored. Taking into account the extended t1/2 of the drug in this category of patients, after changing the dose or taking a loading dose of the drug Rapamune®, monitoring the concentration of the drug in the blood must be carried out until it reaches a stable level (see section “Method of administration and dosage”). In patients with severe hepatic impairment, it is recommended to reduce the maintenance dose by half, which is determined by a decrease in clearance.

Decreased resistance to infections and susceptibility to the development of lymphoma and other malignant diseases, especially of the skin, may be a consequence of suppressed immune system.

Precautions common to patients at increased risk of skin cancer should be taken: limit exposure to sunlight and ultraviolet radiation by wearing protective clothing and using high sunscreen creams.

As a result of excessive suppression of the immune system, it is possible to increase susceptibility to infections, including infections caused by opportunistic microorganisms, the probable consequences of which, sepsis and death, are noted in the “Side Effects” section.

These conditions include nephropathy associated with the BK virus and progressive multifocal leukoencephalopathy associated with the JC virus. These infections are often associated with a high immunosuppressive burden and can lead to severe or fatal conditions. Clinicians should keep this in mind when making a differential diagnosis in patients with reduced immunity and impaired renal function or neurological symptoms.

Since the safety and effectiveness of Rapamune® as an immunosuppressive therapy for patients with liver and lung transplants has not been established, the drug is not recommended for use in these groups of patients.

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

In the same study, as well as in another study in patients with de novo liver transplants, the use of sirolimus with cyclosporine or tacrolimus was associated with an increased incidence 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.

Impaired or delayed wound healing has been reported in patients taking Rapamune®, especially often in patients whose body mass index exceeds 30 kg/m2 (lymphocele, wound dehiscence).

There are reports of bronchial anastomotic dehiscence in patients with de novo lung transplants, most of them fatal, when sirolimus is used as part of immunosuppressive therapy.

Cases of fluid retention, in particular peripheral edema, lymphatic congestion, pleural effusion and pericardial effusion (including hemodynamically significant effusions in children and adults), have been described in patients receiving Rapamune®.

Allergic reactions such as anaphylactic/anaphylactoid reactions, exfoliative dermatitis, angioedema and vasculitis have been reported with the use of sirolimus.

Rapamune® in the form of film-coated tablets contains sucrose and lactose. Before using the drug, patients with a history of sucrase, lactase and isomaltase deficiency, fructose intolerance, malabsorption of glucose and galactose, galactose intolerance (for example, galactosemia), should assess the risk/benefit ratio and, if necessary, replace Rapamune® tablets with Rapamune ® solution for oral administration.

The simultaneous use of Rapamune with angiotensin-converting enzyme (ACE) inhibitors led to the development of reactions such as angioedema. Increased levels of sirolimus (with or without concomitant use of ACE inhibitors) may also increase angioedema (see section “Interaction with other drugs”). In some cases, angioedema resolved after stopping the use of Rapamune or reducing the dose of the drug. There are case reports 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 is necessary.

For 3 months after transplantation, it is advisable to prevent cytomegalovirus infection.

The use of the drug Rapamune® 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 Rapamune® need to be monitored for possible hyperlipidemia. If hyperlipidemia is established, appropriate measures should be taken, including diet, exercise, and cholesterol-lowering medications. Before using immunosuppressants, including Rapamune®, as well as when deciding whether to continue treatment with Rapamune® in 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 recovery of renal function.

Rapamune® was well tolerated in combination with HMG-CoA reductase inhibitors and/or fibrates. During treatment with Rapamune® 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 medical use of these drugs.

When using Rapamune® and cyclosporine together, it is necessary to monitor the patient’s condition for the development of rhabdomyolysis and renal dysfunction. It must be borne in mind that for patients with elevated serum creatinine concentrations, adjustment of the immunosuppressant treatment regimen will be required. Caution must be exercised when used concomitantly with other drugs that adversely affect renal function.

Patients treated with Rapamune® and cyclosporine for more than 3 months had higher serum creatinine concentrations and lower glomerular filtration rates compared with control patients receiving cyclosporine and placebo or cyclosporine and azathioprine. Patients who successfully discontinued cyclosporine had lower serum creatinine concentrations and higher glomerular filtration rates, as well as a lower incidence of malignancy compared with patients who continued to receive cyclosporine. Until further clinical data are obtained, the combined use of cyclosporine and Rapamune® as maintenance therapy is not recommended.

In patients with delayed graft function, Rapamune® may lead to a delay in recovery of renal function.

In addition, renal function should be carefully monitored during concomitant use of Rapamune® and tacrolimus. In patients with elevated plasma creatinine concentrations, immunosuppressive therapy should be adjusted accordingly, including discontinuation of therapy with Rapamune® and/or cyclosporine and/or tacrolimus.

The safety and effectiveness of Rapamune® in primary use without calcineurin inhibitors has not been studied in patients with a transplanted kidney. In two multicenter clinical trials, patients with de novo kidney transplants treated with Rapamune®, mycophenolate mofetil, glucocorticosteroids and IL-2 receptor antagonists had a significantly higher incidence of acute graft rejection and a higher incidence of death compared with patients receiving calcineurin inhibitors, mycophenolate mofetil, glucocorticosteroids and IL-2 receptor antagonists. In terms of the effect on renal function, no visible improvement was observed with primary therapy with Rapamune® without simultaneous use of calcineurin inhibitors. It should be noted that one of the two studies used a shortened course of daclizumab therapy.

It is recommended to periodically monitor the level of protein excretion in the urine. In clinical studies, an increase in protein concentration in the urine was noted after switching patients from calcineurin to Rapamune®. Typically, this increase was observed within 6-24 months after a change in therapy compared with patients who continued therapy with calcineurin inhibitors. Nephrotic syndrome was identified in 2% of patients in clinical studies. The safety and effectiveness of switching patients from calcineurin inhibitors to Rapamune® have not been established. Concomitant use of Rapamune® with inhibitors

Calcineurin may increase the risk of calcineurin-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura.

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

Impact on the ability to drive vehicles and use machinery. Studies have not been conducted to study the impact on the ability to drive vehicles and use machinery.

Side effects

1. Side effects observed during the prevention of graft rejection after kidney transplantation.

The most common side effects (in > 10% of patients) were: thrombocytopenia, anemia, pyrexia, increased blood pressure, hypokalemia, hypophosphatemia, urinary tract infections, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, abdominal pain, lymphocele, peripheral edema, arthralgia, acne , pain of various localizations, constipation, diarrhea, nausea, headache and increased concentrations of plasma creatinine and lactate dehydrogenase.

The incidence of any side effect may increase with increasing trough concentrations of sirolimus in the blood.

The table below shows side effects identified during clinical trials, as well as those reported after the drug was marketed. The listed side effects are classified according to organ affiliation 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 therapy with Rapamune®.

Most patients received combination immunosuppressive therapy, which included Rapamune® and other immunosuppressants.

The frequency of reactions is distributed according to the WHO classification: very common (> 10%), common (> 1% and < 10%), uncommon (> 0.1% and < 1%), rare (> 0.01% and < 0.1%), very rare (<0.01%), unknown – frequency cannot be determined based on available data.

Infectious and parasitic diseases: very common – pneumonia, fungal, viral and bacterial infections, Herpes simplex, urinary tract infections; uncommon – infections caused by mycobacteria (including tuberculosis), infections caused by the Epstein-Barr virus, enterocolitis caused by Clostridium difficile; common – sepsis, pyelonephritis, cytomegalovirus infections, Herpes zoster; Benign, malignant and unspecified neoplasms (including cysts and polyps): common – skin cancer, squamous cell carcinoma, basal cell carcinoma; uncommon – lymphoma/post-transplant lymphoproliferative disorders, melanoma; unknown – neuroendocrine skin carcinoma.

Disorders of the blood and lymphatic system: very common – thrombocytopenia, anemia, leukopenia; common – hemolytic-uremic syndrome, neutropenia; uncommon – pancytopenia, thrombocytopenic purpura.

Immune system disorders: common – hypersensitivity reactions (including angioedema, anaphylactic and anaphylactoid reactions; uncommon – exfoliative dermatitis; rare – allergic vasculitis.

Metabolic and nutritional disorders: very common – hyperlipidemia (including hypercholesterolemia), hypertriglyceridemia, hypokalemia, hypophosphatemia, hyperglycemia, diabetes mellitus, fluid retention.

Nervous system disorders: very common – headache; unknown – posterior reversible encephalopathy syndrome*.

Cardiac disorders: very common – tachycardia; common – pericardial effusion (including hemodynamically significant effusions in children and adults).

Vascular disorders: very common – lymphocele, increased blood pressure; common – venous thrombosis (including deep vein thrombosis); infrequent – lymph stagnation.

Disorders of the respiratory system, chest and mediastinal organs:

common – pneumonitis, pleural effusion, nosebleeds, pulmonary embolism; uncommon – pulmonary hemorrhage; rare – alveolar proteinosis of the lungs.

Gastrointestinal disorders: very common – abdominal pain, diarrhea, constipation, nausea; common – pancreatitis, stomatitis, ascites.

Disorders of the liver and biliary tract: unknown – liver failure.

Disorders of the skin and subcutaneous tissues: very common – rash, acne; uncommon – exfoliative dermatitis.

Musculoskeletal and connective tissue disorders: very common – arthralgia; common – osteonecrosis.

Renal and urinary tract disorders: very common – proteinuria; uncommon – nephrotic syndrome, focal segmental glomerulosclerosis. Disorders of the genital organs and mammary gland: very common – menstrual irregularities (including amenorrhea and menorrhagia); common – ovarian cysts. General disorders and disorders at the injection site: very common – peripheral edema, pyrexia, pain of various localizations, delayed wound healing, edema. Laboratory and instrumental data: very common – increased activity of lactate dehydrogenase, increased concentration of creatinine in blood plasma, increased activity of alanine aminotransferase and aspartate aminotransferase.

*adverse reactions observed during post-marketing use of the drug. Immunosuppression increases the risk of developing lymphoma and other skin malignancies (see section “Special Instructions”).

Data on the hepatotoxicity of Rapamune® have been published. The risk of hepatotoxicity may increase as the trough concentration of sirolimus in the blood increases. There have been reports of rare cases of fatal liver necrosis when the minimum concentration of sirolimus in the blood is exceeded.

Cases of interstitial lung disease (including pneumonitis and, rarely, bronchiolitis obliterans with organizing pneumonia and pulmonary fibrosis), some fatal due to an unidentified pathogen, have been reported in patients receiving immunosuppressive therapy, including Rapamune®. In some cases, discontinuation of Rapamune® or dose reduction led to the elimination of the interstitial pulmonary process. The risk of disease may increase as the trough concentration of sirolimus in the blood increases.

Cases of delayed wound healing after transplantation have been described, including fascial dehiscence, incisional hernias, and anastomotic rupture.

In some patients, during treatment with Rapamune®, a reversible impairment of the functional activity of sperm was observed.

In patients with delayed graft function, sirolimus may result in delayed recovery of renal function.

In the subgroup of patients with an initially reduced glomerular filtration rate (<40 ml/min), as well as in patients after kidney transplantation when switching from calcineurin inhibitor therapy to sirolimus, the frequency of serious adverse events while taking Rapamune® was higher (including pneumonia, acute graft rejection, graft failure and death).

Cases of the development of ovarian cysts and menstrual irregularities (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 perimenopause than during postmenopause. In some cases, these disorders resolved after discontinuation of therapy with Rapamune®.

There are reports of cases of nephropathy associated with the BK virus and progressive multifocal leukoencephalopathy associated with the JC virus in patients receiving immunosuppressants, including Rapamune®. Since these are data obtained in the post-registration period, there is no exact information on the frequency of development of these reactions.

In a study evaluating the safety and effectiveness of switching from tacrolimus to Rapamune therapy 3 to 5 months after kidney transplantation, a higher incidence of acute graft rejection and new-onset diabetes mellitus was observed after switching to Rapamune therapy.

2. Side effects observed in patients with lymphangioleiomyomatosis.

The safety of the drug was assessed in a controlled study on 89 patients and 86 volunteers with lymphangioleiomyomatosis, 46 of whom received Rapamune®. . The side effects observed in this study were consistent with previously identified side effects during use and were consistent with the known safety profile of the drug for the prophylaxis indication prevention of graft rejection after kidney transplantation.

Adverse reactions observed with a frequency of >20% in the group of patients receiving Rapamune®, more often than in the placebo group, included: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory infections pathways, headache, dizziness, muscle pain, hypercholesterolemia. Additionally, weight loss was observed, with a greater frequency in patients receiving Rapamune® than placebo.

Drug interactions

In the intestinal wall and liver, sirolimus is extensively metabolized by the CYP3A4 isoenzyme. In addition, sirolimus is a substrate for P-gp localized in the small intestine, which eliminates many drugs. Therefore, substances affecting these proteins may affect the absorption of sirolimus and its subsequent elimination. Inhibitors of the CYP3A4 and P-gp isoenzyme (ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) reduce the metabolism of sirolimus, which leads to an increase in its concentration. Inducers of the CYP3A4 and P-gp isoenzyme (rifampicin or rifabutin) increase the metabolism of sirolimus, reducing its concentration. It is not recommended to use sirolimus simultaneously with strong inducers or inhibitors of the CYP3A4 and P-gp isoenzymes.

Cyclosporine (substrate and inhibitor of CYP3A4 and P-gp isoenzyme): Cyclosporine significantly increases the rate and extent of absorption of sirolimus. Co-administration of Rapamune 5 mg followed by 5 mg 2 hours later and 10 mg 4 hours after 300 mg cyclosporine microemulsion increased the sirolimus AUC to approximately 183%, 141% and 80%, respectively. The effect of cyclosporine was also manifested in an increase in Cmax and tmax of sirolimus. When sirolimus was taken 2 hours before cyclosporine microemulsion, there was no effect on the AUC or Cmax of sirolimus. In healthy volunteers receiving 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 Rapamune® 4 hours after taking cyclosporine microemulsion. Rifampicin (CYP3A4 and P-gp inducer): Repeated dosing of rifampicin (600 mg once daily for 14 days) decreased sirolimus blood concentrations after a single dose of 20 mg Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased the AUC of sirolimus and Cmax by approximately 82 and 71%, respectively. It is not recommended to use sirolimus concomitantly with rifampicin.

Ketoconazole (CYP3A4 and P-gp inhibitor): Repeated administration of ketoconazole significantly altered the rate, extent of absorption and exposure of sirolimus: as evidenced by 4.4-, 1.4- and 10.9-fold increases, respectively, in Cmax, tmax and AUC. It is not recommended to use sirolimus concomitantly with ketoconazole.

Voriconazole (CYP3A4 inhibitor): When sirolimus (2 mg once) and voriconazole (orally 400 mg every 12 hours on the first day, then 100 mg every 12 hours for 8 days) were coadministered to healthy volunteers, an average of 7-fold effects were observed. increased Cmax and 11-fold increase in AUC of sirolimus. It is not recommended to use sirolimus concomitantly with voriconazole. Diltiazem (CYP3A4 and P-gp substrate and inhibitor): When 10 mg of Rapamune® oral solution was administered concomitantly with 120 mg of diltiazem, the bioavailability of sirolimus was significantly increased. Cmax, tmax and AUC of sirolimus increased by 1.4, 1.3 and 1.6 times, respectively. Sirolimus did not change

pharmacokinetics of diltiazem and its metabolites – desacetyldiltiazem and desmethyldiltiazem. 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 (CYP3A4 inhibitor): When repeated doses of verapamil and sirolimus oral solution were used, the rate and extent of absorption of both compounds changed significantly. Cmax, tmax and AUC of sirolimus in whole blood increased by 2.3, 1.1 and 2.2 times, respectively. The values of Cmax and AUC of S-(-) verapamil in blood plasma increased by 1.5 times, and tmax decreased by 24%. It is necessary to monitor the concentration of sirolimus and, if necessary, reduce the doses of both drugs.

Erythromycin (CYP3A4 inhibitor): With repeated doses of erythromycin and sirolimus oral solution, the rate and extent of absorption of both compounds was significantly increased. Cmax, tmax and AUC of sirolimus in whole blood increased by 4.4, 1.4 and 4.2 times, respectively. Cmax, tmax and AUC of erythromycin in blood plasma increased, respectively, by 1.6, 1.3 and 1.7 times. It is necessary to monitor the concentration of sirolimus and, if necessary, reduce the doses of both drugs.

Oral contraceptives: no clinically significant effects observed

pharmacokinetic interaction between sirolimus and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a study of the interaction of a single dose of the drug Rapamune® and an oral contraceptive indicate the absence of pharmacokinetic interaction, with long-term treatment with the drug Rapamune®, possible changes in pharmacokinetics cannot be excluded, which may affect the effectiveness of the oral contraceptive.

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 (for example, blockers of “slow” calcium channels: nicardipine;

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

Inducers of the CYP3A4 isoenzyme can accelerate the metabolism of sirolimus and reduce the concentration of sirolimus in the blood (for example, the medicinal plant St. John’s wort – Hypericum perforatum; anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although in vitro sirolimus inhibits the activity of isoenzymes of the microsomal cytochrome P450 system in humans (isoenzymes CYP2C9, CYP2C19, CYP2D6, CYP3A4/5), suppression of the activity of these isoenzymes in vivo is unlikely, since for this to happen, concentrations of sirolimus must be significantly higher than in patients receiving the drug in therapeutic doses. P-gp inhibitors may reduce the release of sirolimus from intestinal cells and increase its concentration in the blood. Grapefruit juice reduces CYP3A4-mediated metabolism and potentially increases P-gp-mediated reverse transport from enterocytes to the small intestine and should therefore not be consumed while taking Rapamune.

Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents such as cisapride, metoclopramide.

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

With the simultaneous use of Rapamune® with calcineurin inhibitors, there may be an increased risk of hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy induced by calcineurin inhibitors.

Additional information