Rapamune · 4.3 Contraindications · 2

HOS-084102 · has-adverse-reaction-information · PDF-Seite 11

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation The most commonly reported adverse reactions (occurring in 10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH). The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases. The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Most patients were on immunosuppressive regimens, which included Rapamune in combination with other immunosuppressive agents. System organ Very common Common Uncommon Rare Frequency class (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 not known <1/10) <1/100) to (cannot be <1/1,000) estimated from available data) Infections and Pneumonia; Sepsis; Clostridium infestations Fungal infection; Pyelonephritis; difficile colitis; Viral infection; Cytomegalo- Mycobacterial Bacterial virus infection; infection infection; Herpes zoster (including Herpes simplex caused by the tuberculosis);

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HOS-084108 · has-adverse-reaction-information · PDF-Seite 31

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation The most commonly reported adverse reactions (occurring in 10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH). The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases. The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 31 Most patients were on immunosuppressive regimens, which included Rapamune in combination with other immunosuppressive agents. System organ Very common Common Uncommon Rare Frequency class (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 not known <1/10) <1/100) to (cannot be <1/1,000) estimated from available data) Infections and Pneumonia; Sepsis; Clostridium infestations Fungal infection; Pyelonephritis; difficile colitis; Viral infection; Cytomegalo- Mycobacterial Bacterial virus infection; infection infection; Herpes zoster (including Herpes simplex

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HOS-084098 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Rapamune oral solution contains soya oil. Patients allergic to peanut or soya must not take this medicine.

HOS-084104 · has-contraindication-information · PDF-Seite 25

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 25

HOS-084097 · has-indication-information · PDF-Seite 2

Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued (see sections 4.2 and 5.1). Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function (see sections 4.2 and 5.1).

HOS-084103 · has-indication-information · PDF-Seite 22

Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued (see sections 4.2 and 5.1). 22 Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function (see sections 4.2 and 5.1).

HOS-084106 · has-interaction-information · PDF-Seite 29

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4). Rifampicin (CYP3A4 inducer) Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4). Ketoconazole (CYP3A4 inhibitor) Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus C max, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4). Voriconazole (CYP3A4 inhibitor) Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4). Diltiazem (CYP3A4 inhibitor) The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary. Verapamil (CYP3A

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HOS-084100 · has-interaction-information · PDF-Seite 8

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4). Rifampicin (CYP3A4 inducer) Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4). Ketoconazole (CYP3A4 inhibitor) Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus C max, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4). 8 Voriconazole (CYP3A4 inhibitor) Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4). Diltiazem (CYP3A4 inhibitor) The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored

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HOS-084107 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped (see section 4.5). Pregnancy There are no or limited amount of data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune should not be used during pregnancy unless clearly necessary. Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped. Breast-feeding Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is unknown whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during treatment with Rapamune. Fertility Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

HOS-084101 · has-pregnancy-information · PDF-Seite 10

Women of childbearing potential Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped (see section 4.5). Pregnancy There are no or limited amount of data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune should not be used during pregnancy unless clearly necessary. Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped. Breast-feeding Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is unknown whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during treatment with Rapamune. 10 Fertility Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

HOS-084099 · has-warning-information · PDF-Seite 5

Rapamune has not been adequately studied in renal transplant patients at high immunological risk, therefore use is not recommended in this group of patients (see section 5.1). In renal transplant patients with delayed graft function, sirolimus may delay recovery of renal function. Hypersensitivity reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see section 4.8). Concomitant therapy Immunosuppressive agents (Renal transplant patients only) Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimus in combination with other immunosuppressive agents has not been extensively investigated. Renal function should be monitored during concomitant administration of Rapamune and ciclosporin. Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function. Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had 5 lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin. The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended. Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1). Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1). New onset nephrosis (nephroti

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HOS-084105 · has-warning-information · PDF-Seite 26

Rapamune has not been adequately studied in renal transplant patients at high immunological risk, therefore use is not recommended in this group of patients (see section 5.1). In renal transplant patients with delayed graft function, sirolimus may delay recovery of renal function. Hypersensitivity reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see section 4.8). Concomitant therapy Immunosuppressive agents (Renal transplant patients only) Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimus in combination with other immunosuppressive agents has not been extensively investigated. Renal function should be monitored during concomitant administration of Rapamune and ciclosporin. Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function. Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin. The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended. Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1). Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in th

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