ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 5

2 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains 1 mg sirolimus. For excipients, see PHARMACEUTICAL FORM Oral solution. 4. CLINICAL PARTICULARS Therapeutic indications 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 cyclosporine microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued (refer to sections 4.2 and 5.1). 4.2 Posology and method of administration Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Adults Initial Therapy (2 to 3 months post-transplantation): The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualised, to obtain whole blood trough levels of 4 to 12 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune therapy should be optimised with a tapering regimen of steroids and cyclosporine microemulsion. Suggested 6

3 cyclosporine trough concentration ranges for the first 2-3 months after transplantation are ng/ml (monoclonal assay or equivalent technique). Maintenance Therapy: Cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune should be given with corticosteroids. In patients for whom cyclosporine withdrawal is either unsuccessful or cannot be attempted, the combination of cyclosporine and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted. Black Recipients: There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients. Use in children and adolescents: There is insufficient experience to recommend the use of sirolimus in children and adolescents. Limited pharmacokinetic information is available in children (see Pharmacokinetic Properties, section 5.2). Elderly patients (> 65 years): Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. Patients with renal impairment: No dosage adjustment is required (see Pharmacokinetic properties, section 5.2). Patients with mild or moderate hepatic impairment: It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. It is not necessary to modify the Rapamune loading dose (see Pharmacokinetic properties, section 5.2). Sirolimus pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Therapeutic drug monitoring: Most patients who received 2 mg of Rapamune 4 hours after cyclosporine had whole blood trough concentrations of sirolimus within the 4 to 12 ng/ml target range. Optimal therapy requires therapeutic drug concentration monitoring in all patients. Whole blood sirolimus levels should be closely monitored in the following populations: (1) in patients with hepatic impairment; (2) when strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketaconazole) of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5); and/or (3) if cyclosporine dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements. 7

4 To minimise variability, Rapamune should be taken at the same time in relation to cyclosporine, 4 hours after the cyclosporin dose, and consistently either with or without food (see Pharmacokinetic properties, section 5.2). Optimally, adjustments in Rapamune dosage should be based on more than a single trough level obtained >5 days after a previous dosing change. Following the discontinuation of cyclosporine therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Cyclosporine inhibits the metabolism of sirolimus, and consequently, sirolimus levels will decrease when cyclosporine is discontinued unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of cyclosporine elimination. The recommended ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods, with either ultraviolet or mass spectrometric detection, yield results that are approximately 20% lower than the immunoassay whole blood concentration determinations. Adjustments to the targeted range should be made according to the assay utilised to determine sirolimus trough concentrations. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters. Other considerations for use: Cyclosporine (microemulsion) and other medicinal or non-medicinal products may interact with sirolimus (see section 4.5) Contraindications Rapamune is contra-indicated in patients with a hypersensitivity to sirolimus or any of the excipients Special warnings and special precautions for use Rapamune is for oral administration only. Rapamune has been administered concurrently with the following agents in clinical studies: cyclosporine, azathioprine, mycophenolate mofetil, corticosteroids, and cytotoxic antibodies. Rapamune in combination with other immunosuppressive agents has not been extensively investigated. Rapamune has not been adequately studied in patients at high immunological risk. 8

5 The pharmacokinetics of Rapamune have not been studied in patients with severe hepatic impairment. It is recommended that sirolimus whole blood trough levels be closely monitored in hepatically impaired patients. Co-administration of Rapamune with strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketoconazole) of CYP3A4 is not recommended unless the benefit outweighs the risk due to the potential interaction. It is recommended that sirolimus whole blood trough levels be closely monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5). Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see Undesirable Effects, section 4.8). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune, should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia. In the limited number of patients studied, the concomitant administration of Rapamune and HMG- CoA reductase inhibitors and/or fibrates was well tolerated. Patients administered Rapamune, in conjunction with an HMG-CoA reductase inhibitor or a fibrate, should be monitored for the development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics of these agents Renal function should be monitored during concomitant administration of Rapamune and cyclosporine. 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. 9

6 Patients treated with cyclosporine and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with cyclosporine and placebo or azathioprine controls. Patients who were successfully withdrawn from cyclosporine had lower serum creatinine levels and higher calculated glomerular filtration rates compared to patients remaining on cyclosporine. Until further clinical data are available, the continued co-administration of cyclosporine and Rapamune as maintenance therapy cannot be recommended Interaction with other medicinal products and other forms of interaction 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 systemically absorbed sirolimus may be influenced by substances that affect these proteins. Cyclosporine (CYP3A4 substrate): The rate and extent of sirolimus absorption was significantly affected by CsA. Microemulsion CsA, administered 4 hours prior to sirolimus, increased the sirolimus AUC, C max, and t max 1.8-fold, 1.4-fold, and 1.6-fold, respectively. Single-dose sirolimus did not affect the pharmacokinetics of cyclosporine (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. Based on the design of large Phase III clinical trials, it is recommended that Rapamune be administered 4 hours after cyclosporine (microemulsion). 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 C max by approximately 82% and 71%, respectively. If rifampicin is administered with sirolimus, the dose of sirolimus should be initially increased to 8-times the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of rifampicin therapy, the dose of sirolimus should be gradually reduced to the original maintenance dose. Ketoconazole (CYP3A4 inhibitor): Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure as reflected by increases in sirolimus C max, t max, and AUC of 4.3-fold, 1.4-fold, and 10.9-fold, respectively. If ketoconazole is administered with sirolimus, the dose of sirolimus should be initially reduced to 1/6 the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of ketoconazole therapy, the dose of sirolimus should be increased to the original maintenance dose. 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 C max, t max, 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. 10

7 Oral contraceptives: No clinically significant pharmacokinetic interaction was observed between sirolimus and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol. Although the results of a single dose drug interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long term treatment with Rapamune. Other possible interactions: Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g. calcium channel blockers: nicardipine, verapamil; antifungal agents: clotrimazole, fluconazole, itraconazole; macrolide antibiotics: clarithromycin, erythromycin, troleandomycin; gastrointestinal prokinetic agents: cisapride, metoclopramide; other substances: bromocriptine, cimetidine, danazol, protease inhibitors). Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; antibiotics: rifabutin). Although sirolimus inhibits human liver microsomal cytochrome P 450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the drug is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels. Grapefruit juice affects CYP3A4 mediated metabolism and should therefore be avoided No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole Pregnancy and lactation There are no adequate data from the use of Rapamune in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans in 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. Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in nursing infants from sirolimus, nursing should be discontinued during therapy Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed Undesirable effects The list below contains adverse reactions seen in clinical trials and post-marketing reports. Only events for which there is at least reasonable suspicion of a causal relationship to Rapamune treatment 11

8 are listed. The majority of patients in clinical trials were treated with cyclosporine and corticosteroids; thus the frequency of adverse reactions listed includes Rapamune administration combined with cyclosporine and corticosteroids. The frequency of the adverse reactions taken from clinical trial data listed below was determined in four clinical trials. These included two randomised, double-blind, multicentre controlled trials in which 499 renal transplant patients received Rapamune 2 mg/day and 477 received Rapamune 5 mg/day together with cyclosporine and corticosteriods. Additionally, two open-label studies enrolled 771 patients who initially received Rapamune and cyclosporine. These patients were randomised to continue cyclosporine therapy or to have cyclosporine withdrawn after 2-3 months post-transplant. Adverse reactions are listed according to the following categories: Very common: 10 % Common: 1% and <10% Uncommon: 0.1% and <1% Body as a whole: Very common: Common: Lymphocele Abnormal healing; oedema; fungal, viral, and bacterial infections (such as Mycobacterial infections, Epstein-Barr virus, CMV, and Herpes zoster); Herpes simplex; sepsis Cardiac disorders: Common: Tachycardia Gastrointestinal disorders: Very common: Common: Uncommon: Abdominal pain, diarrhoea Stomatitis Pancreatitis Blood and the lymphatic system disorders: Very common: Anaemia; thrombocytopenia 12

9 Common: Leucopenia; thrombotic thrombocytopenic purpura/haemolytic uremia syndrome Uncommon: Lymphoma / post transplant lymphoproliferative disorder Metabolism and nutrition disorders: Very common: Hypercholesterolemia, hypertriglyceridemia (hyperlipemia); hypokalaemia; increased lactic dehydrogenase (LDH) Common: Liver function tests abnormal. Musculoskeletal, connective tissue and bone disorders: Very common: Common: Arthralgia Bone necrosis Respiratory, thoracic and mediastinal disorders: Common: Epistaxis; pneumonia Skin and subcutaneous tissue disorders: Very common: Common: Acne Rash Renal and urinary disorders: Very common: Common: Urinary tract infection Pyelonephritis Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4). Cases of pneumonitis with no identified infectious etiology, sometimes with an interstitial pattern, have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, pneumonitis has resolved upon discontinuation of Rapamune Overdose 13

10 At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent. 5. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: selective immunosuppressant agents. ATC code: L04A A10. Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of cyclosporine, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mtor), a critical kinase for cell cycle progression. The inhibition of mtor results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression. In animals, sirolimus has a direct effect on T and B cell activation suppressing immune mediated reactions such as allograft rejection. Patients at low to moderate immunological risk were studied in the cyclosporine elimination-sirolimus maintenance trials which included patients receiving a renal allograft from a cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included. Cyclosporine was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400 µmol/l, or who had inadequate renal function to support cyclosporine withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in the cyclosporine eliminationsirolimus maintenance trials and are not recommended for this treatment regimen Pharmacokinetic properties Following oral administration, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered cyclosporine (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62±16h. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements. 14

11 Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion cyclosporine (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; C max,ss 12.2±6.2 ng/ml, t max,ss 3.01±2.40h, AUC τ,ss 158±70 ng h/ml, CL/F/W 182±72 ml/h/kg (parameters calculated from LC-MS/MS assay results). There was no significant difference in any of these parameters over time up to 6 months after transplantation. Mean sirolimus whole blood trough levels from the same phase III trial were 9 ng/ml (5 to 14 ng/ml, immunoassay; n=226) for the 2 mg per day dose and 17 ng/ml (10 to 28 ng/ml, immunoassay; n=219) for the 5 mg per day dose. Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [ 14 C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine. Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus. There was a 34% decrease in the peak blood sirolimus concentration (C max ), a 3.5-fold increase in the time to peak concentration (t max ), and a 35% increase in total exposure (AUC). It is recommended that Rapamune be taken consistently either with or without food. The use of orange juice and water to dilute Rapamune were equivalent with respect to C max, and AUC. Grapefruit juice affects CYP3A4 mediated metabolism and must therefore be avoided. In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 ml/h/kg) than for older paediatric patients (450 ml/h/kg) as compared with adults (287 ml/h/kg). There was a large variability for individuals within the age groups. In mild and moderate hepatically impaired patients (Child-Pugh classification of A or B), mean values for sirolimus AUC and t 1/2 were increased 61% and 43% respectively and CL/F was decreased 33% compared to normal healthy subjects. Sirolimus pharmacokinetics were not evaluated in patients with severe hepatic impairment. The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients). 15

12 Preclinical safety data Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis. Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance. In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification). See Pregnancy and lactation, section PHARMACEUTICAL PARTICULARS List of excipients Polysorbate 80, Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate) Incompatibilities Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice. See Instructions for use and handling, section Shelf life 16

13 18 months. 30 days for opened bottle. 24 hours in the dosing syringe (at room temperature, but not to exceed 25 C). After dilution, (see Instructions for use and handling, section 6.6) the preparation should be used immediately Special precautions for storage Store at 2 C to 8 C (in a refrigerator). Store in the original container in order to protect from light. If necessary, the patient may store the bottles at room temperatures up to 25 C for a short period of time (24 hours) Nature and contents of container 60 ml or 150 ml type III amber glass bottles with syringe adapter and 30 amber, plastic dosing syringes Instructions for use and handling The dosing syringe should be used to withdraw the prescribed amount of Rapamune from the bottle. Empty the correct amount of Rapamune from the syringe into only a glass or plastic container with at least 60 ml of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume (minimum of 120 ml) of water or orange juice, stir vigorously, and drink at once. 7. MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd. 17

14 Huntercombe Lane South Taplow, Maidenhead Berkshire, SL6 0PH United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 18

15 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/1 ml oral solution. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains 1 mg sirolimus. For excipients, see PHARMACEUTICAL FORM Oral solution. 4. CLINICAL PARTICULARS Therapeutic indications 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 cyclosporine microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued (refer to sections 4.2 and 5.1). 4.2 Posology and method of administration Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Adults Initial Therapy (2 to 3 months post-transplantation): The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualised, to obtain whole blood trough levels of 4 to 12 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune therapy should be optimised with a tapering regimen of steroids and cyclosporine microemulsion. Suggested 19

16 cyclosporine trough concentration ranges for the first 2-3 months after transplantation are ng/ml (monoclonal assay or equivalent technique). Maintenance Therapy: Cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune should be given with corticosteroids. In patients for whom cyclosporine withdrawal is either unsuccessful or cannot be attempted, the combination of cyclosporine and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted. Black Recipients: There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients. Use in children and adolescents: There is insufficient experience to recommend the use of sirolimus in children and adolescents. Limited pharmacokinetic information is available in children (see Pharmacokinetic Properties, section 5.2). Elderly patients (> 65 years): Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. Patients with renal impairment: No dosage adjustment is required (see Pharmacokinetic properties, section 5.2). Patients with mild or moderate hepatic impairment: It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. It is not necessary to modify the Rapamune loading dose (see Pharmacokinetic properties, section 5.2). Sirolimus pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Therapeutic drug monitoring: Most patients who received 2 mg of Rapamune 4 hours after cyclosporine had whole blood trough concentrations of sirolimus within the 4 to 12 ng/ml target range. Optimal therapy requires therapeutic drug concentration monitoring in all patients. Whole blood sirolimus levels should be closely monitored in the following populations: (1) in patients with hepatic impairment; (2) when strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketaconazole) of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5); and/or (3) if cyclosporine dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements. 20

17 To minimise variability, Rapamune should be taken at the same time in relation to cyclosporine, 4 hours after the cyclosporin dose, and consistently either with or without food (see Pharmacokinetic properties, section 5.2). Optimally, adjustments in Rapamune dosage should be based on more than a single trough level obtained >5 days after a previous dosing change. Following the discontinuation of cyclosporine therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Cyclosporine inhibits the metabolism of sirolimus, and consequently, sirolimus levels will decrease when cyclosporine is discontinued unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of cyclosporine elimination. The recommended ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods, with either ultraviolet or mass spectrometric detection, yield results that are approximately 20% lower than the immunoassay whole blood concentration determinations. Adjustments to the targeted range should be made according to the assay utilised to determine sirolimus trough concentrations. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters. Other considerations for use: Cyclosporine (microemulsion) and other medicinal or non-medicinal products may interact with sirolimus (see section 4.5) Contraindications Rapamune is contra-indicated in patients with a hypersensitivity to sirolimus or any of the excipients Special warnings and special precautions for use Rapamune is for oral administration only. Rapamune has been administered concurrently with the following agents in clinical studies: cyclosporine, azathioprine, mycophenolate mofetil, corticosteroids, and cytotoxic antibodies. Rapamune in combination with other immunosuppressive agents has not been extensively investigated. Rapamune has not been adequately studied in patients at high immunological risk. 21

18 The pharmacokinetics of Rapamune have not been studied in patients with severe hepatic impairment. It is recommended that sirolimus whole blood trough levels be closely monitored in hepatically impaired patients. Co-administration of Rapamune with strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketoconazole) of CYP3A4 is not recommended unless the benefit outweighs the risk due to the potential interaction. It is recommended that sirolimus whole blood trough levels be closely monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5). Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see Undesirable Effects, section 4.8). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune, should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia. In the limited number of patients studied, the concomitant administration of Rapamune and HMG- CoA reductase inhibitors and/or fibrates was well tolerated. Patients administered Rapamune, in conjunction with an HMG-CoA reductase inhibitor or a fibrate, should be monitored for the development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics of these agents Renal function should be monitored during concomitant administration of Rapamune and cyclosporine. 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. 22

19 Patients treated with cyclosporine and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with cyclosporine and placebo or azathioprine controls. Patients who were successfully withdrawn from cyclosporine had lower serum creatinine levels and higher calculated glomerular filtration rates compared to patients remaining on cyclosporine. Until further clinical data are available, the continued co-administration of cyclosporine and Rapamune as maintenance therapy cannot be recommended Interaction with other medicinal products and other forms of interaction 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 systemically absorbed sirolimus may be influenced by substances that affect these proteins. Cyclosporine (CYP3A4 substrate): The rate and extent of sirolimus absorption was significantly affected by CsA. Microemulsion CsA, administered 4 hours prior to sirolimus, increased the sirolimus AUC, C max, and t max 1.8-fold, 1.4-fold, and 1.6-fold, respectively. Single-dose sirolimus did not affect the pharmacokinetics of cyclosporine (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. Based on the design of large Phase III clinical trials, it is recommended that Rapamune be administered 4 hours after cyclosporine (microemulsion). 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 C max by approximately 82% and 71%, respectively. If rifampicin is administered with sirolimus, the dose of sirolimus should be initially increased to 8-times the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of rifampicin therapy, the dose of sirolimus should be gradually reduced to the original maintenance dose. Ketoconazole (CYP3A4 inhibitor): Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure as reflected by increases in sirolimus C max, t max, and AUC of 4.3-fold, 1.4-fold, and 10.9-fold, respectively. If ketoconazole is administered with sirolimus, the dose of sirolimus should be initially reduced to 1/6 the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of ketoconazole therapy, the dose of sirolimus should be increased to the original maintenance dose. 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 C max, t max, 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. 23

20 Oral contraceptives: No clinically significant pharmacokinetic interaction was observed between sirolimus and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol. Although the results of a single dose drug interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long term treatment with Rapamune. Other possible interactions: Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g. calcium channel blockers: nicardipine, verapamil; antifungal agents: clotrimazole, fluconazole, itraconazole; macrolide antibiotics: clarithromycin, erythromycin, troleandomycin; gastrointestinal prokinetic agents: cisapride, metoclopramide; other substances: bromocriptine, cimetidine, danazol, protease inhibitors). Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; antibiotics: rifabutin). Although sirolimus inhibits human liver microsomal cytochrome P 450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the drug is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels. Grapefruit juice affects CYP3A4 mediated metabolism and should therefore be avoided No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole Pregnancy and lactation There are no adequate data from the use of Rapamune in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans in 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. Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in nursing infants from sirolimus, nursing should be discontinued during therapy Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed Undesirable effects The list below contains adverse reactions seen in clinical trials and post-marketing reports. Only events for which there is at least reasonable suspicion of a causal relationship to Rapamune treatment 24

21 are listed. The majority of patients in clinical trials were treated with cyclosporine and corticosteroids; thus the frequency of adverse reactions listed includes Rapamune administration combined with cyclosporine and corticosteroids. The frequency of the adverse reactions taken from clinical trial data listed below was determined in four clinical trials. These included two randomised, double-blind, multicentre controlled trials in which 499 renal transplant patients received Rapamune 2 mg/day and 477 received Rapamune 5 mg/day together with cyclosporine and corticosteriods. Additionally, two open-label studies enrolled 771 patients who initially received Rapamune and cyclosporine. These patients were randomised to continue cyclosporine therapy or to have cyclosporine withdrawn after 2-3 months post-transplant. Adverse reactions are listed according to the following categories: Very common: 10 % Common: 1% and <10% Uncommon: 0.1% and <1% Body as a whole: Very common: Common: Lymphocele Abnormal healing; oedema; fungal, viral, and bacterial infections (such as Mycobacterial infections, Epstein-Barr virus, CMV, and Herpes zoster); Herpes simplex; sepsis Cardiac disorders: Common: Tachycardia Gastrointestinal disorders: Very common: Common: Uncommon: Abdominal pain, diarrhoea Stomatitis Pancreatitis Blood and the lymphatic system disorders: Very common: Anaemia; thrombocytopenia 25

22 Common: Leucopenia; thrombotic thrombocytopenic purpura/haemolytic uremia syndrome Uncommon: Lymphoma / post transplant lymphoproliferative disorder Metabolism and nutrition disorders: Very common: Hypercholesterolemia, hypertriglyceridemia (hyperlipemia); hypokalaemia; increased lactic dehydrogenase (LDH) Common: Liver function tests abnormal. Musculoskeletal, connective tissue and bone disorders: Very common: Common: Arthralgia Bone necrosis Respiratory, thoracic and mediastinal disorders: Common: Epistaxis; pneumonia Skin and subcutaneous tissue disorders: Very common: Common: Acne Rash Renal and urinary disorders: Very common: Common: Urinary tract infection Pyelonephritis Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4). Cases of pneumonitis with no identified infectious etiology, sometimes with an interstitial pattern, have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, pneumonitis has resolved upon discontinuation of Rapamune Overdose 26

23 At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent. 5. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: selective immunosuppressant agents. ATC code: L04A A10. Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of cyclosporine, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mtor), a critical kinase for cell cycle progression. The inhibition of mtor results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression. In animals, sirolimus has a direct effect on T and B cell activation suppressing immune mediated reactions such as allograft rejection. Patients at low to moderate immunological risk were studied in the cyclosporine elimination-sirolimus maintenance trials which included patients receiving a renal allograft from a cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included. Cyclosporine was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400 µmol/l, or who had inadequate renal function to support cyclosporine withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in the cyclosporine eliminationsirolimus maintenance trials and are not recommended for this treatment regimen Pharmacokinetic properties Following oral administration, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered cyclosporine (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62±16h. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements. 27

24 Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion cyclosporine (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; C max,ss 12.2±6.2 ng/ml, t max,ss 3.01±2.40h, AUC τ,ss 158±70 ng h/ml, CL/F/W 182±72 ml/h/kg (parameters calculated from LC-MS/MS assay results). There was no significant difference in any of these parameters over time up to 6 months after transplantation. Mean sirolimus whole blood trough levels from the same phase III trial were 9 ng/ml (5 to 14 ng/ml, immunoassay; n=226) for the 2 mg per day dose and 17 ng/ml (10 to 28 ng/ml, immunoassay; n=219) for the 5 mg per day dose. Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [ 14 C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine. Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus. There was a 34% decrease in the peak blood sirolimus concentration (C max ), a 3.5-fold increase in the time to peak concentration (t max ), and a 35% increase in total exposure (AUC). It is recommended that Rapamune be taken consistently either with or without food. The use of orange juice and water to dilute Rapamune were equivalent with respect to C max, and AUC. Grapefruit juice affects CYP3A4 mediated metabolism and must therefore be avoided. In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 ml/h/kg) than for older paediatric patients (450 ml/h/kg) as compared with adults (287 ml/h/kg). There was a large variability for individuals within the age groups. In mild and moderate hepatically impaired patients (Child-Pugh classification of A or B), mean values for sirolimus AUC and t 1/2 were increased 61% and 43% respectively and CL/F was decreased 33% compared to normal healthy subjects. Sirolimus pharmacokinetics were not evaluated in patients with severe hepatic impairment. The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients) Preclinical safety data 28

25 Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis. Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance. In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification). See Pregnancy and lactation, section PHARMACEUTICAL PARTICULARS List of excipients Polysorbate 80, Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate) Incompatibilities Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice. See Instructions for use and handling, section Shelf life 29

26 18 months. Use sachet immediately after opening After dilution, (see Instructions for use and handling, section 6.6) the preparation should be used immediately Special precautions for storage Store at 2 C to 8 C (in a refrigerator). If necessary, the patient may store the sachets at room temperatures up to 25 C for a short period of time (24 hours) Nature and contents of container 1 ml laminated aluminium foil sachets in cartons of Instructions for use and handling Squeeze the entire contents of the sachet into a glass or plastic container only, with at least 60 ml of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume (minimum of 120 ml) of water or orange juice, stir vigorously, and drink at once. 7. MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd. Huntercombe Lane South Taplow, Maidenhead Berkshire, SL6 0PH United Kingdom 30

27 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 31

28 1. NAME OF THE MEDICINAL PRODUCT Rapamune 2 mg/2 ml oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains 1 mg sirolimus. For excipients, see PHARMACEUTICAL FORM Oral solution. 4. CLINICAL PARTICULARS Therapeutic indications 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 cyclosporine microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued (refer to sections 4.2 and 5.1). 4.2 Posology and method of administration Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Adults Initial Therapy (2 to 3 months post-transplantation): The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualised, to obtain whole blood trough levels of 4 to 12 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune therapy should be optimised with a tapering regimen of steroids and cyclosporine microemulsion. Suggested 32

29 cyclosporine trough concentration ranges for the first 2-3 months after transplantation are ng/ml (monoclonal assay or equivalent technique). Maintenance Therapy: Cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune should be given with corticosteroids. In patients for whom cyclosporine withdrawal is either unsuccessful or cannot be attempted, the combination of cyclosporine and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted. Black Recipients: There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients. Use in children and adolescents: There is insufficient experience to recommend the use of sirolimus in children and adolescents. Limited pharmacokinetic information is available in children (see Pharmacokinetic Properties, section 5.2). Elderly patients (> 65 years): Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. Patients with renal impairment: No dosage adjustment is required (see Pharmacokinetic properties, section 5.2). Patients with mild or moderate hepatic impairment: It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. It is not necessary to modify the Rapamune loading dose (see Pharmacokinetic properties, section 5.2). Sirolimus pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Therapeutic drug monitoring: Most patients who received 2 mg of Rapamune 4 hours after cyclosporine had whole blood trough concentrations of sirolimus within the 4 to 12 ng/ml target range. Optimal therapy requires therapeutic drug concentration monitoring in all patients. Whole blood sirolimus levels should be closely monitored in the following populations: (1) in patients with hepatic impairment; (2) when strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketaconazole) of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5); and/or (3) if cyclosporine dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements. 33

30 To minimise variability, Rapamune should be taken at the same time in relation to cyclosporine, 4 hours after the cyclosporin dose, and consistently either with or without food (see Pharmacokinetic properties, section 5.2). Optimally, adjustments in Rapamune dosage should be based on more than a single trough level obtained >5 days after a previous dosing change. Following the discontinuation of cyclosporine therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Cyclosporine inhibits the metabolism of sirolimus, and consequently, sirolimus levels will decrease when cyclosporine is discontinued unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of cyclosporine elimination. The recommended ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods, with either ultraviolet or mass spectrometric detection, yield results that are approximately 20% lower than the immunoassay whole blood concentration determinations. Adjustments to the targeted range should be made according to the assay utilised to determine sirolimus trough concentrations. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters. Other considerations for use: Cyclosporine (microemulsion) and other medicinal or non-medicinal products may interact with sirolimus (see section 4.5) Contraindications Rapamune is contra-indicated in patients with a hypersensitivity to sirolimus or any of the excipients Special warnings and special precautions for use Rapamune is for oral administration only. Rapamune has been administered concurrently with the following agents in clinical studies: cyclosporine, azathioprine, mycophenolate mofetil, corticosteroids, and cytotoxic antibodies. Rapamune in combination with other immunosuppressive agents has not been extensively investigated. Rapamune has not been adequately studied in patients at high immunological risk. 34

31 The pharmacokinetics of Rapamune have not been studied in patients with severe hepatic impairment. It is recommended that sirolimus whole blood trough levels be closely monitored in hepatically impaired patients. Co-administration of Rapamune with strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketoconazole) of CYP3A4 is not recommended unless the benefit outweighs the risk due to the potential interaction. It is recommended that sirolimus whole blood trough levels be closely monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5). Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see Undesirable Effects, section 4.8). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune, should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia. In the limited number of patients studied, the concomitant administration of Rapamune and HMG- CoA reductase inhibitors and/or fibrates was well tolerated. Patients administered Rapamune, in conjunction with an HMG-CoA reductase inhibitor or a fibrate, should be monitored for the development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics of these agents Renal function should be monitored during concomitant administration of Rapamune and cyclosporine. 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. 35

32 Patients treated with cyclosporine and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with cyclosporine and placebo or azathioprine controls. Patients who were successfully withdrawn from cyclosporine had lower serum creatinine levels and higher calculated glomerular filtration rates compared to patients remaining on cyclosporine. Until further clinical data are available, the continued co-administration of cyclosporine and Rapamune as maintenance therapy cannot be recommended Interaction with other medicinal products and other forms of interaction 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 systemically absorbed sirolimus may be influenced by substances that affect these proteins. Cyclosporine (CYP3A4 substrate): The rate and extent of sirolimus absorption was significantly affected by CsA. Microemulsion CsA, administered 4 hours prior to sirolimus, increased the sirolimus AUC, C max, and t max 1.8-fold, 1.4-fold, and 1.6-fold, respectively. Single-dose sirolimus did not affect the pharmacokinetics of cyclosporine (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. Based on the design of large Phase III clinical trials, it is recommended that Rapamune be administered 4 hours after cyclosporine (microemulsion). 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 C max by approximately 82% and 71%, respectively. If rifampicin is administered with sirolimus, the dose of sirolimus should be initially increased to 8-times the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of rifampicin therapy, the dose of sirolimus should be gradually reduced to the original maintenance dose. Ketoconazole (CYP3A4 inhibitor): Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure as reflected by increases in sirolimus C max, t max, and AUC of 4.3-fold, 1.4-fold, and 10.9-fold, respectively. If ketoconazole is administered with sirolimus, the dose of sirolimus should be initially reduced to 1/6 the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of ketoconazole therapy, the dose of sirolimus should be increased to the original maintenance dose. 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 C max, t max, 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. 36

33 Oral contraceptives: No clinically significant pharmacokinetic interaction was observed between sirolimus and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol. Although the results of a single dose drug interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long term treatment with Rapamune. Other possible interactions: Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g. calcium channel blockers: nicardipine, verapamil; antifungal agents: clotrimazole, fluconazole, itraconazole; macrolide antibiotics: clarithromycin, erythromycin, troleandomycin; gastrointestinal prokinetic agents: cisapride, metoclopramide; other substances: bromocriptine, cimetidine, danazol, protease inhibitors). Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; antibiotics: rifabutin). Although sirolimus inhibits human liver microsomal cytochrome P 450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the drug is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels. Grapefruit juice affects CYP3A4 mediated metabolism and should therefore be avoided No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole Pregnancy and lactation There are no adequate data from the use of Rapamune in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans in 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. Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in nursing infants from sirolimus, nursing should be discontinued during therapy Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed Undesirable effects The list below contains adverse reactions seen in clinical trials and post-marketing reports. Only events for which there is at least reasonable suspicion of a causal relationship to Rapamune treatment 37

34 are listed. The majority of patients in clinical trials were treated with cyclosporine and corticosteroids; thus the frequency of adverse reactions listed includes Rapamune administration combined with cyclosporine and corticosteroids. The frequency of the adverse reactions taken from clinical trial data listed below was determined in four clinical trials. These included two randomised, double-blind, multicentre controlled trials in which 499 renal transplant patients received Rapamune 2 mg/day and 477 received Rapamune 5 mg/day together with cyclosporine and corticosteriods. Additionally, two open-label studies enrolled 771 patients who initially received Rapamune and cyclosporine. These patients were randomised to continue cyclosporine therapy or to have cyclosporine withdrawn after 2-3 months post-transplant. Adverse reactions are listed according to the following categories: Very common: 10 % Common: 1% and <10% Uncommon: 0.1% and <1% Body as a whole: Very common: Common: Lymphocele Abnormal healing; oedema; fungal, viral, and bacterial infections (such as Mycobacterial infections, Epstein-Barr virus, CMV, and Herpes zoster); Herpes simplex; sepsis Cardiac disorders: Common: Tachycardia Gastrointestinal disorders: Very common: Common: Uncommon: Abdominal pain, diarrhoea Stomatitis Pancreatitis Blood and the lymphatic system disorders: Very common: Anaemia; thrombocytopenia 38

35 Common: Leucopenia; thrombotic thrombocytopenic purpura/haemolytic uremia syndrome Uncommon: Lymphoma / post transplant lymphoproliferative disorder Metabolism and nutrition disorders: Very common: Hypercholesterolemia, hypertriglyceridemia (hyperlipemia); hypokalaemia; increased lactic dehydrogenase (LDH) Common: Liver function tests abnormal. Musculoskeletal, connective tissue and bone disorders: Very common: Common: Arthralgia Bone necrosis Respiratory, thoracic and mediastinal disorders: Common: Epistaxis; pneumonia Skin and subcutaneous tissue disorders: Very common: Common: Acne Rash Renal and urinary disorders: Very common: Common: Urinary tract infection Pyelonephritis Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4). Cases of pneumonitis with no identified infectious etiology, sometimes with an interstitial pattern, have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, pneumonitis has resolved upon discontinuation of Rapamune Overdose 39

36 At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent. 5. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: selective immunosuppressant agents. ATC code: L04A A10. Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of cyclosporine, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mtor), a critical kinase for cell cycle progression. The inhibition of mtor results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression. In animals, sirolimus has a direct effect on T and B cell activation suppressing immune mediated reactions such as allograft rejection. Patients at low to moderate immunological risk were studied in the cyclosporine elimination-sirolimus maintenance trials which included patients receiving a renal allograft from a cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included. Cyclosporine was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400 µmol/l, or who had inadequate renal function to support cyclosporine withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in the cyclosporine eliminationsirolimus maintenance trials and are not recommended for this treatment regimen Pharmacokinetic properties Following oral administration, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered cyclosporine (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62±16h. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements. 40

37 Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion cyclosporine (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; C max,ss 12.2±6.2 ng/ml, t max,ss 3.01±2.40h, AUC τ,ss 158±70 ng h/ml, CL/F/W 182±72 ml/h/kg (parameters calculated from LC-MS/MS assay results). There was no significant difference in any of these parameters over time up to 6 months after transplantation. Mean sirolimus whole blood trough levels from the same phase III trial were 9 ng/ml (5 to 14 ng/ml, immunoassay; n=226) for the 2 mg per day dose and 17 ng/ml (10 to 28 ng/ml, immunoassay; n=219) for the 5 mg per day dose. Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [ 14 C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine. Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus. There was a 34% decrease in the peak blood sirolimus concentration (C max ), a 3.5-fold increase in the time to peak concentration (t max ), and a 35% increase in total exposure (AUC). It is recommended that Rapamune be taken consistently either with or without food. The use of orange juice and water to dilute Rapamune were equivalent with respect to C max, and AUC. Grapefruit juice affects CYP3A4 mediated metabolism and must therefore be avoided. In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 ml/h/kg) than for older paediatric patients (450 ml/h/kg) as compared with adults (287 ml/h/kg). There was a large variability for individuals within the age groups. In mild and moderate hepatically impaired patients (Child-Pugh classification of A or B), mean values for sirolimus AUC and t 1/2 were increased 61% and 43% respectively and CL/F was decreased 33% compared to normal healthy subjects. Sirolimus pharmacokinetics were not evaluated in patients with severe hepatic impairment. The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients). 41

38 Preclinical safety data Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis. Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance. In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification). See Pregnancy and lactation, section PHARMACEUTICAL PARTICULARS List of excipients Polysorbate 80, Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate) Incompatibilities Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice. See Instructions for use and handling, section Shelf life 42

39 18 months. Use sachet immediately after opening. After dilution, (see Instructions for use and handling, section 6.6) the preparation should be used immediately Special precautions for storage Store at 2 C to 8 C (in a refrigerator). If necessary, the patient may store both the sachets and the bottles at room temperatures up to 25 C for a short period of time (24 hours) Nature and contents of container 2 ml laminated aluminium foil sachets in cartons of Instructions for use and handling Squeeze the entire contents of the sachet into a glass or plastic container only, with at least 60 ml of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume (minimum of 120 ml) of water or orange juice, stir vigorously, and drink at once. 7. MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd. Huntercombe Lane South Taplow, Maidenhead Berkshire, SL6 0PH United Kingdom 43

40 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 44

41 1. NAME OF THE MEDICINAL PRODUCT Rapamune 5 mg/5 ml oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each ml contains 1 mg sirolimus. For excipients, see PHARMACEUTICAL FORM Oral solution. 4. CLINICAL PARTICULARS Therapeutic indications 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 cyclosporine microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued (refer to sections 4.2 and 5.1). 4.2 Posology and method of administration Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Adults Initial Therapy (2 to 3 months post-transplantation): The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily. The Rapamune dose should then be individualised, to obtain whole blood trough levels of 4 to 12 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune therapy should be optimised with a tapering regimen of steroids and cyclosporine microemulsion. Suggested 45

42 cyclosporine trough concentration ranges for the first 2-3 months after transplantation are ng/ml (monoclonal assay or equivalent technique). Maintenance Therapy: Cyclosporine should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see Therapeutic drug monitoring). Rapamune should be given with corticosteroids. In patients for whom cyclosporine withdrawal is either unsuccessful or cannot be attempted, the combination of cyclosporine and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted. Black Recipients: There is limited information indicating that black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in black recipients. Use in children and adolescents: There is insufficient experience to recommend the use of sirolimus in children and adolescents. Limited pharmacokinetic information is available in children (see Pharmacokinetic Properties, section 5.2). Elderly patients (> 65 years): Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. Patients with renal impairment: No dosage adjustment is required (see Pharmacokinetic properties, section 5.2). Patients with mild or moderate hepatic impairment: It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. It is not necessary to modify the Rapamune loading dose (see Pharmacokinetic properties, section 5.2). Sirolimus pharmacokinetics have not been evaluated in patients with severe hepatic impairment. Therapeutic drug monitoring: Most patients who received 2 mg of Rapamune 4 hours after cyclosporine had whole blood trough concentrations of sirolimus within the 4 to 12 ng/ml target range. Optimal therapy requires therapeutic drug concentration monitoring in all patients. Whole blood sirolimus levels should be closely monitored in the following populations: (1) in patients with hepatic impairment; (2) when strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketaconazole) of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5); and/or (3) if cyclosporine dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements. 46

43 To minimise variability, Rapamune should be taken at the same time in relation to cyclosporine, 4 hours after the cyclosporin dose, and consistently either with or without food (see Pharmacokinetic properties, section 5.2). Optimally, adjustments in Rapamune dosage should be based on more than a single trough level obtained >5 days after a previous dosing change. Following the discontinuation of cyclosporine therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Cyclosporine inhibits the metabolism of sirolimus, and consequently, sirolimus levels will decrease when cyclosporine is discontinued unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of cyclosporine (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of cyclosporine elimination. The recommended ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods, with either ultraviolet or mass spectrometric detection, yield results that are approximately 20% lower than the immunoassay whole blood concentration determinations. Adjustments to the targeted range should be made according to the assay utilised to determine sirolimus trough concentrations. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters. Other considerations for use: Cyclosporine (microemulsion) and other medicinal or non-medicinal products may interact with sirolimus (see section 4.5) Contraindications Rapamune is contra-indicated in patients with a hypersensitivity to sirolimus or any of the excipients Special warnings and special precautions for use Rapamune is for oral administration only. Rapamune has been administered concurrently with the following agents in clinical studies: cyclosporine, azathioprine, mycophenolate mofetil, corticosteroids, and cytotoxic antibodies. Rapamune in combination with other immunosuppressive agents has not been extensively investigated. Rapamune has not been adequately studied in patients at high immunological risk. 47

44 The pharmacokinetics of Rapamune have not been studied in patients with severe hepatic impairment. It is recommended that sirolimus whole blood trough levels be closely monitored in hepatically impaired patients. Co-administration of Rapamune with strong inducers (e.g. rifampin, rifabutin) or inhibitors (e.g. ketoconazole) of CYP3A4 is not recommended unless the benefit outweighs the risk due to the potential interaction. It is recommended that sirolimus whole blood trough levels be closely monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5). Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see Undesirable Effects, section 4.8). Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis. As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune, should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia. In the limited number of patients studied, the concomitant administration of Rapamune and HMG- CoA reductase inhibitors and/or fibrates was well tolerated. Patients administered Rapamune, in conjunction with an HMG-CoA reductase inhibitor or a fibrate, should be monitored for the development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics of these agents Renal function should be monitored during concomitant administration of Rapamune and cyclosporine. 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. 48

45 Patients treated with cyclosporine and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with cyclosporine and placebo or azathioprine controls. Patients who were successfully withdrawn from cyclosporine had lower serum creatinine levels and higher calculated glomerular filtration rates compared to patients remaining on cyclosporine. Until further clinical data are available, the continued co-administration of cyclosporine and Rapamune as maintenance therapy cannot be recommended Interaction with other medicinal products and other forms of interaction 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 systemically absorbed sirolimus may be influenced by substances that affect these proteins. Cyclosporine (CYP3A4 substrate): The rate and extent of sirolimus absorption was significantly affected by CsA. Microemulsion CsA, administered 4 hours prior to sirolimus, increased the sirolimus AUC, C max, and t max 1.8-fold, 1.4-fold, and 1.6-fold, respectively. Single-dose sirolimus did not affect the pharmacokinetics of cyclosporine (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. Based on the design of large Phase III clinical trials, it is recommended that Rapamune be administered 4 hours after cyclosporine (microemulsion). 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 C max by approximately 82% and 71%, respectively. If rifampicin is administered with sirolimus, the dose of sirolimus should be initially increased to 8-times the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of rifampicin therapy, the dose of sirolimus should be gradually reduced to the original maintenance dose. Ketoconazole (CYP3A4 inhibitor): Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure as reflected by increases in sirolimus C max, t max, and AUC of 4.3-fold, 1.4-fold, and 10.9-fold, respectively. If ketoconazole is administered with sirolimus, the dose of sirolimus should be initially reduced to 1/6 the maintenance dose, followed by trough sampling within 5 to 7 days for purposes of therapeutic drug monitoring. Upon termination of ketoconazole therapy, the dose of sirolimus should be increased to the original maintenance dose. 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 C max, t max, 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. 49

46 Oral contraceptives: No clinically significant pharmacokinetic interaction was observed between sirolimus and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol. Although the results of a single dose drug interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long term treatment with Rapamune. Other possible interactions: Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g. calcium channel blockers: nicardipine, verapamil; antifungal agents: clotrimazole, fluconazole, itraconazole; macrolide antibiotics: clarithromycin, erythromycin, troleandomycin; gastrointestinal prokinetic agents: cisapride, metoclopramide; other substances: bromocriptine, cimetidine, danazol, protease inhibitors). Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; antibiotics: rifabutin). Although sirolimus inhibits human liver microsomal cytochrome P 450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the drug is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels. Grapefruit juice affects CYP3A4 mediated metabolism and should therefore be avoided No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole Pregnancy and lactation There are no adequate data from the use of Rapamune in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans in 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. Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in nursing infants from sirolimus, nursing should be discontinued during therapy Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed Undesirable effects The list below contains adverse reactions seen in clinical trials and post-marketing reports. Only events for which there is at least reasonable suspicion of a causal relationship to Rapamune treatment 50

47 are listed. The majority of patients in clinical trials were treated with cyclosporine and corticosteroids; thus the frequency of adverse reactions listed includes Rapamune administration combined with cyclosporine and corticosteroids. The frequency of the adverse reactions taken from clinical trial data listed below was determined in four clinical trials. These included two randomised, double-blind, multicentre controlled trials in which 499 renal transplant patients received Rapamune 2 mg/day and 477 received Rapamune 5 mg/day together with cyclosporine and corticosteriods. Additionally, two open-label studies enrolled 771 patients who initially received Rapamune and cyclosporine. These patients were randomised to continue cyclosporine therapy or to have cyclosporine withdrawn after 2-3 months post-transplant. Adverse reactions are listed according to the following categories: Very common: 10 % Common: 1% and <10% Uncommon: 0.1% and <1% Body as a whole: Very common: Common: Lymphocele Abnormal healing; oedema; fungal, viral, and bacterial infections (such as Mycobacterial infections, Epstein-Barr virus, CMV, and Herpes zoster); Herpes simplex; sepsis Cardiac disorders: Common: Tachycardia Gastrointestinal disorders: Very common: Common: Uncommon: Abdominal pain, diarrhoea Stomatitis Pancreatitis Blood and the lymphatic system disorders: Very common: Anaemia; thrombocytopenia 51

48 Common: Leucopenia; thrombotic thrombocytopenic purpura/haemolytic uremia syndrome Uncommon: Lymphoma / post transplant lymphoproliferative disorder Metabolism and nutrition disorders: Very common: Hypercholesterolemia, hypertriglyceridemia (hyperlipemia); hypokalaemia; increased lactic dehydrogenase (LDH) Common: Liver function tests abnormal. Musculoskeletal, connective tissue and bone disorders: Very common: Common: Arthralgia Bone necrosis Respiratory, thoracic and mediastinal disorders: Common: Epistaxis; pneumonia Skin and subcutaneous tissue disorders: Very common: Common: Acne Rash Renal and urinary disorders: Very common: Common: Urinary tract infection Pyelonephritis Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4). Cases of pneumonitis with no identified infectious etiology, sometimes with an interstitial pattern, have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, pneumonitis has resolved upon discontinuation of Rapamune Overdose 52

49 At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent. 5. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: selective immunosuppressant agents. ATC code: L04A A10. Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of cyclosporine, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mtor), a critical kinase for cell cycle progression. The inhibition of mtor results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression. In animals, sirolimus has a direct effect on T and B cell activation suppressing immune mediated reactions such as allograft rejection. Patients at low to moderate immunological risk were studied in the cyclosporine elimination-sirolimus maintenance trials which included patients receiving a renal allograft from a cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included. Cyclosporine was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400 µmol/l, or who had inadequate renal function to support cyclosporine withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in the cyclosporine eliminationsirolimus maintenance trials and are not recommended for this treatment regimen Pharmacokinetic properties Following oral administration, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered cyclosporine (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62±16h. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements. 53

50 Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion cyclosporine (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; C max,ss 12.2±6.2 ng/ml, t max,ss 3.01±2.40h, AUC τ,ss 158±70 ng h/ml, CL/F/W 182±72 ml/h/kg (parameters calculated from LC-MS/MS assay results). There was no significant difference in any of these parameters over time up to 6 months after transplantation. Mean sirolimus whole blood trough levels from the same phase III trial were 9 ng/ml (5 to 14 ng/ml, immunoassay; n=226) for the 2 mg per day dose and 17 ng/ml (10 to 28 ng/ml, immunoassay; n=219) for the 5 mg per day dose. Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [ 14 C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine. Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus. There was a 34% decrease in the peak blood sirolimus concentration (C max ), a 3.5-fold increase in the time to peak concentration (t max ), and a 35% increase in total exposure (AUC). It is recommended that Rapamune be taken consistently either with or without food. The use of orange juice and water to dilute Rapamune were equivalent with respect to C max, and AUC. Grapefruit juice affects CYP3A4 mediated metabolism and must therefore be avoided. In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 ml/h/kg) than for older paediatric patients (450 ml/h/kg) as compared with adults (287 ml/h/kg). There was a large variability for individuals within the age groups. In mild and moderate hepatically impaired patients (Child-Pugh classification of A or B), mean values for sirolimus AUC and t 1/2 were increased 61% and 43% respectively and CL/F was decreased 33% compared to normal healthy subjects. Sirolimus pharmacokinetics were not evaluated in patients with severe hepatic impairment. The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients). 54

51 Preclinical safety data Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis. Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance. In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification). See Pregnancy and lactation, section PHARMACEUTICAL PARTICULARS List of excipients Polysorbate 80, Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate) Incompatibilities Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice. See Instructions for use and handling, section Shelf life 55

52 18 months. Use sachet immediately after opening After dilution, (see Instructions for use and handling, section 6.6) the preparation should be used immediately Special precautions for storage Store at 2 C to 8 C (in a refrigerator). If necessary, the patient may store the sachets at room temperatures up to 25 C for a short period of time (24 hours) Nature and contents of container 5 ml laminated aluminium foil sachets in cartons of Instructions for use and handling Squeeze the entire contents of the sachet into a glass or plastic container only, with at least 60 ml of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume (minimum of 120 ml) of water or orange juice, stir vigorously, and drink at once. 7. MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd. Huntercombe Lane South Taplow, Maidenhead Berkshire, SL6 0PH United Kingdom 56

53 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 57

54 ANNEX II A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION 58

55 59

56 A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Manufacturer responsible for batch release Wyeth Medica Ireland Little Connell Newbridge, Co. Kildare Ireland Manufacturing Authorisation issued on 28 January 1999 by the Irish Medicines Board. B CONDITIONS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, 4.2) 60

57 ANNEX III LABELLING AND PACKAGE LEAFLET 61

58 A. LABELLING 62

59 TEXT FOR 60 ml OUTER CARTON (CONTAINING SYRINGES/BOTTLE IN CARTON) 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 60 ml oral solution 30 dosing syringes 1 syringe adapter 1 carrying case 5. METHOD AND ROUTE(S) OF ADMINISTRATION 63

60 Oral use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. The bottle containing Rapamune can be removed from the carton and stored directly in the refrigerator at 2 C-8 C. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 64

61 Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER S BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 65

62 TEXT FOR RAPAMUNE INTERMEDIATE CARTON: 60 ml BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 60 ml oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 66

63 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 67

64 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER(S) BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 68

65 TEXT FOR RAPAMUNE FIX-A-FORM BOTTLE LABEL: 60 ml BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 60 ml oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 69

66 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 70

67 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER(S) BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 71

68 Peel back for further information Date opened 72

69 TEXT FOR 150 ml OUTER CARTON (CONTAINING SYRINGES/BOTTLE IN CARTON) 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 150 ml oral solution 30 dosing syringes 1 syringe adapter 1 carrying case 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 73

70 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. The bottle containing Rapamune can be removed from the carton and stored directly in the refrigerator at 2 C-8 C. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd., 74

71 Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER S BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 75

72 TEXT FOR RAPAMUNE INTERMEDIATE CARTON: 150 ml BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 150 ml oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 76

73 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 77

74 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER S BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 78

75 TEXT FOR RAPAMUNE FIX-A-FORM BOTTLE LABEL: 150 ml BOTTLE 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/ml oral solution. Sirolimus 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 150 ml oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 79

76 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). Protect from light. Use within 30 days after opening bottle. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 80

77 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER S BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. Peel back for further information 81

78 Date opened 82

79 TEXT FOR RAPAMUNE CARTON : 1 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT Rapamune 1 mg/1 ml oral solution. Sirolimus. 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 30 Sachets Each sachet contains 1 ml of oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 83

80 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard sachet after single use. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 84

81 Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER(S) BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 85

82 TEXT FOR IMMEDIATE PACKAGING: 1 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Rapamune 1 mg/1 ml oral solution. Sirolimus. Oral use. 2. METHOD OF ADMINISTRATION Please read the package leaflet before use. 3. EXPIRY DATE EXP: XX/YYYY 4. BATCH NUMBER Lot: AAAA 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 ml. 86

83 TEXT FOR RAPAMUNE CARTON : 2 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT Rapamune 2 mg/2 ml oral solution. Sirolimus. 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 30 Sachets Each sachet contains 2 ml of oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 87

84 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard sachet after single use. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 88

85 Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER(S) BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 89

86 TEXT FOR IMMEDIATE PACKAGING: 2 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Rapamune 2 mg/2 ml oral solution. Sirolimus. Oral use. 2. METHOD OF ADMINISTRATION Please read the package leaflet before use. 3. EXPIRY DATE EXP: XX/YYYY 4. BATCH NUMBER Lot: AAAA 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 2 ml. 90

87 TEXT FOR RAPAMUNE CARTON : 5 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT Rapamune 5 mg/5 ml oral solution. Sirolimus. 2. STATEMENT OF ACTIVE SUBSTANCE Each ml of Rapamune contains 1 mg sirolimus. 3. LIST OF EXCIPIENTS Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids. 4. PHARMACEUTICAL FORM AND CONTENTS 30 Sachets Each sachet contains 5 ml of oral solution. 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. 91

88 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP: XX/YYYY 9. SPECIAL STORAGE CONDITIONS Store at 2 C-8 C (in a refrigerator). 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Discard sachet after single use. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 92

89 Wyeth Europa Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 0PH, United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/x/xx/xxx/xxx 13. MANUFACTURER(S) BATCH NUMBER Lot: AAAA 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE Please read the package leaflet before use. 93

90 94

91 TEXT FOR IMMEDIATE PACKAGING: 5 ml SACHET 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Rapamune 5 mg/5 ml oral solution. Sirolimus. Oral use. 2. METHOD OF ADMINISTRATION Please read the package leaflet before use. 3. EXPIRY DATE EXP: XX/YYYY 4. BATCH NUMBER Lot: AAAA 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 5 ml. 95

92 B. PACKAGE LEAFLET 96

93 PACKAGE LEAFLET Rapamune 1 mg/1 ml oral solution (Sirolimus) Please read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or pharmacist. This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their medical condition is the same as yours. In this leaflet: 1. What Rapamune is and what it is used for 2. Before you take Rapamune 3. How to take Rapamune 4. Possible side effects 5. Storing Rapamune 6. Further information The name of your medicine is Rapamune oral solution. Each ml of Rapamune contains 1 mg of the active substance sirolimus. The other ingredients are: polysorbate 80 and phosal 50 PG (phosphatidylcholine, propylene glycol, monodiglycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate). The marketing authorisation holder for Rapamune is: Wyeth Europa Ltd Huntercombe Lane South Taplow, Maidenhead Berkshire, SL6 0PH Rapamune is manufactured by: Wyeth Medica Ireland Little Connell Newbridge Co. Kildare Ireland. United Kingdom. 97

94 1. WHAT IS RAPAMUNE AND WHAT IS IT USED FOR? Rapamune belongs to a group of medicines called immunosuppressants. It helps to control your body s immune system after you have received an organ transplant. It is used to prevent your body from rejecting transplanted kidneys and is normally used with medicines called cyclosporine and corticosteroids. Rapamune oral solution is supplied in 60 ml and 150 ml amber glass bottles Not all pack sizes may be marketed. 2. BEFORE YOU TAKE RAPAMUNE Do not take Rapamune: if you are hypersensitive (allergic) to sirolimus or any of the other ingredients of Rapamune. Take special care with Rapamune: if you have any liver problems or have had a disease which may have affected your liver, please tell your doctor as this may affect the dose of Rapamune that you receive. immunosuppressive medicines may decrease your body s ability to fight infection, and may increase the risk of developing cancer of the lymphoid tissues and skin. Taking Rapamune with food and drink Rapamune should be taken consistently, either with or without food. Rapamune should be diluted only with water or orange juice. Do not take Rapamune with grapefruit juice. Pregnancy You must use effective contraception methods during treatment with Rapamune and for 12 weeks after treatment has stopped. If you are unsure, or think you may have become pregnant, talk to your doctor. Ask your doctor or pharmacist for advice before taking your medicine. Breast-feeding 98

95 It is not known whether Rapamune passes into breast milk. Patients taking Rapamune should discontinue breast-feeding. Ask your doctor or pharmacist for advice before taking your medicine. Use in children and adolescents There is limited experience with the administration of Rapamune in children and adolescents. Driving and using machinery No specific studies on the effects of Rapamune on the ability to drive and use machines have been conducted. Although Rapamune treatment is not expected to affect your ability to drive, if you have any concerns please consult your doctor. Important information about one of the ingredients of Rapamune WARNING: This medicine contains 1.5% to 2.5% ethanol. Each 2 mg dose contains up to 50 mg of alcohol. Alcohol may be harmful for those suffering from alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. Alcohol may modify or increase the effect of other medicines. Taking other medicines: Are you taking, or have you recently taken any other medicines, even those not prescribed for you? Some medicines can interfere with the action of Rapamune. In particular, you should inform your doctor or pharmacist if you are taking any of the following: any other immunosuppressive agents excluding cyclosporine or corticosteroids. antibiotics or antifungal medicines used to treat infection e.g. rifampicin, clarithromycin, erythromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole, ketoconazole. high blood pressure medicines or medicines for heart problems including nicardipine, verapamil and diltiazem. anti-epileptic medicines including carbamazepine, phenobarbital, phenytoin. Medicines used to treat-ulcers or other gastrointestinal disorders such as cisapride, cimetidine, metoclopramide. Bromocriptine (used in the treatment of Parkinsons disease and various hormonal disorders), danazol (used in the treament of gynaecological disorders), or protease inhibitors (used in the treatment of HIV). 99

96 3. HOW TO TAKE RAPAMUNE Rapamune is for oral use only. Always take Rapamune exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure. Your doctor will decide exactly what dose of Rapamune you must take and how often to take it. Follow your doctor s instructions exactly and never change the dose yourself. Do not stop taking your medicine unless your doctor tells you to. Usually for an adult your doctor will give you an initial dose of 6 mg at the time of the kidney transplant operation. Then you will need to take 2 mg of Rapamune each day, unless otherwise directed by your doctor. Your dose may be adjusted depending on the level of Rapamune in your blood. Your doctor will need to perform a blood test to measure Rapamune levels. If you are also taking cyclosporine, then you must take the two medicines approximately 4 hours apart. Instructions on how to dilute Rapamune 1. Remove the safety cap from the bottle by squeezing the tabs on the cap and twisting. Insert the syringe adapter into the bottle until it is flush with the top of the bottle. Do not attempt to remove the syringe adapter from the bottle once inserted. 2. With the plunger fully depressed, insert one of the dosing syringes into the opening in the adapter. 3. Withdraw the exact amount of Rapamune oral solution as prescribed by your doctor by gently pulling out the plunger of the dosing syringe until the bottom of the black line of the plunger is 100

97 level with the appropriate mark on the dosing syringe. The bottle should remain in an upright position when withdrawing the solution. If bubbles form in the dosing syringe during withdrawal, empty the Rapamune solution back into the bottle and repeat the withdrawal procedure. 4. You may have been instructed to take your Rapamune oral solution at a particular time of day. If it is necessary to carry your medication with you, fill the dosing syringe to the appropriate mark and place a cap securely on it the cap should snap into place. Then place the capped dosing syringe in the carrying case provided. Once in the syringe the medication may be kept at room temperature (not exceeding 25 C) or refrigerated and should be used within 24 hours. Empty the contents of the dosing syringe into only a glass or plastic container holding at least 60 ml of water or orange juice. Stir well for one minute and drink immediately. Refill the glass with at least 120 ml of water or orange juice, stir well, and drink immediately. No other liquids, including grapefruit juice, should be used for dilution. The dosing syringe and cap are to be used once and then discarded. Additional information When refrigerated the solution in the bottle may develop a slight haze. If this occurs, simply bring your Rapamune 1 mg/1 ml oral solution to room temperature and shake gently. The presence of this haze does not affect the quality of Rapamune. 101