CELLCEPT Composition Properties Pharmacokinetics

Transcription

1 CELLCEPT Roche Composition Active ingredient: Mycophenolate mofetil. Capsules with 250 mg mycophenolate mofetil. Excipients: coloring agent E132, excipients for capsules. TABLETS with 500 mg mycophenolate mofetil. Excipients: coloring agent E132, excipients for tablets. SUSPENSION (bottle containing 35 g of mycophenolate mofetil): 1 ml of the reconstituted suspension contains 200 mg of mycophenolate mofetil. Excipients: flavoring agents, vanillin, aspartame, preservative E218, excipients for suspension. Properties Mycophenolate mofetil is the 2 morpholineoethyl ester of mycophenolic acid (MPA). MPA is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMP DH) and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without being incorporated into DNA. Because T and B lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilize salvage pathways, MPA has a more potent cytostatic effect on lymphocytes than on other cells. Carcinogenicity, mutagenicity, impairment of fertility In studies in the rat and mouse, mycophenolate mofetil was not tumorigenic. In experimental models, mycophenolate mofetil did not demonstrate mutagenic activity. Mycophenolate mofetil had no effect on fertility of male rats. In a female fertility and reproduction study conducted in rats, malformations (principally of the head and eyes) occurred in the first generation (Fl) offspring in the absence of maternal toxicity. No effects on fertility were identified in the treated females (P1 females) or in the first generation offspring (P2 females or P2 males). Pharmacokinetics Absorption Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to MPA, the active metabolite. Mycophenolate mofetil is not detectable in plasma after oral administration. Food intake had no effect on the degree of absorption (MPA AUC) of mycophenolate mofetil administered to renal transplant patients in doses of 1.5 g twice daily. However, the peak concentration (C max ) of MPA decreased by 40% in the presence of food (see Dosage and Administration). The capsules and tablets differ in terms of C max but are bioequivalent in terms of AUC. The mean bioavailability of oral mycophenolate mofetil, based on the AUC of MPA, is 94% of that of I.V. mycophenolate mofetil. Distribution As a result of enterohepatic recirculation, a secondary rise in plasma MPA concentration is generally observed at approximately 6 12 hours post dose. The AUC of MPA is reduced by approximately 40% when mycophenolate mofetil is administered simultaneously with cholestyramine (4 g t.i.d.), indicating that there is a significant amount of enterohepatic recirculation. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at the MPAGconcentration range normally seen in stable renal transplant patients; however at higher concentrations of MPAG such as those seen in patients with delayed graft function or severe renal failure, the bound fraction in vitro decreases to 62%. Metabolism MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active. Elimination Enterohepatic recirculation makes determination of the t ½ of MPA difficult. The apparent half life is

2 approximately hours. Approximately 93% of a dose is eliminated via the kidneys mostly as MPAG, while approximately 5.5% is eliminated in the feces. Pharmacokinetics in special clinical situations In a single dose study (6 subjects per group), plasma MPA AUCs observed in subjects with severe chronic renal failure (glomerular filtration rate <25 ml/min/1.73 m 2 ) were 28 75% higher than those of healthy subjects or patients with less severe renal failure. The mean increase in MPA AUC observed in subjects with severe renal failure was comparable to the increase in MPA AUC seen when the daily dose of mycophenolate mofetil is increased from 2 3 g. Mean MPA AUC 0-12 in post transplant patients with delayed renal graft function was comparable to that seen in post transplant patients without delayed function. In patients with primary nonfunction of the transplanted kidney, MPAG accumulated in the plasma. Accumulation of the MPA where it occurred at all was much less marked. Liver failure has no influence on pharmacokinetics. Pharmacokinetics in elderly patients were not investigated. Indications Established Indications Renal transplantation: Prophylaxis of acute graft rejection in patients receiving allogenic renal transplants. Heart transplantation: CelICept is indicated in allogenic heart transplantation for the prophylaxis of acute graft rejection. CellCept should be used in renal and heart transplantation concomitantly with cyclosporine and corticosteroids. Contraindications As allergic reactions to CellCept have been observed, CellCept is contraindicated in patients who are hypersensitive to mycophenolate mofetil or mycophenolic acid. Tolerance and efficacy in children have not been ascertained. Side Effects Clinical Experience Because of the possible effects of the basic disease and the generally extensive concomitant medication, it is often difficult to establish the side-effect profile of immunosuppressants. The principal side effects associated with the administration of CellCept in combination with cyclosporine and corticosteroids are diarrhea, leukopenia, sepsis and vomiting. There is also evidence of a higher frequency of certain infectious diseases, such as tuberculosis and atypical mycobacterial infections. Severe lifethreatening infections, such as meningitis and infective endocarditis, have occasionally been reported. As in patients receiving immunosuppressants regimes involving combinations of drugs, patients receiving CellCept as part of an immunosuppressant regime are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see Precautions). In the controlled studies on rejection prophylaxis, lymphoproliferative disease or lymphoma developed within 3 years after transplantation in 1.6% and 0.6% of renal transplant patients treated with 3 g and 2 g, respectively, of CellCept immunosuppressive combination therapies, as compared with 0% of patients in the placebo group and 0.6% in the azathioprine group. In heart transplant recipients the incidence of lymphoproliferative disease was 0.7% in patients receiving CellCept 3 g daily, as compared with 2.1% in those treated with azathioprine. The incidence of non melanoma skin tumors was 5.5% in heart transplant patients treated with CellCept 3 g daily, as compared with 6.9% in those treated with azathioprine. The heart transplant patients were followed for a maximum of 3 years; 26% for less than one year and 34% for more than 2 years. All patients are at increased risk of opportunistic infections, and this risk is greater at higher doses. Elderly patients may be at greater risk of developing certain infections (including tissue-invasive cytomegalovirus [CMV] disease), and possibly gastrointestinal hemorrhage and pulmonary edema, than

3 younger patients, especially if they take CellCept as part of an immunosuppressive combination therapy (see Dosage and Administration). Other side effects observed distinctly more often in elderly renal transplant patients were leukopenia, raised serum creatinine and dyspnea. However, their incidence was no greater on CellCept than in patients treated with azathioprine. Increased malignancy or mortality was not observed in this age group of renal transplant recipients. Adverse reactions reported in 10% of patients treated with CellCept in the three controlled phase III trials on rejection prophylaxis after renal transplantation and the controlled phase III study on rejection prophylaxis after heart transplantation are listed in Table 1. Side effects not mentioned above and reported in 3% to 10% of kidney and/or heart transplant patients are listed in Table 2. In controlled studies on the prevention of rejection after renal transplantation, patients receiving 2 g per day of mycophenolate mofetil demonstrated an overall better safety profile than did those receiving 3 g per day. Sepsis (generally caused by cytomegalovirus) occurred somewhat more often in renal transplant patients treated with CellCept than in control patients, and was somewhat more frequent on treatment with 3 g daily than on 2 g daily. In the controlled heart transplantation study, no difference in the incidence of sepsis was observed between patients treated with CellCept and controls. Among gastrointestinal side effects in kidney and heart transplant recipients, diarrhea occurred more commonly on treatment with CellCept than on azathioprine or placebo. Vomiting was also somewhat more frequent in these two patient groups. These gastrointestinal side effects occurred more often in renal transplant patients receiving 3 g daily than in those on 2 g daily. Urinary tract infections were frequently observed after renal transplantation in all treatment groups, though more often on CellCept than azathioprine or placebo. Leukopenia also occurred more commonly in renal transplant patients taking CellCept than in the control groups; it was most common in patients receiving 3 g mycophenolate mofetil per day. By contrast, leukopenia in heart transplant patients occurred more frequently on azathioprine than on treatment with CellCept. In the studies on prevention of transplant rejection, invasive cytomegalovirus disease occurred more commonly in renal transplant patients receiving 3 g of mycophenolate mofetil per day than in those receiving 2 g per day or control therapy. Similarly, the incidence of candidemia, tissue invasive candidiasis, and invasive aspergillosis was slightly higher in patients receiving CellCept than in those receiving control therapy. In heart transplant patients the overall incidence of opportunistic infections on treatment with CellCept was about 10% higher than on azathioprine. In the studies on prevention of renal graft rejection, fatal infection occurred with similar frequency (<1%) on treatment with CellCept and the comparator product, in both cases in combination with other immunosuppressants. In the controlled study of heart transplant rejection prophylaxis, fatal infection or sepsis occurred in 1.7% of patients treated with CellCept and 3.8% of those receiving azathioprine, in each case combined with other immunosuppressants. Up to 1.5% of renal transplant patients receiving CellCept for prevention of graft rejection developed severe neutropenia (absolute neutrophil count <500/µl). Following heart transplantation, severe neutropenia was observed in up to 2.8% of patients treated with CellCept 3 g daily to prevent graft rejection and in no patients treated with azathioprine. Post marketing experience with CellCept is similar to that acquired during the renal and heart transplantation studies. Post marketing Experience Digestive: colitis, pancreatitis. Resistance mechanism disorders: Severe lifethreatening infections, such as meningitis and infective endocarditis, have occasionally been reported.

4 There is also evidence of a higher frequency of certain infectious diseases, such as tuberculosis and atypical mycobacterial infections. Precautions As in patients receiving immunosuppressant regimes involving combinations of drugs, patients receiving CellCept as part of an immunosuppressant regime are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As in all patients at increased risk of skin cancer, sun and ultraviolet exposure should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Over-suppression of the immune system can also increase susceptibility to infection. In controlled studies on prophylaxis of rejection, lymphoproliferative disease or lymphoma developed in 0.6 1% of renal transplant patients taking CellCept with other immunosuppressant agents as compared with 0 and 0.3% of patients in control groups. In a controlled study on rejection prophylaxis in heart transplant patients, these diseases occurred with a frequency of about 0.7%. In three controlled studies on prophylaxis of rejection following renal transplantation, the rate of fatal infections in patients receiving CellCept plus other immunosuppressant agents was similar (<1%) to that in patients receiving control therapy plus other immunosuppressant agents. In the controlled study on rejection prophylaxis following heart transplantation, fatal infections occurred in 1.7% of patients treated with CellCept and 3.8% treated with azathioprine in combination with other immunosuppressants. Up to 1.5% of renal transplant patients receiving CellCept for prophylaxis of rejection developed severe neutropenia (ANC <500/µl). Up to 2.8% of heart transplant patients receiving CellCept 3 g daily and no patients receiving azathioprine developed severe neutropenia. The neutrophil count of patients receiving CellCept should be monitored. If neutropenia develops (ANC <1.3x10 3 /µl), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient treated as required. Patients treated with CellCept must be told to report immediately any evidence of infection, unexpected bruising, bleeding or other symptoms of bone marrow aplasia. Gastrointestinal hemorrhage has been observed in approximately 3% of renal transplant patients treated with CellCept 3 g daily, and in 1.4% of renal transplant patients treated with CellCept 2 g daily. Gastrointestinal perforations (colon, gallbladder) have rarely been observed in renal and heart transplant patients. Because CellCept has been associated with an increased incidence of gastrointestinal adverse events-including gastrointestinal ulcers, hemorrhage, and perforations, it should be administered with caution to patients with severe active disease of the digestive tract. Patients with severe chronic renal failure (glomerular filtration <25 mi/mm/1.73 m 2 ) who received single doses of CellCept showed higher plasma MPA and MPAG AUCs than did patients with less severe renal failure or healthy subjects. Such renal transplant patients should not receive CellCept at doses of more than 1 g twice daily, and they should be carefully monitored. No data are available on heart transplant patients with severe chronic renal failure. CellCept should be used in such patients only if the expected benefit outweighs the potential risk. In post transplant patients with delayed graft function following renal transplantation, mean MPA AUC0 12 was comparable to, but MPAG AUC0 12 was two to three fold higher compared to that seen in post transplant patients without delayed graft function. No dose adjustment is recommended for these patients, however they should be carefully observed. It is recommended that CellCept not be administered concomitantly with azathioprine.

5 In view of the significant reduction of MPA AUC by cholestyramine, caution should be exercised when CellCept is administered concomitantly with drugs that interfere with enterohepatic recirculation, as this can reduce the efficacy of CellCept. CellCept suspension contains aspartame and should therefore be used only with caution in patients with phenylketonuria. Laboratory Tests Full blood counts should be performed weekly during the first month, twice monthly during the second and third months of treatment, then monthly throughout the first year. Pregnancy and Nursing Mothers There is clear evidence of risks to the human fetus, however the therapeutic benefit to the mother can outweigh this. Effective contraception is required in patients receiving CelICept. Studies in rats have shown mycophenolate mofetil to be excreted in milk. It is not known whether this also occurs in humans. As many drugs are excreted in human milk and in view of the potential risk of severe adverse reactions to mycophenolate mofetil in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Overdosage There have been no reports of overdosage of mycophenolate mofetil in humans. MPA and MPAG cannot be removed by hemodialysis. However, at high MPAG plasma-concentrations (>100 µg/mi), small amounts of MPAG are removed. By increasing elimination of MPA, bite acid sequestrants such as cholestyramine can remove the drug. Special Remarks Handling of the capsules/tablets/suspension Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, CellCept tablets should not be crushed and CellCept capsules should not be opened or crushed, Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in CellCept capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain wafer. Avoid direct contact between the powder (for preparing a suspension) and skin or mucous membranes, or between the prepared suspension and skin. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Incompatibilities CelICept suspension must not be mixed with other drugs. Stability This medicine should not be used after the expiry date (EXP) shown on the pack. Do not store above 30ºC. The reconstituted CellCept suspension can be stored for up to 60 days. Drug Interactions CellCept has not been administered concomitantly with azathioprine. Acyclovir: Higher MPAG (8.6%) and acyclovir (17.4%) plasma AUCs were observed when mycophenolate mofetil was administered with acyclovir in comparison to administration of each drug alone. Because MPAG and acyclovir plasma concentrations are increased in the presence of renal failure, the potential exists for the two drugs to compete for tubular secretion, hence further increases in concentrations of both drugs may occur. Antacids with magnesium and aluminum hydroxides: Absorption of mycophenolate mofefil was reduced when administered concomitantly with antacids. Cholestyramine: There was a 40% reduction in the AUC of MPA, Cyclosporin A: Cyclosporin A pharmacokinetics were unaffected by mycophenolate mofetil. Ganciclovir: No pharmacokinetic interaction was observed between mycophenolate mofetil and I.V. ganciclovir. Oral contraceptives: No pharmacokinetic interaction was observed between mycophenolate mofetil and 1 mg norethindrone and 35 µg ethinyl estradiol. This

6 single dose study demonstrates the absence of any gross pharmacokinetic interaction, but cannot exclude the possibility of changes in the pharmacokinetics of the oral contraceptive under longterm dosing conditions with Cellcept which might adversely affect the efficacy of the oral contraceptive. Trimethoprim/sulfamethoxazole: No effect on the bioavailability of MPA was observed. Other interactions: Coadministration of probenecid and mycophenolate mofetil in monkeys causes a three fold increase in the plasma AUC of MPAG. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion. Dosage and Administration Prophylaxis of Rejection Reactions The first CellCept dose should be administered orally as soon as possible after renal or cardiac transplantation. Renal transplantation: The best therapeutic benefit-risk ratio is observed with a daily dose of 2 g (4 capsules bid. or 2 tablets b.i.d. or 5 ml of suspension bid.). Therefore a daily dose of 2 g is generally recommended for renal transplant patients. Where a higher level of immunosuppression appears warranted in selected patients, a daily dose of 3 g CellCept (6 capsules b.i.d. or 3 tablets b.i.d. or 7.5 ml of suspension b.i.d.) can be given. Heart transplantation: The recommended dose for heart transplant patients is 1.5 g twice daily (daily dose 3 g). CelICept should be used in renal and heart transplantation concomitantly with cyclosporine and corticosteroids. Preparation of the Suspension It is recommended that CellCept suspension be prepared by a pharmacist before it is dispensed to the patient: 1. Shake the closed bottle several times to loosen the powder. 2. Add 94 ml of purified water (aqua purificata) to a measuring cylinder. 3. Pour about half the purified water into the bottle. Then close the bottle and shake carefully for about 1 minute. 4. Add the rest of the water to the bottle and again shake the closed bottle for about 1 minute. 5. Remove the childproof cap and insert the bottle adaptor into the neck of the bottle. 6. Reclose the bottle tightly with the childproof cap. This ensures childproof closure of the bottle and correct positioning of the adaptor. 7. Write the expiry date of the reconstituted suspension on the bottle label (the reconstituted suspension can be stored for up to 60 days). The reconstituted suspension has a volume of 175 ml; the removable volume is ml. Special Dosage Instructions CellCept should be taken on an empty stomach (see Pharmacokinetics). In renal transplant patients with severe chronic renal failure (glomerular filtration rate <25 mi/min/1.73 m 2 ) outside of the immediate posttransplant period, doses of more than 1 g CellCept twice daily should be avoided. No dosage adjustment is required in patients with delayed graft function after the operation. No data are available on heart transplant patients with severe chronic renal failure. In such patients CellCept should be used only it the expected benefit outweighs the potential risk. Elderly patients may be treated with the recommended dose of 1 g twice daily after renal transplantation and 1.5 g twice daily after heart transplantation. In general, the risk of side effects may be increased in patients in this age group. This also applies to patients receiving CellCept in combination with immunosuppressants (see Side Effects). Dose adjustment is unnecessary in renal transplant patients with severe parenchymal liver disease. No data are available on heart transplant patients with severe parenchymal liver disease. If neutropenia develops (ANC) [absolute neutrophil count] <1.3x10 3 /µl), dosing with CellCept should be

7 interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient treated as required. Renal transplant rejection is associated with no pharmacokinetic changes for mycophenoic acid (MPA) that would necessitate dose reduction or cessation of use. Note: If necessary, CelICept suspension can be administered via a nasogastric tube of at least 8 French (minimum internal diameter 1.7 mm).