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    Active Ingredient
    Mycophenolate Mofetil 250 mg, 500 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Capsules

    100 x 250 mg

    partial basket chart 33840 3390

    Film Coated Tablets

    50 x 500 mg

    partial basket chart 33841 3391

    Related information


    Dosage

    Use in renal transplant: Adults: oral Mycophenolate mofetil should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
    Children and adolescents (aged 2 to 18 years): the recommended dose of mycophenolate mofetil is 600 mg/m2 administered orally twice daily (up to a maximum of 2 g daily). Mycophenolate mofetil tablets should only be prescribed to patients with a body surface area greater than 1.5 m2, at a dose of 1 g twice daily (2 g daily dose). Mycophenolate mofetil capsules should only be prescribed to patients with a body surface area of at least 1.25 m2. Patients with a body surface area of 1.25 to 1.5 m2 may be prescribed Mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m2 may be prescribed Mycophenolate mofetil capsules at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.
    Children (< 2 years): there are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make dosage recommendations and therefore use in this age group is not recommended.
    Use in cardiac transplant: Adults: oral Mycophenolate mofetil should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).
    Children: no data are available for paediatric cardiac transplant patients.
    Use in hepatic transplant: Adults: IV Mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral Mycophenolate mofetil initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose). Children: no data are available for paediatric hepatic transplant patients.
    Use in elderly (> 65 years): the recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.
    Use in renal impairment: in renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 mlXmin-1X1.73 m-2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
    Use in severe hepatic impairment: no dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
    Treatment during rejection episodes: MPA (mycophenolic acid) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Mycophenolate mofetil is not required. There is no basis for Mycophenolate mofetil dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.     


    Indications

    Prophylaxis of rejection in renal allograft recepients, and in patients receiving allogenic cardiac transplants. Mycophenolate mofetil should be used concomitantly with cyclosporin and corticosteroids. Allogenic hepatic transplant. Hypersensitivity reactions to Mycophenolate mofetil have been observed. Therefore, Mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid. Mycophenolate mofetil is contraindicated in women who are breastfeeding.          


    Contra-Indications

    Hypersensitivity to mycophenolate mofetil or mycophenolic acid. Mycophenolate mofetil is contraindicated in women who are breastfeeding. Women of childbearing potential who are not using highly effective contraception. Mycophenolate mofetil treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy. Mycophenolate mofetil should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.
    For full details see prescribing information.


    Special Precautions

    Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Mycophenolate mofetil, 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 general advice to minimise the 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. Patients receiving Mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Patients treated with immunosuppressants, including Mycophenolate mofetil, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyoma viruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
    There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching Mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Mycophenolate mofetil who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
    There have been published reports of bronchiectasis in adults and children who received Mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching Mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
    Patients receiving Mycophenolate mofetil should be monitored for neutropenia, which may be related to Mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Mycophenolate mofetil should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 103/μl), it may be appropriate to interrupt or discontinue Mycophenolate mofetil. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Mycophenolate mofetil therapy. Changes to Mycophenolate mofetil therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.
    Patients should be advised that during treatment with Mycophenolate mofetil, vaccinations may be less effective, and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Because Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, Mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease. Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. It is recommended that Mycophenolate mofetil should not be administered concomitantly with azathioprine because such concomitant administration has not been studied. In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of Mycophenolate mofetil with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of Mycophenolate mofetil.
    The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established.


    Side Effects

    Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster, Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis.Skin cancer, benign neoplasm of skin disorders.
    See prescribing information for full details.


    Drug interactions

    Aciclovir: Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8 %) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.
    Antacids and proton pump inhibitors (PPIs): Decreased mycophenolic acid (MPA) exposure has  been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with Mycophenolate mofetil. When comparing rates of transplant rejection or rates of graft loss between Mycophenolate mofetil patients taking PPIs vs. Mycophenolate mofetil patients not taking PPIs, no significant differences were seen. These data support extrapolation of this finding to all antacids because the reduction in exposure when Mycophenolate mofetil was co- administered with magnesium and aluminium hydroxides is considerably less than when Mycophenolate mofetil was co-administered with PPIs.
    Cholestyramine: Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40 % reduction in the AUC of MPA. Caution should be used during concomitant administration because of the potential to reduce efficacy of Mycophenolate mofetil.
    Medicinal products that interfere with enterohepatic circulation: Caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of Mycophenolate mofetil.
    Ciclosporin A: Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil.In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.
    Ganciclovir: Based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of Mycophenolate mofetil and ganciclovir, it is anticipated that co administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and Mycophenolate mofetil dose adjustment is not required. In patients with renal impairment in which Mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.
    Oral contraceptives: The pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by coadministration of Mycophenolate mofetil.
    Rifampicin:In patients not also taking ciclosporin, concomitant administration of Mycophenolate mofetil and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust Mycophenolate mofetil doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.
    Sirolimus: In renal transplant patients, concomitant administration of Mycophenolate mofetil and CsA resulted in reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus and similar doses of Mycophenolate mofetil.
    Sevelamer: Decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when Mycophenolate mofetil was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer Mycophenolate mofetil at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on Mycophenolate mofetil with phosphate binders other than sevelamer.
    Trimethoprim/sulfamethoxazole: No effect on the bioavailability of MPA was observed.
    Norfloxacin and metronidazole: In healthy volunteers, no significant interaction was observed when Mycophenolate mofetil was concomitantly administered with norfloxacin and metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of Mycophenolate mofetil.
    Ciprofloxacin and amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of Mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
    Tacrolimus: In hepatic transplant patients initiated on Mycophenolate mofetil and tacrolimus, the AUC and Cmax of MPA, the active metabolite of Mycophenolate mofetil, were not significantly affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of Mycophenolate mofetil (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by Mycophenolate mofetil.
    Other interactions: Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.
    Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
    Telmisartan: Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of MPA concentrations.
    Ciclosporin A: Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil.In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: It is recommended that Mycophenolate mofetil therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Mycophenolate mofetil therapy, during therapy, and for six weeks following discontinuation of therapy . Patients should be instructed to consult their physician immediately should pregnancy occur.
    Lactation: It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, Mycophenolate mofetil is contraindicated in nursing mothers.
    For full details please see prescribing information.          


    Overdose

    Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product. It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with Mycophenolate mofetil should be interrupted or the dose reduced. Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug.


    Important notes

    Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Mycophenolate mofetil capsules and tablets should not be opened or crushed.


    Manufacturer
    Hoffmann La Roche, Switzerland
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