Mphetas-500 (Mycophenolate Mofetil Tablets USP 500 mg)

Mphetas-500 (Mycophenolate Mofetil Tablets USP 500 mg)

Mycophenolate Mofetil Tablets USP 500 mg

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA.

Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

Therapeutic indications

Mycophenolate mofetil 500mg Tablets are indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

Posology and method of administration

Treatment with Mycophenolate mofetil 500mg Tablets should be initiated and maintained by appropriately qualified transplant specialists.

Use in renal transplant

Adults: Oral Mycophenolate mofetil 500mg Tablets should be initiated within 72 hoursfollowing transplantation. The recommended dose in renal transplant patients is1g administered twice daily (2g daily dose).

Paediatric population aged 2 to 18 years: The recommended dose of mycophenolate mofetil is 600mg/m2 administeredorally twice daily (up to a maximum of 2g daily). Mycophenolate mofetil 500mgTablets should only be prescribed to patients with a body surface area greater than1.5 m2, at a dose of 1g twice daily (2g daily dose). As some adverse reactions occurwith 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.

Paediatric population < 2 years: There are limited safety and efficacy data in children below the age of 2 years. Theseare insufficient to make dosage recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant Adults

Oral Mycophenolate mofetil 500mg Tablets should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5g administered twice daily (3g daily dose).

Paediatric population: 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 followinghepatic transplant, with oral Mycophenolate mofetil 500mg Tablets initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplantpatients is 1.5g administered twice daily (3g daily dose).

Paediatric population: No data are available for paediatric hepatic transplant patients.

Elderly: The recommended dose of 1g administered twice a day for renal transplant patientsand 1.5g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment: In renal transplant patients with severe chronic renal impairment (glomerularfiltration rate < 25 ml/min-1/1.73 m-2), outside the immediate post-transplant period, doses greater than 1g 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 (see section 5.2). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment: No dose adjustments are needed for renal transplant patients with severe hepaticparenchymal disease. No data are available for cardiac transplant patients withsevere hepatic parenchymal disease.

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Treatment during rejection episodes

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renaltransplant rejection does not lead to changes in MPA pharmacokinetics; dosagereduction or interruption of Mycophenolate mofetil 500mg Tablets is not required.There is no basis for Mycophenolate mofetil 500mg Tablets dose adjustmentfollowing cardiac transplant rejection. No pharmacokinetic data are available duringhepatic transplant rejection.

Method of administration

Oral administration.

Precautions to be taken before handling or administering the medicinal product. Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Mycophenolate mofetil 500mg tablets should not be crushed.

Contraindications

  • Mycophenolate mofetil 500mg tablets should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients. Hypersensitivity reactions to Mycophenolate mofetil 500mg tablets have been observed.
  • Mycophenolate mofetil 500mg Tablets should not be given to women of childbearing potential who are not using highly effective contraception.
  • Mycophenolate mofetil 500mg Tablets 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 500mg Tablets should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection
  • Mycophenolate mofetil 500mg Tablets sjould not be given to women who are Breastfeeding.

Special warnings and special precautions for use

Neoplasms: Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Mycophenolate mofetil 500mg Tablets, 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.

Infections: 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 polyomaviruses (BK virus associated nephropathy and 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.

Blood and immune system: Patients receiving Mycophenolate mofetil 500mg Tablets should be monitored for neutropenia, which may be related to Mycophenolate mofetil 500mg Tablets itself, concomitant medications, viral infections, or some combination of these causes.

Patients taking Mycophenolate mofetil 500mg Tablets 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 500mg Tablets. 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.

Gastro-intestinal: 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 500mg Tablets should be administered with caution in patients with active serious digestive system disease.

Interactions: Caution should be exercised when switching combination therapy from regimens

containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs of other classes which interfere with MPA’s enterohepatic cycle e.g. colestyramine should be used with caution due to their potential to reduce the plasma levels and efficacy of Mycophenolate mofetil 500mg Tablets.

It is recommended that Mycophenolate mofetil 500mg Tablets should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

Interaction with other medicinal products and other forms of interaction

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 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 coadministered with magnesium and aluminium hydroxides is considerably less than when mycophenolate mofetil was co-administered with PPIs.

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.

Sevelamer: Decrease in MPA Cmax and AUC (0-12h) 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 are 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 or 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 antibiotic 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 hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by mycophenolate mofetil

Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.

Fertility, pregnancy and lactation

Contraception in males and females: Mycophenolate mofetil 500mg Tablets is contraindicated in women of childbearing potential who are not using highly effective contraception.

Because of the genotoxic and teratogenic potential of Mycophenolate mofetil 500mg Tablets, women with childbearing potential should use two reliable forms of contraception simultaneously before starting Mycophenolate mofetil 500mg Tablets therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception.

Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with Mycophenolate mofetil 500mg Tablets are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of Mycophenolate mofetil 500mg Tablets.

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Pregnancy: Mycophenolate mofetil 500mg Tablets is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy. Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to Mycophenolate mofetil 500mg Tablets in combination with other immunosuppressants during pregnancy.

Breast-feeding: Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. 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 500mg Tablets are contraindicated in nursing mothers.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

Undesirable effects

The principal adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections.

Malignancies: 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,

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 500mg Tablets 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 colestyramine, can remove MPA by decreasing the enterohepatic recirculation of the drug.

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