mycophenolate mofetil

Each capsule contains 250 mg mycophenolate mofetil.

Capsules, hard. Arzip 250 mg Capsules: light blue/peach, size '1' hard gelatin capsule imprinted with 'MMF' on cap and '250' on body.

Arzip 250 mg Capsules are indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

Treatment with Arzip 250 mg Capsules should be initiated and maintained by appropriately qualified transplant specialists.

Use in renal transplant:

Adults: oral Arzip 250 mg Capsules should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1.0 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). Arzip 250 mg 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 Arzip 250 mg Capsules at a dose of 750 mg twice daily (1.5g daily dose). Patients with a body surface area greater than 1.5m² may be prescribed Arzip 250 mg 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. There are insufficient to make dosage recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant:

Adults: oral Arzip 250 mg Capsules 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 Arzip 250 mg Capsules 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 1.0 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 ml•min-¹•1.73 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 Arzip 250 mg Capsules is not required. There is no basis for Arzip 250 mg Capsules dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Hypersensitivity reactions to Arzip 250 mg Capsules have been observed. Therefore, Arzip 250 mg Capsules are contraindicated in patients with a hypersensivity to mycophenolate mofetil or mycophenolic acid.

Arzip 250 mg Capsules are contraindicated in women who are breastfeeding.

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Arzip 250 mg Capsules, 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 Arzip 250 mg Capsules 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, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). 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

Patients receiving Arzip 250 mg Capsules should be monitored for neutropenia, which may be related to Arzip 250 mg Capsules itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Arzip 250 mg Capsules 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 Arzip 250 mg Capsules.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Arzip 250mg Capsules in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Arzip 250mg Capsules therapy. Changes to Arzip 250mg Capsules 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 Arzip 250 mg Capsules 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 Arzip 250 mg Capsules have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, Arzip 250 mg Capsules should be administered with caution in patients with active serious digestive system disease.

Arzip 250 mg Capsules are 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 Arzip 250 mg Capsules 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 colestyramine, caution should be used in the concomitant administration of Arzip 250 mg Capsules with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of Arzip 250 mg Capsules.

The risk: benefit of Mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established.

Interaction studies have only been performed in adults.

Aciclovir: higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of each substance 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 with magnesium and aluminium hydroxides: absorption of mycophenolate mofetil was decreased when administered with antacids.

Colestyramine: following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of colestyramine 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 Arzip 250 mg Capsules.

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 Arzip 250 mg Capsules.

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 Arzip 250 mg Capsules 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 are anticipated and Arzip 250 mg Capsules dose adjustment is not required. In patients with renal impairment in which Arzip 250 mg Capsules 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 Arzip 250 mg Capsules.

Rifampicin: in patients not also taking ciclosporin, concomitant administration of Arzip 250 mg Capsules 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 Arzip 250 mg Capsules doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.

Sirolimus: in renal transplant patients, concomitant administration of Arzip 250 mg Capsules and CsA resulted in reduced MPA exposure by 30-50% compared with patients receiving the combination of sirolimus and similar doses of Arzip 250 mg Capsules.

Sevelamer: decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when Arzip 250 mg Capsules was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer Arzip 250 mg Capsules 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 Arzip 250 mg Capsules 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 Arzip 250 mg Capsules 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 Arzip 250 mg Capsules.

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 Arzip 250mg Capsues 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 recipients initiated on Arzip 250 mg Capsules and tacrolimus, the AUC and Cmax of MPA, the active metabolite of Arzip 250 mg Capsules, were not significantly affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of Arzip 250 mg Capsules (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by Arzip 250 mg Capsules.

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 drug 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.

The following undesirable effects cover adverse reactions from clinical trials:

The principal adverse reactions associated with the administration of Arzip 250 mg Capsules 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 Arzip 250 mg Capsules, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Lymphoproliferative disease or lymphoma developed in 0.6 % of patients receiving Arzip 250 mg Capsules (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6 % of patients; other types of malignancy occurred in 1.1 % of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Opportunistic infections:

All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load. The most common opportunistic infections in patients receiving Arzip 250 mg Capsules (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5 %.

Children and adolescents (aged 2 to 18 years):

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g Arzip 250 mg Capsules twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopoenia, anemia and infection.

Elderly patients ( 65 years):

Elderly patients ( 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving Arzip 250 mg Capsules as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Other adverse reactions:

Adverse drug reactions, probably or possibly related to Arzip 250 mg Capsules, reported in 1/10 and in 1/100 to < 1/10 of patients treated with Arzip 250 mg Capsules in the controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients are listed in the following table.

Adverse reactions, probably or possibly related to Arzip 250 mg Capsules, reported in patients treated with Arzip 250 mg Capsules in renal, cardiac and hepatic clinical trials when used in combination with Ciclosporin and Corticosteroids.

Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common ( 1/10); common ( 1/100 to < 1/10) ; uncommon ( 1/1,000 to < 1/100) ; rare ( 1/10,000 to < 1/1,000) ; very rare (< 1/10,000) not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Note: 501 (2 g mycophenolate daily), 289 (3 g mycophenolate daily) and 277 (2 g IV / 3 g oral mycophenolate daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively

The following undesirable effects cover adverse reactions from post-marketing experience:

The types of adverse reactions reported during post-marketing with Arzip 250 mg Capsules are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.

Gastrointestinal: gingival hyperplasia (1/100 to <1/10), colitis including cytomegalovirus colitis, ( 1/100 to < 1/10), pancreatitis ( 1/100 to < 1/10) and intestinal villous atrophy.

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate.

Agranulocytosis ( 1/1,000 to < 1/100) and neutropenia has been reported; therefore regular monitoring of patients taking Arzip 250 mg Capsules is advised. There have been reports of aplastic anaemia and bone marrow depression in patients treated with Arzip 250 mg Capsules, some of which have been fatal.

Blood and lymphatic system disorder:

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Arzip 250mg Capsules.

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with Arzip 250mg Capsules. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive Arzip 250mg Capsules.

Hypersensitivity: Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reactions, have been reported.

Respiratory, thoracic and mediastinal disorders:

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with Arzip 250mg Capsules in combination with other immunosuppressants, some of which have been fatal.

Winthrop Pharmaceuticals UK Ltd

POM – Prescription Only Medicine

22 November 2011