SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Arzip 250mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg mycophenolate mofetil.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsules, hard.

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2    Posology and method of administration

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 1.5m 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 (see section 4.8) 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 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 (see section 5.2). 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.

4.3 Contraindications

Hypersensitivity reactions to Arzip 250 mg Capsules have been observed (see section 4.8). Therefore, Arzip 250 mg Capsules are contraindicated in patients with a hypersensivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1.

Arzip 250 mg Capsules are contraindicated in women who are breastfeeding (see section 4.6).

For information on use in pregnancy and contraceptive requirements see section 4.6.

4.4 Special warnings and precautions for use

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 (see section 4.8). 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.

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Arzip 250 mg Capsules in combination with other immunosuppressants. In some of these cases switching Arzip 250 mg Capsules to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Arzip 250 mg Capsules 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 Arzip 250 mg Capsules in combination with other immunosuppressants. In some of these cases switching Arzip 250 mg Capsules 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 (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.

Patients treated with immunosuppressants, including my cophenol ate, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). 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

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/pl) 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 (see section 4.8).

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 (see section 4.5). 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 bycholestyramine, 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 (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

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 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 Arzip 250 mg Capsules. When comparing rates of transplant rejection or rates of graft loss between Arzip 250 mg Capsules patients taking PPIs vs. Arzip 250 mg Capsules 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 Arzip 250 mg Capsules were co-administered with magnesium and aluminium hydroxides is considerably less than when Arzip 250 mg Capsules were 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. (see sections 4.4 and 5.2). 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 (see section 4.2) 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 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 co-administration of Arzip 250 mg Capsules (see also section 5.2).

Rifampicin: in patients not also taking ciclosporin, concomitant administration of Arzip 250 mg Capsules and rifampicin resulted in a decrease in MPA exposure (AUC_0-12h) 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 (see section 4.4.).

Sevelamer: decrease in MPA Cmax and AUC_0-12 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 patients 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 co-administration 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 (see section 4.4).

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 (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

It is recommended that Arzip 250 mg Capsules therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Arzip 250 mg Capsules therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5). Patients should be instructed to consult their physician immediately should pregnancy occur.

The use of Arzip 250 mg Capsules is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. Arzip 250 mg Capsules should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of Arzip 250 mg Capsules in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to Arzip 250 mg Capsules in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patient exposed to Arzip 250 mg Capsules. Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding

Mycophenolate Mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, Arzip 250 mg Capsules are contraindicated in nursing mothers (see section 4.3).

4.7 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.

4.8 Undesirable effects

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 (see section 4.4).

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 (see section 4.4). 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. Nonmelanoma 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 (see section 4.4). 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

2

recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m 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 mycophenolate mofetil 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.

System organ class		Adverse drug reactions
Infections and infestations	Very common	Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster
	Common	Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteris, infection, bronchitis, pharyngitis, sinusistis, fungal

		skin infection, skin candida, vaginal candidiasis, rhinitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
	Common	Skin cancer, benign neoplasm of skin
Blood and lymphatic system disorders	Very common	Leucopenia, thrombocytopenia, anaemia
	Common	Pancytopenia, leukocytosis
Metabolism and nutrition disorders
	Common	Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hyperchlosterolaemia, hyperlipidaemia, hypophosphataemia, Hyperuricaemia, gout, anorexia
Psychiatric disorders
	Common	Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia
Nervous system disorders
	Common	Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia
Cardiac disorders
	Common	Tachycardia
Vascular disorder
	Common	Hypotension, hypertension, vasodilatation
Respiratory, thoracic and mediastinal disorders
	Common	Pleural effusion, dyspnoea, cough
Gastrointestinal disorders	Very common	Vomiting, abdominal pain, diarrhoea, nausea
	Common	Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation
Hepatobiliary disorders
	Common	Hepatitis, jaundice,

		hyperbilirubinaemia
Skin and subcutaneous tissue disorders
	Common	Skin hypertrophy, rash, acne, alopecia
Musculoskeletal and connective tissue disorders
	Common	Arthralgia
Renal and urinary disorders
	Common	Renal impairment
General disorders and administration site conditions
	Common	Oedema, pyrexia, chills, pain malaise, asthenia
Investigations
	Common	Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, blood alkaline phosphatase increased, weight decreased

Note: 501 (2 g mycophenolate mofetil daily), 289 (3 g mycophenolate mofetil 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 mycophneolate moetilare 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 Arzip 250 mg Capsules. Agranulocytosis (> 1/1,000 to < 1/100) and neutropenia has been reported; therefore regular monitoring of patients taking Arzip 250 mg Capsules is advised (see section 4.4). 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 mycophneolate moetil (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophneolate moetil.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.

Congenital disorders: see further details in section 4.6.

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. There have also been reports of bronchiectasis in children and adults (frequency not known).

Immune system disorders: Hypogammaglobulinaemia has been reported in patients receiving Arzip 250 mg Capsules in combination with other immunosuppressants (frequency not known).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 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 (see section 4.4.). If neutropenia develops, dosing with Arzip 250 mg Capsules should be interrupted or the dose reduced (see section 4.4.)

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 recirculation of the drug (see section 5.2)

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressive agents ATC code L04AA06

Mechanism of action

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.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of Arzip 250 mg Capsules is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94 % relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40 % in the presence of food.

Mycophenolate mofetil is not measurable systemically in plasma following oral administration.

Distribution

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately 40 % is associated with the coadministration of colestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation. MPA at clinically relevant concentrations is 97% bound to plasma albumin.

Biotransformation

MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.

Elimination

A negligible amount of substance is excreted as MPA (< 1 % of dose) in the urine. Orally administered radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93 % of the administered dose recovered in the urine and 6 % recovered in the faeces. Most (about 87 %) of the administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100^g/ml), small amounts of MPAG are removed.

In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30 % lower and Cmax approximately 40 % lower compared to the late post-transplant period (3 - 6 months post-transplant).

Renal impairment:

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 ml»min-'•1.73 m-²) were 28 - 75 % higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3 - 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function:

In patients with delayed renal graft function post-transplant, mean MPA AUC (0-12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2 - 3-fold higher than in posttransplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of Arzip 250 mg Capsules does not appear to be necessary.

Hepatic impairment:

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Children and adolescents (aged 2 to 18 years):

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Arzip 250 mg Capsules at a dose of 1 g bid in the early and late posttransplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly patients (> 65 years):

Pharmacokinetic behaviour of Arzip 250 mg Capsules in the elderly has not been formally evaluated.

Oral contraceptives:

The pharmacokinetics of oral contraceptives were unaffected by co-administration of Arzip 250 mg Capsules (see also section 4.5). A study of the co-administration of Arzip 250 mg Capsules (1g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 nontransplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of Arzip 250 mg Capsules on the ovulation suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected.

5.3 Preclinical safety data

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 - 2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity. Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg»kg^-1,day^-1. The systemic exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3 - 2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg»kg^-i»day^-i caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg»kg^-i»day^-i (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg»kg^-uday^-i (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. Refer to section 4.6.

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The non-clinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials, which now provide safety data of more relevance to the patient population (see section 4.8).

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Content of the capsules: cellulose microcrystalline hydroxy propyl cellulose povidone K 90 croscarmellose sodium talc

magnesium stearate

Capsule shells: gelatin

sodium lauryl sulphate potassium hydroxide shellac

propylene glycol indigo carmine (E132) titanium dioxide (E171) iron oxide red (E172) iron oxide yellow (E172) black iron oxide (E 172)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months

6.4 Special precautions for storage

Store below 30°C. Store in the original package in order to protect from moisture.

Nature and contents of container

Arzip 250 mg Capsules are available in blister pack of 20, 100, 300 . The PVC /PVdC-aluminium blisters packed in final carton along with package insert. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Arzip 250 mg Capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Arzip 250 mg Capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK Or

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0323

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/10/2014

10 DATE OF REVISION OF THE TEXT

12/10/2014