SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Accempa 360 mg Gastro-resistant Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 360 mg mycophenolic acid (as mycophenolate sodium).

Excipients with known effect: Each tablet contains 27.9 mg (1.21 mmol) sodium For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gastro-resistant tablet

Peach colored, oblong shaped, biconvex, enteric-coated tablets imprinted with M2 on one side with black ink and plain on the other side.

Note: Length and Width of the tablet is 17.50 ± 0.2 mm and 10.35 ± 0.2 mm

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Accempa is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.

4.2 Posology and method of administration

Treatment with Accempa should be initiated and maintained by appropriately qualified transplant specialists.

The recommended dose is 720 mg administered twice daily (1,440 mg daily dose). This dose of mycophenolate sodium corresponds to 1 g mycophenolate mofetil administered twice daily (2 g daily dose) in terms of mycophenolic acid (MPA) content.

For additional information about the corresponding therapeutic doses of mycophenolate sodium and mycophenolate mofetil, see sections 4.4 and 5.2.

In de novo patients, Accempa should be initiated within 72 hours following transplantation.

Accempa can be taken with or without food. Patients may select either option but must adhere to their selected option (see section 5.2).

In order to retain the integrity of the enteric coating, Accempa should not be crushed.

Where crushing of Accempa is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.

Paediatric population

Insufficient data are available to support the efficacy and safety of Accempa in children and adolescents. Limited pharmacokinetic data are available for paediatric renal transplant patients (see section 5.2).

Elderly patients

The recommended dose in elderly patients is 720 mg twice daily.

Patients with renal impairment

In patients experiencing delayed renal graft function post-operatively, no dose adjustments are needed (see section 5.2).

Patients with severe renal impairment (glomerular filtration rate <25 mlmin^_1T.73 m ²) should be carefully monitored and the daily dose of Accempa should not exceed 1,440 mg.

Patients with hepatic impairment

No dose adjustments are needed for renal transplant patients with severe hepatic impairment.

Treatment during rejection episodes

Renal transplant rejection does not lead to changes in mycophenolic acid (MPA) pharmacokinetics; dosage modification or interruption of Accempa is not required.

4.3 Contraindications

Hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients listed in section 6.1.

Accempa is contraindicated in women who are breastfeeding and in women of child bearing potential (WOCBP) not using highly effective contraception methods (see section 4.6).

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

4.4 Special warnings and precautions for use

Patients receiving immunosuppressive regimens involving combinations of drugs, including Accempa, 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 Accempa should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

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

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate sodium in combination with other immunosuppressants. In some of these cases switching MPA derivatives to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on mycophenolate sodium 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 reports of bronchiectasis in patients who received mycophenolate sodium in combination with other immunosuppressants. In some of these cases switching MPA derivatives 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 (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated for any evidence of underlying interstitial lung disease.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (which include mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants. The mechanism for MPA derivatives induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of therapy. Changes to Accempa 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 receiving Accempa should be monitored for blood disorders (e.g. neutropenia or anemia - see section 4.8), which may be related to MPA itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Accempa 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 blood disorders occur (e.g. neutropenia with (absolute neutrophil count <1.5 x 10³/pl or anemia) it may be appropriate to interrupt or discontinue Accempa.

Patients should be advised that during treatment with MPA 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 MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and haemorrhage and perforation, Accempa should be administered with caution in patients with active serious digestive system disease.

It is recommended that Accempa not be administered concomitantly with azathioprine because concomitant administration of these drugs has not been evaluated.

Mycophenolic acid (as sodium salt) and mycophenolate mofetil should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.

Accempa has been administered in combination with corticosteroids and ciclosporin.

There is limited experience with its concomitant use with induction therapies such as anti-T-lymphocyte globulin or basiliximab. The efficacy and safety of the use of Accempa with other immunosuppressive agents (for example, tacrolimus) have not been studied.

The concomitant administration of Accempa and drugs which interfere with enterohepatic circulation, for example cholestyramine or activated charcoal, may result in sub-therapeutic systemic MPA exposure and reduced efficacy.

Accempa is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. 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.

Accempa therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Accempa therapy, during therapy and for six weeks following therapy discontinuation (see section 4.6).

Each Accempa 360mg Gastro-resistant Tablet contains 1.21 mmol (27.9 mg) sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

The following interactions have been reported between MPA and other medicinal products:

Aciclovir and ganciclovir

The potential for myelosuppression in patients receiving both Accempa and aciclovir or ganciclovir has not been studied. Increased levels of mycophenolic acid glucuronide (MPAG) and aciclovir/ganciclovir may be expected when aciclovir/ganciclovir and Accempa are administered concomitantly, possibly as a result of competition for the tubular secretion pathway.

The changes in MPAG pharmacokinetics are unlikely to be of clinical significance in patients with adequate renal function. In the presence of renal impairment, the potential exists for increases in plasma MPAG and aciclovir/ganciclovir concentrations; dose recommendations for aciclovir/ganciclovir should be followed and patients carefully observed.

Gastroprotective agents

Magnesium and aluminium containing antacids:

MPA AUC and C_max have been shown to decrease by approximately 37% and 25%, respectively, when a single dose of magnesium-aluminium containing antacids is given concomitantly with Accempa. Magnesium aluminium-containing antacids may be used intermittently for the treatment of occasional dyspepsia. However the chronic, daily use of magnesium-aluminium containing antacids with Accempa is not recommended due to the potential for decreased mycophenolic acid exposure and reduced efficacy.

Proton pump inhibitors

In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Accempa and pantoprazole given at 40 mg twice daily during the four previous days. No data are available with other proton pump inhibitors given at high doses.

Oral contraceptives

Interaction studies between MMF and oral contraceptives indicate no interaction. Given the metabolic profile of MPA, no interactions would be expected for Accempa and oral contraceptives.

Cholestyramine and drugs that bind bile acids

Caution should be used when co-administering drugs or therapies that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to decrease MPA exposure and thus reduce the efficacy of Accempa.

Ciclosporin

When studied in stable renal transplant patients, ciclosporin pharmacokinetics were unaffected by steady state dosing of Accempa. When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA.

When co-administered with Accempa, ciclosporin may decrease the concentration of MPA as well (by approximately 20%, extrapolated from mycophenolate mofetil data), but the exact extent of this decrease is unknown because such an interaction has not been studied. However, as efficacy studies were conducted in combination with ciclosporin, this interaction does not modify the recommended posology of Accempa. In case of interruption or discontinuation of ciclosporin, Accempa dosage should be re-evaluated depending on the immunosuppressive regimen.

Tacrolimus

In a calcineurin cross-over study in stable renal transplant patients, steady-state Accempa pharmacokinetics were measured during both Neoral and tacrolimus treatment. Mean MPA AUC was 19% higher (90% CI: -3, +47), whereas mean MPAG AUC was about 30% lower (90% CI: 16, 42) on tacrolimus compared to Neoral treatment. In addition, MPA AUC intra-subject variability was doubled when switching from Neoral to tacrolimus. Clinicians should note this increase both in MPA AUC and variability, and adjustments to Accempa dosing should be dictated by the clinical situation. Close clinical monitoring should be performed when a switch from one calcineurin inhibitor to another is planned.

Live attenuated vaccines

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

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

Accempa therapy should not be initiated until a negative pregnancy test has been obtained

Contraception in males and females

Women of childbearing potential must use highly effective contraception methods before beginning Accempa therapy, during Accempa therapy and for six weeks after their last dose of Accempa.

Sexually active men are recommended to use condoms during treatment, and for a total of 13 weeks after their last dose of Accempa. In addition, female partners of these male patients are recommended to use highly effective contraception during treatment and for a total of 13 weeks after the last dose of Accempa.

Pregnancy

The use of Accempa is not recommended during pregnancy and should be reserved for cases where no alternative treatment is available.

There is limited data from the use of Accempa in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, cleft palate and cleft lip, micrognathia and cardiopathies have been reported in children of patients exposed to mycophenolate during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to mycophenolic acid compounds. Studies in animals have shown reproductive toxicity (see section 5.3).

Breast feeding

MPA is excreted in milk in lactating rats. It is unknown whether Accempa is excreted in human breast milk. Because of the potential for serious adverse reactions to MPA in breast-fed infants, Accempa is contra-indicated in women who are breast-feeding (see section 4.3).

Fertility

No specific studies with Accempa in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen up to a dose of 40 mg/kg and 20 mg/kg respectively (see section 5.3).

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 mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

4.8 Undesirable effects

The following undesirable effects cover adverse drug reactions from clinical trials:

Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients and in 2 maintenance patients (1.3%) receiving Accempa for up to 1 year. Non-melanoma skin carcinomas occurred in 0.9% of de novo and 1.8% of maintenance patients receiving Accempa for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.

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 de novo renal transplant patients receiving Accempa with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serology, viraemia or disease) was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.

Elderly patients

Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression.

Other adverse drug reactions

Table 1 below contains adverse drug reactions possibly or probably related to Accempa reported in the controlled clinical trials in renal transplant patients, in which Accempa was administered together with ciclosporin microemulsion and corticosteroids at a dose of 1,440 mg/day for 12 months. It is compiled according to MedDRA system organ class.

Adverse reactions are listed according to the following categories:

Very common	(A 1/10)
Common	(>1/100 to <1/10)
Uncommon	(A 1/1,000 to <1/100)

Rare	(>1/10,000 to <1/1,000)
Very rare	(<1/10,000)

Infections and infestations
Very common:	Viral, bacterial and fungal infections
Common:	Upper respiratory tract infections, pneumonia
Uncommon:	Wound infection, sepsis*, osteomyelitis*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon:	Skin papilloma*, basal cell carcinoma*, Kaposi's sarcoma*, lymphoproliferative disorder, squamous cell carcinoma*
Blood and lymphatic system disorders
Very common:	Leukopenia
Common:	Anaemia, thrombocytopenia
Uncommon:	lymphopenia*, neutropenia*, lymphadenopathy*
Metabolism and nutrition disorders
Uncommon:	Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia
Psychiatric disorders
Uncommon:	Abnormal dreams*, delusional perception*, Insomnia*
Nervous system disorders
Common:	Headache
Uncommon:	Tremor
Eye disorders
Uncommon:	Conjunctivitis*, vision blurred*
Cardiac disorders
Uncommon:	Tachycardia, ventricular extrasystoles
Vascular disorders:
Uncommon	Lymphocele*
Respiratory, thoracic and mediastinal disorders
Common:	Cough
Uncommon:	Pulmonary congestion*, wheezing*, pulmonary oedema*
Gastrointestinal disorders
Very common:	Diarrhoea
Common:	Abdominal distension, abdominal pain, constipation, dyspepsia,

	flatulence, gastritis, nausea, vomiting
Uncommon:	Abdominal tenderness, gastrointestinal haemorrhage, eructation, halitosis*, ileus*, lip ulceration*, oesophagitis*, subileus*, tongue discolouration*, dry mouth*, gastro-oesophageal reflux disease*, gingival hyperplasia*, pancreatitis, parotid duct obstruction*, peptic ulcer*, peritonitis*
Hepato-biliary disorders
Common:	Hepatic function tests abnormal
Skin and subcutaneous tissue disorders
Uncommon:	Alopecia
Musculoskeletal and connective tissue disorders
Uncommon:	Arthritis*, back pain*, muscle cramps
Renal and urinary disorders
Common:	Blood creatinine increased
Uncommon:	Haematuria*, renal tubular necrosis*, urethral stricture
Reproductive system and breast disorders
Uncommon:	Impotence*
General disorders and administration site conditions
Common:	Fatigue, pyrexia
Uncommon:	Influenza like illness, oedema lower limb*, pain, rigors*, thirst*, weakness*
Injury, poisoning and procedural complications
Uncommon:	Contusion*

* event reported in a single patient (out of 372) only.

Note: renal transplant patients were treated with 1,440 mg Accempa daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.

Rash has been identified as an adverse drug reaction from post marketing experience.

Respiratory, thoracic and mediastinal disorders:

There have been isolated reports of interstitial lung disease in patients treated with mycophenolate sodium in combination with other immunosuppressants. There have also been reports of bronchiectasis in combination with other immunosuppressants.

Immune system disorders:

Hypogammaglobulinaemia has been reported in patients receiving mycophenolate sodium in combination with other immunosuppressants.

The following additional adverse reactions are attributed to MPA derivatives as a class effect:

Gastrointestinal disorders

colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

Infections and infestations

serious, life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Accempa (see section 4.4).

Blood and lymphatic system disorders neutropenia, pancytopenia.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (see section 4.4).

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

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

There have been reports of intentional or accidental overdoses with Accempa, whereas not all patients experienced related adverse events.

In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the class (mainly blood dyscrasias, sepsis...) (see sections 4.4 and 4.8).

Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants: selective immunosupressants, ATC code: L04AA06

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 utilize salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal concentration (Tmax) of MPA was approximately 1.5-2 hours. Approximately 10% of all morning pharmacokinetic profiles showed a delayed Tmax, sometimes up to several hours, without any expected impact on 24 hour/daily MPA exposure.

In stable renal transplant patients on ciclosporin based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Accempa pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2,160 mg.

Compared to the fasting state, administration of a single dose of Accempa 720 mg with a high fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC), which is the most relevant pharmacokinetic parameter linked to efficacy. However there was a 33% decrease in the maximal concentration of MPA (C_max). Moreover, T_lag and T_max were on average 3-5 hours delayed, with several patients having a T_max of>15 hours. The effect of food on Accempa may lead to an absorption overlap from one dose interval to another. However, this effect was not shown to be clinically significant.

Distribution

The volume of distribution at steady state for MPA is 50 litres. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound (97% and 82%, respectively). The free MPA concentration may increase under conditions of decreased protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs with high protein binding). This may put patients at increased risk of MPA-related adverse effects.

Elimination

The half life of MPA is approximately 12 hours and the clearance is 8.6 l/h.

Metabolism

MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). MPAG is the predominant metabolite of MPA and does not manifest biological activity. In stable renal transplant patients on ciclosporin-based immunosuppression, approximately 28% of the oral Accempa dose is converted to MPAG by presystemic metabolism. The half life of MPAG is longer than that of MPA, approximately 16 hours and its clearance is 0.45 l/h.

Excretion

Although negligible amounts of MPA are present in the urine (<1.0%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hours after Accempa dosing a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA. There is large variability in the MPA trough levels inherent to MPA preparations, and high morning trough levels (C₀> 10 pg/ml) have been observed in approximately 2% of patients treated with Accempa. However, across studies, the AUC at steady state (0-12h) which is indicative of the overall exposure showed a lower variability than the one corresponding to Ctrough.

Pharmacokinetics in renal transplant patients on ciclosporin based immunosuppression

Shown in Table 2 are mean pharmacokinetic parameters for MPA following the administration of Accempa. In the early post transplant period, mean MPA AUC and mean MPA C_max were approximately one-half of the values measured six months post transplant.

Table 2 Mean (SD) pharmacokinetic parameters for MPA following oral administration of Accempa to renal transplant patients on ciclosporin-based immunosuppression

Adult chronic, multiple	Dose	T * Amax	Cmax	AUC 0-12
dosing 720 mg BID		(h)	(Pg/ml)	(pg x h/ml)

(Study ERLB 301) n=48
14 days post-transplant	720 mg	2	13.9 (8.6)	29.1 (10.4)
3 months post -transplant	720 mg	2	24.6 (13.2)	50.7 (17.3)
6 months post-transplant	720 mg	2	23.0 (10.1)	55.7 (14.6)
Adult chronic, multiple dosing 720 mg BID 18 months post-transplant (Study ERLB 302) n=18	Dose	T * A max (h)	Cmax (Pg/ml)	AUC 0-12 (pg x h/ml)
	720 mg	1.5	18.9 (7.9)	57.4 (15.0)
Paediatric 450 mg/m single dose (Study ERL 0106) n=16	Dose	T * Amax (h)	Cmax (Pg/ml)	AUC o- oo (pg x h/ml)
	450 mg/m2	2.5	31.9 (18.2)	74.5 (28.3)

* median values

Renal impairment

MPA pharmacokinetics appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by haemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased plasma protein binding of MPA in the presence of high blood urea concentration.

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.

Paediatric population

Limited data are available on the use of Accempa in children and adolescents. In Table 2 above the mean (SD) MPA pharmacokinetics are shown for stable paediatric renal transplant patients (aged 5-16 years) on ciclosporin-based immunosuppression. Mean MPA AUC at a dose of 450 mg/m² was similar to that measured in adults receiving 720 mg Accempa. The mean apparent clearance of MPA was approximately 6.7 l/h/m².

Gender

There are no clinically significant gender differences in Accempa pharmacokinetics.

Elderly

Pharmacokinetics in the elderly have not formally been studied. MPA exposure does not appear to vary to a clinically significant degree by age.

5.3 Preclinical safety data

The haematopoetic and lymphoid system were the primary organs affected in repeated-dose toxicity studies conducted with mycophenolate sodium in rats and mice. Aplastic, regenerative anemia was identified as being the dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a marked decrease in erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent enlargement of the spleen and increase in extramedullary hematopoiesis.These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of Accempa in renal transplant patients.

Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses.

The non-clinical toxicity profile of mycophenolic acid (as sodium salt) 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).

Three genotoxicity assays (in vitro mouse lymphoma assay, micronucleus test in V79 Chinese hamster cells and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolic acid 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.

Mycophenolic acid (as sodium salt) was not tumourigenic in rats and mice. The highest dose tested in the animal carcinogenicity studies resulted in approximately 0.6-5 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 1.44 g/day.

Mycophenolic acid (as sodium salt) had no effect on fertility of male or female rats up to dose levels at which general toxicity and embryotoxicity were observed.

In a teratology study performed with mycophenolic acid (as sodium salt) in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia.

The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of Accempa (see section 4.6).

In a pre- and postnatal development study in rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg that also induced malformations.

Mycophenolic acid (as sodium salt) showed a phototoxic potential in an in vitro 3T3 NRU phototoxicity assay.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core

Cellulose Microcrystalline (E460)

Croscarmellose sodium (E468)

Povidone K30 (E1201)

Talc (E553b)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470b)

Coating

Methacrylic acid - ethyl acrylate copolymer (1:1), Talc (E553b),

Titanium dioxide (E171),

Triethyl citrate (E1505),

Silica, colloidal anhydrous (E551),

Sodium hydrogen carbonate (E500),

Iron oxide yellow (E172),

Iron oxide red (E172),

Sodium laurilsulfate (E487).

Imprinting

Shellac glaze, partially esterified (E904),

Iron oxide black (E172),

Propylene glycol (E1520).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

The tablets are packed in

Aluminium-aluminium blisters: 50, 100, 120 and 250 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

In order to retain the integrity of the enteric coating, Accempa should not be crushed (see section 4.2).

Mycophenolic acid has demonstrated teratogenic effects (see section 4.6). Where crushing of Accempa is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.

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

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road,

Hampden Park,

Eastbourne,

East Sussex BN22 9AG UNITED KINGDOM

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1896

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/02/2015

10    DATE OF REVISION OF THE TEXT

20/02/2015