CellCept 1 g/ 5 ml Powder for Oral Suspension

EU SPC and PIL EMEA/H/C/000082/IA/in

New multipack presentation for the capsules, i.e., multipack 300(3 packs of 100) capsules, correction of the Annex III-A oral suspension (bottle label), and several corrections within the whole annexes set. Following the registration of Delpharm as an additional packaging site, a new commercial presentation is introduced to the market. This triggered the update of the PI (SmpC section 6.5, section 8, annexx III-A: new section).Alignement to QRD 10.1

Underlined text has been added, text with strike-through deleted:

 

7.            MARKETING AUTHORISATION HOLDER

 

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

 

10.          DATE OF REVISION OF THE TEXT

 

12 March 2018

 

Underlined text has been added, text with strike-through deleted:

4.4          Special warnings and precautions for use

[…]

Teratogenic effects

Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45% to -49%) and congenital malformations (estimated rate of 23-%- to 27%) have been reported following MMF exposure during pregnancy.  Therefore CellCept is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection.  Female and male patients of reproductive childbearing potential should be made aware of the risks and follow the recommendations provided in section 4.6. (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with CellCept. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.

 

Contraception (see section 4.6)

Because of robust clinical evidence showing a high risk of abortion and congential malformations when mycophenolate mofetil is used in pregnancy every effort to avoid pregnancy during treatment should be taken.the genotoxic and teratogenic potential of CellCept, Therefore women with childbearing potential should must use at least one form of reliable contraception (see section 4.3)two reliable forms of contraception simultaneously before starting CellCept therapy, during therapy, and for six weeks after stopping the  therapy; , unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preffered to minimise the potential for contraceptive failure and unintended pregnancy. (see section 4.5).

 

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

For contraception advice for men see section 4.6.

 

[…]

4.6          Pregnancy and lactation

 

Contraception in males and females

CellCept is contraindicated in women of childbearing potential who are not using highly effective contraception.

Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception (see section 4.5).

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

Women of childbearing potential

Pregnancy whilst taking mycophenolate must be avoided. Therefore women of childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred.

Pregnancy

CellCept  is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy.

 

Female and male patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counseled regarding pregnancy prevention, and planning.

 

Before starting CellCept treatment, women of child bearing potential should have atwo negative serum or urine pregnancy testtests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of the embryo to mycophenolate.  Two serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL are recommended; the It is recommended that the second test should be performed 8 – 10 days after the first test.one and immediately before starting mycophenolate mofetil. For transplants from deceased donors, if it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a further test performed 8-10 days later. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.

 

Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy;

•          Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.

•          Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3 % of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil).

 

Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to CellCept during pregnancy in combination with other immunosuppressants. . The following malformations were most frequently reported:

 

•          Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear), external auditory canal artesia; (middle ear);

•             Congenital heart disease such as atrial and ventricular septal defects;

•             Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;

•             Abnormalities of the eye (e.g. coloboma);

•             Congenital heart disease such as atrial and ventricular septal defects;

•             Malformations of the fingers (e.g. polydactyly, syndactyly);

•             Tracheo-Oesophageal malformations (e.g. oesophageal atresia);

•             Nervous system malformations such as spina bifida;

•             Renal abnormalities.

 

In addition there have been isolated reports of the following malformations:

•             Microphthalmia;

•             congenital choroid plexus cyst;

•             septum pellucidum agenesis;

•             olfactory nerve agenesis.

 

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 substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing mothers (see section 4.3).

Men

Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate mofetil.

MPA is a powerful teratogen. It is not known if MPA is present in semen. Calculations based on animal data show that the maximum amount of MPA that could potentially be transferred to woman is so low that it would be unlikely to have an effect.  Mycophenolate has been shown to be genotoxic in animal studies at concentrations exceeding the human therapeutic exposures only by small margins such that the risk of genotoxic effects on sperm cells cannot completely be excluded.

Therefore, the following precautionary measures are recommended: sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 90 days after cessation of mycophenolate mofetil. Male patients of reproductive potential should be made aware of and discuss the potential risks of fathering a child with a qualified health-care professional.

 

10.          DATE OF REVISION OF THE TEXT

 

05 March 2018

Underlined text has been added, text with strike-through deleted:

4.4          Special warnings and precautions for use

[…]

Interactions

 

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others devoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs  which interfere with MPA’s enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce plasma levels and efficacy of CellCept (see also section 4.5). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics).

[…]

10.          DATE OF REVISION OF THE TEXT

18 January 2018

 

Underlined text has been added, text with strike-through deleted:

4.4          Special warnings and precautions for use

[…]

Interactions

 

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others devoid of this effect, e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs of other classes which interfere with MPA’s enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see also section 4.5).

[…]

4.5          Interaction with other medicinal products and other forms of interaction

[…]

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 section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.

Medicinal products that interfere with enterohepatic circulation (e.g. cholestyramine, ciclosporin A,  

antibiotics)

Caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of CellCept.

 

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 section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.

 

[…]

Antibiotics eliminating b-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning the following antibiotics is available:

Ciprofloxacin and or amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept 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.

Norfloxacin and metronidazole

In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept.

Trimethoprim/sulfamethoxazole

No effect on the bioavailability of MPA was observed.

Medicinal products that affect glucuronidation (e.g. isavuconazole, telmisartan)

Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure. Caution is therefore recommended when administering these drugs concomitantly with CellCept.

 

Isavuconazole

An increase of MPA AUC_0-∞ by 35% was observed with concomitant administration of isavuconazole.

[…]

Trimethoprim/sulfamethoxazole

No effect on the bioavailability of MPA was observed.

Norfloxacin and metronidazole

In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept.

Ciprofloxacin and amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept 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 CellCept and tacrolimus, the AUC and C_max of MPA, the active metabolite of CellCept, 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 CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also 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 substance undergoing tubular secretion.

Live vaccines

Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).

 

Paediatric population

Interaction studies have only been performed in adults.

 

OtherPotential interactions

Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.

 

[…]

 

6.6          Special precautions for disposal and other handling

 

It is recommended that CellCept 1 g/5 ml powder for oral suspension be reconstituted by the pharmacist prior to dispensing to the patient. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution.

[…]

10.          DATE OF REVISION OF THE TEXT

 

23 November 2017

 

Text underlined has been added, text with strike-through deleted

 

2.       Qualitative and quantitative composition

 

Each bottle contains 35 g mycophenolate mofetil in 110 g powder for oral suspension. 5 mlmL of the reconstituted suspension contains 1 g of mycophenolate mofetil.

 

For the full list of excipients, see section 6.1.

 

 

 

4.2       Posology and method of administration

 

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

 

 

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

 

Posology

 

Use in renal transplant:

 

Adults

Oral CellCept 1 g/5 ml powder for oral suspension should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose), i.e. Adults: oral CellCept 1 g/5 ml powder for oral suspension should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose), i.e. 5 mlmL oral suspension twice daily.

 

Children and adolescents (Paediatric population aged 2 to 18 years): the

The recommended dose of CellCept 1 g/5 ml powder for oral suspension is 600 mg/m² administered twice daily (up to a maximum of 2 g/10 mlmL oral suspension daily). 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.

 

Paediatric population < 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 CellCept 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 (< 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 CellCept 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: noPaediatric population

No data are available for paediatric cardiac transplant patients.

 

Use in hepatic transplant:

 

Adults

IV CellCept should be administered for the first 4 days following hepatic transplant, with oral CellCept 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).

 

Adults: IV CellCept should be administered for the first 4 days following hepatic transplant, with oral CellCept 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: noPaediatric population

No data are available for paediatric hepatic transplant patients.

 

Use in elderly (³ 65 years): thespecial populations

 

Elderly

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

 

Use in renal  Renal impairment: in

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml·mL/min^-1·/1.73 m^-2m²), 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.

 

 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

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of CellCept is not required. There is no basis for CellCept dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

 

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: mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of CellCept is not required. There is no basis for CellCept dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

 

Method of administration

 

Oral administration.

Note

: If required, CellCept 1 g/5 ml powder for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

 

Precautions to be taken before handling or administering the medicinal product.

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid inhalation or direct contact with skin or mucous membranes of the dry powder as well as direct contact of the reconstituted suspension with the skin. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

 

For instruction on reconstitution of the medicinal product before administration, see section 6.6.

 

4.3       Contraindications

 

 

4.3       Contraindications

 

•        CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1.  Hypersensitivity reactions to CellCept have been observed (see section 4.8). Therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.

 

•        CellCept is contraindicated inshould not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).

 

•        CellCept treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

 

•        CellCept should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).

 

•        CellCept should not be given to 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

 

Neoplasms

 

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, 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.

 

Infections

 

Patients treated with immunosuppressants, including CellCept, 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, JC virus associated progressive multifocal leukoencephalopathy PML) . Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

 

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept 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 CellCept in combination with other immunosuppressants. In some of these cases switching CellCept 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 receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, 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 CellCept 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 CellCept, 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, JC virus associated progressive multifocal leukoencephalopathy PML) . Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

 

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept 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 CellCept in combination with other immunosuppressants. In some of these cases switching CellCept 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.

 

Blood and immune system

 

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

 

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes to CellCept 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 CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

 

Patients should be advised that during treatment with CellCept, 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.

 

Gastro-intestinal

 

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

 

CellCept is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, thereforeTherefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

 

Interactions

It is recommended that CellCept should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

 

Caution should be exercised  when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs of other classes which interfere with MPA’s enterohepatic cycle e.g. cholestyramine, should be used with caution due to their potential to reduce plasma levels andefficacyand efficacy of CellCept (see also section 4.5).

 

 

It is recommended that CellCept should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

 

CellCept 1 g/5 ml powder for oral suspension contains aspartame. Therefore, care should be taken if CellCept 1 g/5 ml powder for oral suspension is administered to patients with phenylketonuria (see section 6.1)

 

The risk: /benefit ratio of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see also section 4.5).

 

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

 

Special populations

 

Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals (see section 4.8).

 

Teratogenic effects

Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45-49%) and congenital malformations (estimated rate of 23-27%) have been reported following MMF exposure during pregnancy.  Therefore CellCept is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection.  Female and male patients of reproductive potential should be made aware of the risks and follow the recommendations provided in section 4.6. (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with CellCept. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.

 

Contraception (see section 4.6)

Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before starting CellCept therapy, during therapy, and for six weeks after stopping the  therapy; unless abstinence is the chosen method of contraception (see section 4.5).

 

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

 

Educational materials

In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.

 

Additional precautions

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Aciclovir

HigherInteraction 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.

 

 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): Antacids and proton pump inhibitors (PPIs)

Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept 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 CellCept was co- administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.

 

Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept 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 CellCept was co- administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.

 

Cholestyramine: following

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 section 4.4, and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.

 

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 CellCept.

Caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of CellCept.

 

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. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30‑50% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of CellCept (see also section 4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which does not interfere with MPA´s enterohepatic cycle.

 

Telmisartan

Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic drug-drug interaction were seen.

 

Ganciclovir: based

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 CellCept (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 CellCept dose adjustment is not required. In patients with renal impairment in whom CellCept 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

The pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by coadministrationco‑administration of CellCept (see also section 5.2).

 

Rifampicin: in

In patients not also taking ciclosporin, concomitant administration of CellCept 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 CellCept doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.

 

Sevelamer: decrease

Decrease in MPA C_max and AUC0-12AUC (0-12h) by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There are no data on CellCept with phosphate binders other than sevelamer.

 

Trimethoprim/sulfamethoxazole: no effect on the bioavailability of MPA was observed.

No effect on the bioavailability of MPA was observed.

 

Norfloxacin and metronidazole: in

In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept.

 

Ciprofloxacin and amoxicillin plus clavulanic acid:

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept 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

In hepatic transplant patients initiated on CellCept and tacrolimus, the AUC and C_max of MPA, the active metabolite of CellCept, were not significantly affected by coadministrationco‑administration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4).

 

Other interactions: co

Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.

 

Live vaccines

LiveLive vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).

 

Paediatric population

Interaction studies have only been performed in adults.

 

4.6       Pregnancy and lactation

 

Pregnancy:

It isContraception in males and females

CellCept is contraindicated in women of childbearing potential who are not using highly effective contraception.

 

Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception (see section 4.5).

 

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

 

Pregnancy

that CellCept therapy

CellCept  is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.Treatment should not be initiated untilwithout providing a negative pregnancy test has been obtained. Effective contraceptionresult to rule out unintended use in pregnancy.

 

Female and male patients of reproductive potential must be used before made aware of the increased risk of pregnancy loss and congenital malformations at the beginning CellCept therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5).of the treatment and must be counseled regarding pregnancy prevention, and planning.

 

Before starting CellCept treatment, women of child bearing potential should have a pregnancy test in order to exclude unintended exposure of the embryo to mycophenolate.  Two serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL are recommended; the second test should be performed 8 – 10 days after the first one and immediately before starting mycophenolate mofetil. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.

 

The use of CellCept is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. CellCept should be used in Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy;

•        Spontaneous abortions have been reported in 45 to 49% of  pregnant women only if the potential benefit outweighs the potential riskexposed to the foetus. There is limited data from the usemycophenolate mofetil, compared to a reported rate of CellCeptbetween 12 and 33% in pregnant women. However, congenitalsolid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.

•        Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3 % of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil).

 

Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to CellCept during pregnancy in combination with other immunosuppressants. . The following malformations were most frequently reported:

 

•        Abnormalities of the ear malformations, i.(e.g. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to CellCept in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to CellCept. ), external auditory canal artesia;

•           Congenital heart disease such as atrial and ventricular septal defects;

•           Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;

•           Abnormalities of the eye (e.g. coloboma);

•           Malformations of the fingers (e.g. polydactyly, syndactyly);

•           Tracheo-Oesophageal malformations (e.g. oesophageal atresia);

•           Nervous system malformations such as spina bifida;

•           Renal abnormalities.

 

In addition there have been isolated reports of the following malformations:

•           Microphthalmia;

•           congenital choroid plexus cyst;

•           septum pellucidum agenesis;

•           olfactory nerve agenesis.

 

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 substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing mothers (see section 4.3).

 

4.8       Undesirable effects

 

The following undesirable effects cover adverse reactions from clinical trials:

The principal adverse reactions associated with the administration of CellCept 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).

 

MalignanciesLactation:

 

Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is 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 CellCept 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 CellCept, 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 CellCept (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 (see section 4.4). The most common opportunistic infections in patients receiving CellCept (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):

Paediatric population

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 CellCept 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, leucopenia, anaemia and infection.

 

Elderly patients (³ 65 years):

Elderly patients (³ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving CellCept 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 reactions, probably or possibly related to CellCept, reported in ³1/10 and in ³1/100 to <1/10 of patients treated with CellCept 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 CellCept, Reported in Patients Treated with CellCept 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 formfrom 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, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Very common	-
	Common	Skin cancer, benign neoplasm of skin
Blood and lymphatic system disorders	Very common	Leucopenia, thrombocytopenia, anaemia
	Common	Pancytopenia, leukocytosis
Metabolism and nutrition disorders	Very common	-
	Common	Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout, anorexia
Psychiatric disorders	Very common	-
	Common	Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia
Nervous system disorders	Very common	-
	Common	Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia
Cardiac disorders	Very common	-
	Common	Tachycardia
Vascular disorders	Very common	-
	Common	Hypotension, hypertension, vasodilatation
Respiratory, thoracic and mediastinal disorders	Very common	-
	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	Very common	-
	Common	Hepatitis, jaundice, hyperbilirubinaemia
Skin and subcutaneous tissue disorders	Very common	-
	Common	Skin hypertrophy, rash, acne, alopecia,
Musculoskeletal and connective Tissue disorders	Very common	-
	Common	Arthralgia
Renal and urinary disorders	Very common	-
	Common	Renal impairment
General disorders and administration site conditions	Very common	-
	Common	Oedema, pyrexia, chills, pain, malaise, asthenia,
Investigations	Very common	-
	Common	Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, blood alkaline phosphatase increased, weight decreased

Note: 501 (2 g CellCept daily), 289 (3 g CellCept daily) and 277 (2 g IV / 3 g oral CellCept 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 CellCept 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

Gingival hyperplasia (≥1/100 to <1/10), colitis including cytomegaloviruscolitis, (≥1/100 to <1/10), pancreatitis (≥1/100 to <1/10) and intestinal villous atrophy.

 

Disorders related to immunosuppression: seriousInfections

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 CellCept.

Agranulocytosis (≥1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking CellCept is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in patients treated with CellCept, 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 CellCept (see section 4.4).

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

 

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

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

 

Hypersensitivity:

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

 

Pregnancy, puerperium and perinatal conditions

Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.

 

Congenital disorders: see further details in section 4.6.

 

Respiratory, thoracic and mediastinal disorders:

ThereCongenital malformations have been isolated reportsobserved post-marketing in children of interstitial lung disease and pulmonary fibrosis in patients treated withexposed to CellCept 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).see section 4.6.

 

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept 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 disordersImmune system disorders:

 

Hypogammaglobulinaemia has been reported in patients receiving CellCept 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 (see details below).

 

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

 

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

 

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 CellCept 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 C_max 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 co-administration of cholestyramine (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 (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

 

Elimination

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

 

Elimination

 

A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Oral administration of 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 (> 100µg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC (see section 4.9).

MPA’s disposition depends on several transporters. Organic anion‑transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides’ biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.

 

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

 

Special populations

 

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 < 25ml·25mL/min^-1·/1.73 m^-2m²) 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 post-transplant 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 CellCept 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):

Paediatric population

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) 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 CellCept at a dose of 1 g bid in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

 

Elderly patients (³ 65 years):

Pharmacokinetic behaviour of CellCept in the elderly (³ 65 years) has not been formally evaluated.

 

OralPatients taking oral contraceptives:

The pharmacokinetics of oral contraceptives were unaffected by coadministrationco‑administration of CellCept (see also section 4.5). A study of the coadministrationco‑administration of CellCept (1 g 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 non-transplant women (not taking other immunosupressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of CellCept 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 C_max) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 – 2 times the systemic exposure (AUC or C_max) 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^-1·^-/day^-1 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^-1·/day^-1 (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg·kg¹·/kg/day^-1 (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. (see section 4.6).

 

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 dose. 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 nonclinical 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

 

CellCept 1 g/5 ml powder for oral suspension:

sorbitol

silica, colloidal anhydrous

sodium citrate

soybean lecithin

mixed fruit flavour

xanthan gum

aspartame* (E951)

methyl parahydroxybenzoate (E218)

citric acid anhydrous

 

* contains phenylalanine equivalent to 2.78 mg/5 mlmL of suspension.

 

6.5       Nature and contents of container

 

Each bottle contains 35 g mycophenolate mofetil in 110 g powder for oral suspension.  When reconstituted, the volume of the suspension is 175 mlmL, providing a usable volume of 160 – 165 mlmL. 5 mlmL of the reconstituted suspension contains 1 g of mycophenolate mofetil.

A bottle adapter and 2 oral dispensers are also provided.

 

6.6       Special precautions for disposal and other handling

 

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid inhalation or direct contact with skin or mucous membranes of the dry powder as well as direct contact of the reconstituted suspension with the skin. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

 

It is recommended that CellCept 1 g/5 ml powder for oral suspension be reconstituted by the pharmacist prior to dispensing to the patient.

 

Preparation of suspension

 

1.         Tap the closed bottle several times to loosen the powder.

2.         Measure 94 mlmL of purified water in a graduated cylinder.

3.       Add approximately half of the total amount of purified water to the bottle and shake the closed bottle well for about 1 minute.

4.         Add the remainder of water and shake the closed bottle well for about 1 minute.

5.         Remove child-resistant cap and push bottle adapter into neck of bottle.

6.       Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.

7.       Write the date of expiration of the reconstituted suspension on the bottle label. (The shelf-life of the reconstituted suspension is two months.)

 

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

 

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 14 February 1996

Date of latest renewal: 14 February 13 March 2006

 

 

10.       DATE OF REVISION OF THE TEXT

 

27 November 2015

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency  http://www.ema.europa.euhttp://www.ema.europa.eu/

 

 

 

Underlined text has been added, text with strike-through deleted:

4.2       Posology and method of administration

[…]

Treatment during rejection episodes: mycophenolic acid (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 CellCept is not required. There is no basis for CellCept dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

[…]

4.4       Special warnings and precautions for use

[…]

It is recommended that CellCept should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

In view of the significant reduction in the AUC of MPA by cholestyramine, cCaution should be used exercised in the concomitant administration of CellCept with medicinal products that when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation because of e.g. ciclosporin to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs of other classes which interfere with MPA’s enterohepatic cycle e.g. cholestyramine, should be used with caution due to their the potential to reduce plasma levels and the efficacy of CellCept (see also section 4.5).

[…]

4.5       Interaction with other medicinal products and other forms of interaction

[…]

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 CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept 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 CellCept was co- administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.

Cholestyramine: following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40 % reduction in the AUC of MPA. (see section 4.4, and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.

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 CellCept.

 

Ciclosporin A:

ciclosporin 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. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30‑50% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of CellCept (see also section 4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which does not interfere with MPA´s enterohepatic cycle.

Telmisartan

Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic drug-drug interaction were seen.

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 CellCept (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 CellCept dose adjustment is not required. In patients with renal impairment in which whom CellCept 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 CellCept (see also section 5.2).

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

Sirolimus: in renal transplant patients, concomitant administration of CellCept and CsA resulted in reduced MPA exposures by 30‑50% compared with patients receiving the combination of sirolimus and similar doses of CellCept (see also section 4.4).

Sevelamer: decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is are no data on CellCept 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 CellCept was concomitantly administered with norfloxacin and or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of CellCept.

 

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 antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept 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 CellCept and tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also 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 substance undergoing tubular secretion.

Live vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).

5.2       Pharmacokinetic properties

[…]

Biotransformation

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG), which is not pharmacologically active. In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

Elimination

A negligible amount of substance is excreted as MPA (< 1 % of dose) in the urine. Orally administered administration of 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 (> 100µg/mlmL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC (see section 4.9).

MPA’s disposition depends on several transporters. Organic anion‑transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides’ biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.

[…]

10.       DATE OF REVISION OF THE TEXT

26 March 2015

 

 

4.4     Special warnings and precautions for use

[....]

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept 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 CellCept in combination with other immunosuppressants. In some of these cases switching CellCept 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.

 

[....]

4.8     Undesirable effects

 

[....]

Respiratory, thoracic and mediastinal disorders:

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept 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 CellCept in combination with other immunosuppressants (frequency not known).

 

 

[....]

10.     DATE OF REVISION OF THE TEXT

 

19 December 2014

 

Underlined text = new text

Strike through text = deleted text

 

SUMMARY OF PRODUCT CHARACTERISTICS

 

 

 

4.4     Special warnings and precautions for use

 

[ … ]

 

Patients treated with immunosuppressants, including CellCept, 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 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.

 

[ … ]

 

4.6     Pregnancy and lactation

 

Pregnancy:

It is recommended that CellCept therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning CellCept 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 CellCept is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. CellCept 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 CellCept 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 CellCept in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to CellCept. Studies in animals have shown reproductive toxicity (see section 5.3).

 

Lactation:

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

 

4.8     Undesirable effects

 

[ … ]

 

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 (see details below).

 

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

 

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

 

 

 

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 CellCept 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 C_max was decreased by 40 % in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. MPA at clinically relevant concentrations is 97 % bound to plasma albumin.

 

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 co-administration of cholestyramine (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.

 

[ … ]

 

 

6.5     Nature and contents of container

 

Each bottle contains 35 g mycophenolate mofetil in 110 g powder for oral suspension. Each bottle contains 110 g of powder for oral suspension. When reconstituted, the volume of the suspension is 175 ml, providing a usable volume of 160 – 165 ml. 5 ml of the reconstituted suspension contains 1 g of mycophenolate mofetil.

A bottle adapter and 2 oral dispensers are also provided.

 

10.     DATE OF REVISION OF THE TEXT

 

20 July 201225 July 2013

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/

 

 

 

Underlined text = new text
Struck through text = deleted text

4.5     Interaction with other medicinal products and other forms of interaction

 

[…]

 

Antacids with magnesium and aluminium hydroxides: absorption of mycophenolate mofetil was decreased when administered with antacids.

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 CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept 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 CellCept was co- administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.

 

[…]

 

10.     DATE OF REVISION OF THE TEXT

 

13 October 200920 July 2012

Underlined text has been added, text with strike through deleted:

 

4.8 Undesirable effects

 

Respiratory, thoracic and mediastinal disorders:

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

 

 



Underlined text has been added, text with strike through deleted:

 

4.4       Special warnings and precautions for use

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes to CellCept therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).

 

4.5     Interaction with other medicinal products and other forms of interaction

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 CellCept 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.

 

4.8     Undesirable effects

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

 

Blood and lymphatic system disorder:

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

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

 

 

Underlined text has been added, text with strike through deleted:

 

4.4     Special warnings and precautions for use

Oversuppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see section 4.8).

 

Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated. Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk.Patients treated with immunosuppressants, including CellCept, 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.

 

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

 

4.8     Undesirable effects

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. 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 CellCept.

 

Underlined text has been added, text with strike through deleted:

 

4.4       Special warnings and precautions for use

Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated.

Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk.

 

4.6     Pregnancy and lactation

Cases of spontaneous abortions have been reported in patients exposed to CellCept.

 

4.8     Undesirable effects

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function.

 

Underlined text has been added, text with strike through deleted:

 

4.6       Pregnancy and lactation

The use of CellCept is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. CellCept should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There are no adequateis limited data from the use of CellCept 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 CellCept in combination with other immunosuppressants during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

 

4.8     Undesirable effects

Congenital disorders: see further details in section 4.6.

 

Underlined text has been added, text with strike through deleted:

 

4.5              Interaction with other medicinal products and other forms of interaction

 

Ciclosporin A: ciclosporin A (CsA) pharmacokinetics were are unaffected by mycophenolate mofetil.

 

In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.

 

Several studies have demonstrated that ciclosporin A reduces MPA plasma AUC levels by 19 - 38 %, possibly as a result of inhibiting biliary secretion with consequent reduction of the entero-hepatic recirculation. However, as efficacy studies were carried out using CellCept combined with ciclosporin A and corticosteroids, these findings do not affect the recommended dose requirements (see section 4.2).

 

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

 

Sirolimus: in renal transplant patients, concomitant administration of CellCept and CsA resulted in reduced MPA exposures by 30‑50% compared with patients receiving the combination of sirolimus and similar doses of CellCept (see also section 4.4).

 

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

 

Tacrolimus: in renal transplant patients: stable renal transplant patients receiving ciclosporin and CellCept (1 g BID) showed about a 30 % increase in MPA plasma AUC and about a 20 % decrease in MPAG plasma AUC when ciclosporin was replaced with tacrolimus. MPA C_max was not affected, while MPAG C_max was reduced by approximately 20 %. The mechanism of this finding is not well understood. Increased biliary secretion of MPAG accompanied with increased enterohepatic recirculation of MPA may be partly responsible for the finding, since the elevation of MPA concentrations associated with tacrolimus administration was more pronounced in the later portions of the concentration-time profile (4 – 12 hours after dosing). In another study in renal transplant patients it was shown that the tacrolimus concentration did not appear to be altered by CellCept.

 

 

In hepatic transplant patients: very limited pharmacokinetic data on MPA AUC are available in hepaticliver transplant patientsrecipients treated withinitiated on CellCept in combination withand tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by trough coadministration with tacrolimus level. In renal transplant patients, the tacrolimus concentration did not appear to be altered by CellCept. In a study designed to evaluate the effect of CellCept on the pharmacokinetics of tacrolimus in stable hepatic transplant patients, contrast,However, in hepatic transplant patients, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4).

 

4.9              Overdose

 

The experience with overdose of CellCept in humans is very limited. The events received from reports of 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 CellCept 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. By interfering with enterohepatic circulation of the medicinal product, bBile acid sequestrants, such as cholestyramine, reduce the can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2).AUC.