CellCept 500 mg powder for concentrate for solution for infusion

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, annex III-A: new section). Alignment to QRD 10.1

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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

 

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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

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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

 

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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.

 

[…]

10.          DATE OF REVISION OF THE TEXT

 

23 November 2017

 

 

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2.         Qualitative and quantitative composition

 

Each vial contains the equivalent of 500 mg mycophenolate mofetil (as hydrochloride salt).

 

For athe 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.

 

CAUTION: CELLCEPT I.V. SOLUTION SHOULD NEVERMUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION.

 

Posology

 

CellCept 500 mg powder for concentrate for solution for infusion is an alternative dosage form to CellCept oral forms (capsules, tablets and powder for oral suspension) that may be administered for up to 14 days. The initial dose of CellCept 500 mg powder for concentrate for solution for infusion should be given within 24 hours following transplantation.

 

Following reconstitution to a concentration of 6 mg/ml, CellCept 500 mg powder for concentrate for solution for infusion must be administered by slow intravenous infusion over a period of 2 hours by either a peripheral or a central vein (see section 6.6).

 

Use in renalRenal transplant: the

The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

 

Use in hepaticHepatic transplant: the

The recommended dose of CellCept for infusion in hepatic transplant patients is 1 g administered twice daily (2 g daily dose). IV CellCept should continue for the first 4 days following hepatic transplant, with oral CellCept initiated as soon after this as it can be tolerated. The recommended dose of oral CellCept in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

 

 

Use in children: safetyspecial populations

 

Paediatric population

Safety and efficacy of CellCept for infusion in paediatric patients have not been established. No pharmacokinetic data with CellCept for infusion are available for paediatric renal transplant patients. No pharmacokinetic data are available for paediatric patients following hepatic transplants.

 

Use in elderly (³ 65 years): theElderly

The recommended dose of 1 g administered twice a day for renal 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 hepatic transplant patients with severe chronic renal impairment.

 

Use in severe Severe hepatic impairment: no

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

 

Treatment during rejection episodes: mycophenolic

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. No pharmacokinetic data are available during hepatic transplant rejection.

 

Method of administration

 

Following reconstitution to a concentration of 6 mg/mL, CellCept 500 mg powder for concentrate for solution for infusion must be administered by slow intravenous infusion over a period of 2 hours by either a peripheral or a central vein (see section 6.6).

 

Precautions to be taken before handling or administering the medicinal product

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid direct contact of the dry powder or prepared solutions of CellCept 500 mg powder for concentrate for solution for infusion with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

 

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

 

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 500 mg powder for concentrate for solution for infusion is contraindicated in patients who are allergic to polysorbate 80.

 

•        CellCept is contraindicatedshould 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 to 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.

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.

 

Blood and immune system

 

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.

 

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 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 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

 

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 phosphoribosyltransferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

 

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

 

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. cholesterolamine, should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see also section 4.5). Some degree of enterohepatic recirculation is anticipated following intravenous administration of CellCept.

 

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

 

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

 

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

 

Interaction studies have only been performed in adults.

 

Aciclovir: higher

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.

 

Cholestyramine: following

Following single dose, oral 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

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 is recommended that CellCept therapy should not be initiated until a negative pregnancy test has been obtained. EffectiveContraception in males and females

 

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

 

Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before beginning CellCept therapy, during therapy, and for six weeks following discontinuation of 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

 

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 counselled 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 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. CasesMycophenolate 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 patients 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 CellCept. 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;

•           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

 

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

 

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). The adverse reaction profile associated with the administration of CellCept 500 mg powder for concentrate for solution for infusion has been shown to be similar to that observed after oral administration.

 

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%.

 

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:

The following data refer to the safety experience of oral CellCept in renal transplant patients. Data in hepatic transplant patients are based on i.v. dosing of CellCept for up to 14 days followed by oral dosing. Adverse reactions, probably or possibly related to CellCept, reported in ≥1/10 and in ≥1/100 to <1/10 of patients treated with CellCept in the controlled clinical trials of renal (2 g data) 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 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, anorexia
Psychiatric disorders	Very common	-
	Common	Depression, thinking abnormal, insomnia
Nervous system disorders	Very common	-
	Common	Convulsion, hypertonia, tremor, somnolence, headache, paraesthesia
Cardiac disorders	Very common	-
	Common	Tachycardia
Vascular disorders	Very common	-
	Common	Hypotension, hypertension
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
Hepatobiliary disorders	Very common	-
	Common	Hepatitis
Skin and subcutaneous tissue disorders	Very common	-
	Common	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 alkaline phosphatase increased, weight decreased

Note: 501 (2 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 and hepatic transplantation, respectively.

 

Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CellCept 500 mg powder for concentrate for solution for infusion.

 

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

 

Adverse reactions reported during post-marketing with CellCept are similar to those seen in the controlled renal and hepatic transplant studies. Additional adverse reactions reported during post-marketing experience with CellCept are described below with the frequencies reported within brackets if known.

 

Gastrointestinal:

Adverse reactions reported during post-marketing with CellCept are similar to those seen in the controlled renal and hepatic transplant studies. Additional adverse reactions reported during post-marketing experience with CellCept are described below with the frequencies reported within brackets if known.

 

Gastrointestinal: gingival

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

 

Disorders related to immunosuppression: 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.

 

Hypersensitivity

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

:

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.

Congenital malformations have been observed post-marketing in children of patients exposed to CellCept in combination with other immunosuppressants, 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 disorders

Hypogammaglobulinaemia has been reported in patients receiving CellCept in combination with other immunosuppressants (frequency not known).

 

Reporting of suspected adverse reactions

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).

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

 

 

4.9       Overdose

 

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

 

It is expected that an overdose of mycophenolate mofetil could possibly result in over suppression 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. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2).

 

 

5.         Pharmacological properties

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

 

Mechanism of action

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

 

5.2       Pharmacokinetic properties

 

Distribution

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. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2).

 

 

5.         Pharmacological properties

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

 

Mechanism of action

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

 

5.2       Pharmacokinetic properties

 

Distribution

 

Following intravenous administration, mycophenolate mofetil undergoes rapid and complete

 metabolism to the active metabolite, MPA. The parent substance mycophenolate mofetil can be

 measured systemically during intravenous infusion. MPA at clinically relevant concentrations is 97%

 bound to plasma albumin.

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.

 

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

 

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 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).

 

Equivalence with oral dosage forms

 

MPA AUC values obtained following administration of 1 g BID intravenous CellCept to renal transplant patients in the early post-transplant phase are comparable to those observed following 1 g BID oral CellCept. In hepatic transplant patients, administration of 1 g BID intravenous CellCept followed by 1.5 g BID oral CellCept resulted in MPA AUC values similar to those found in renal transplant patients administered 1 g CellCept BID.

 

 

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 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).

 

MPA AUC values obtained following administration of 1 g BID intravenous CellCept to renal transplant patients in the early post-transplant phase are comparable to those observed following 1 g BID oral CellCept. In hepatic transplant patients, administration of 1 g BID intravenous CellCept followed by 1.5 g BID oral CellCept resulted in MPA AUC values similar to those found in renal transplant patients administered 1 g CellCept BID.

 

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 < 25 ml·mL/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 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.

 

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 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.

 

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 co‑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.

 

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/day. The systemic exposure at this dose represents 2 – 3 times the clinical exposure at the recommended clinical dose of 2 g/day. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day 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. 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

coadministration 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.

 

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 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. 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. (see 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. 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 500 mg powder for concentrate for solution for infusion

polysorbate 80

citric acid

hydrochloric acid

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. 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 500 mg powder for concentrate for solution for infusion:

polysorbate 80

citric acid

hydrochloric acid

sodium chloride.

 

6.2       Incompatibilities

 

CellCept 500 mg powder for concentrate for solution for infusion solution should not be mixed or administered concurrently via the same catheter with other intravenous medicinal products or infusion admixtures.

 

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

 

6.3       Shelf-life

 

Powder for concentrate for solution for infusion: 3 years.

 

Reconstituted solution and infusion solution: If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product.

 

6.4       Special precautions for storage

 

Powder for concentrate for solution for infusion: Do not store above 30 °C.

 

Reconstituted solution and infusion solution: Store at 15 – 30°C.

 

6.5       Nature and contents of container

 

20 mL type I clear glass vials with grey butyl rubber stopper and aluminium seals with plastic flip-off caps. CellCept 500 mg powder for concentrate for solution for infusion is available in packs containing 4 vials.

 

6.6       Special precautions for disposal and other handling

 

Preparation of Infusion Solution (6 mg/mL)

 

CellCept 500 mg powder for concentrate for solution for infusion does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.

 

CellCept 500 mg powder for concentrate for solution for infusion must be prepared in two steps: the first step is a reconstitution step with glucose intravenous infusion 5% and the second step is a dilution step with glucose intravenous infusion 5%. A detailed description of the preparation is given below:

 

Step 1

a.         Two vials of CellCept 500 mg powder for concentrate for solution for infusion are used for preparing each 1 g dose. Reconstitute the content of each vial by injecting 14 

6.2       Incompatibilities

 

CellCept 500 mg powder for concentrate for solution for infusion solution should not be mixed or administered concurrently via the same catheter with other intravenous medicinal products or infusion admixtures.

 

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

 

6.3       Shelf-life

 

Powder for concentrate for solution for infusion: 3 years.

 

Reconstituted solution and infusion solution: If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product.

 

6.4       Special precautions for storage

 

Powder for concentrate for solution for infusion: Do not store above 30 °C.

 

Reconstituted solution and infusion solution: Store at 15 – 30°C.

 

6.5       Nature and contents of container

 

20 ml type I clear glass vials with grey butyl rubber stopper and aluminium seals with plastic flip-off caps. CellCept 500 mg powder for concentrate for solution for infusion is available in packs containing 4 vials.

 

6.6       Special precautions for disposal and other handling

 

Preparation of Infusion Solution (6 mg/ml)

 

CellCept 500 mg powder for concentrate for solution for infusion does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.

 

CellCept 500 mg powder for concentrate for solution for infusion must be prepared in two steps: the first step is a reconstitution step with glucose intravenous infusion 5% and the second step is a dilution step with glucose intravenous infusion 5%. A detailed description of the preparation is given below:

 

Step 1

a.         Two vials of CellCept 500 mg powder for concentrate for solution for infusion are used for preparing each 1 g dose. Reconstitute the content of each vial by injecting 14 mlmL of glucose intravenous infusion 5%.

 

b.         Gently shake the vial to dissolve the medicinal product yielding a slightly yellow solution.

 

c.         Inspect the resulting solution for particulate matter and discoloration prior to further dilution. Discard the vial if particulate matter or discoloration is observed.

 

Step 2

a.         Further dilute the content of the two reconstituted vials (approx.

b.         Gently shake the vial to dissolve the medicinal product yielding a slightly yellow solution.

 

c.         Inspect the resulting solution for particulate matter and discoloration prior to further dilution. Discard the vial if particulate matter or discoloration is observed.

 

Step 2

a.       Further dilute the content of the two reconstituted vials (approx. 2 x 15 mlmL) into 140 mlmL of glucose intravenous infusion 5%. The final concentration of the solution is 6 mg/ml mycophenolate mofetil.

 

b.         Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.

 

If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product. Keep solutions at 15 – 30° C.

 

BecausemL mycophenolate mofetil.

 

b.         Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.

 

If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product. Keep solutions at 15 – 30° C.

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 14 February 1996

Date of latest renewal: 14 February13 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.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

 

[....]

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, leucocytosisleukocytosis

[....]

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

 

 

4.2     Posology and method of administration

 

[ … ]

 

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6

 

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

 

Distribution

Following intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to the active metabolite, MPA. . MPA at clinically relevant concentrations is 97 % bound to plasma albumin. The parent substance mycophenolate mofetil can be measured systemically during intravenous infusion; however, after oral administration it is below the limit of quantitation (0.4 mg/ml)

metabolism to the active metabolite, MPA. The parent substance mycophenolate mofetil can be

measured systemically during intravenous infusion. MPA at clinically relevant concentrations is 97 %

bound to plasma albumin.

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.

 

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 faeces. Most (about 87 %) of the administered dose is excreted in the urine as MPAG.

 

[ … ]

 

 

 

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/