Cellcept - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Mycophenolate mofetil

CellCept 250 mg capsules

Cellcept package inserts are available for pack sizes:
  • CellCept 250 mg capsules
  • CellCept 1 g / 5 ml powder for oral suspension
  • CellCept 500 mg film-coated tablets

Indications Why is Cellcept used? What is it for?

The full name of the medicine is CellCept 250 mg capsules.

The abbreviated name CellCept will be used in this leaflet.

CellCept contains mycophenolate mofetil.

This belongs to a group of medicines called 'immunosuppressants'.

CellCept is used to prevent the body from rejecting a transplanted organ.

  • Kidney, heart or liver.

CellCept must be used in combination with other medicines:

  • cyclosporine and corticosteroids.

Contraindications When Cellcept should not be used

WARNING

Mycophenolate causes birth defects and miscarriage. If you are a woman capable of having children, you must have a negative pregnancy test before starting treatment and follow your doctor's advice on contraception.

Your doctor will talk to you and give you written information, especially about the effects of mycophenolate on your unborn baby. Read the information carefully and follow the instructions. If you do not fully understand these instructions ask your doctor to explain them again before taking mycophenolate. Please also read the information in this section under "Warnings and precautions" and "Pregnancy and breastfeeding".

Do not take CellCept:

  • if you are allergic (hypersensitive) to mycophenolate mofetil, mycophenolic acid or any of the other ingredients of this medicine (listed in section 6)
  • if you are a woman capable of having children and did not submit a negative pregnancy test before the first prescription, as mycophenolate causes birth defects and miscarriage
  • if you are pregnant, suspect or are planning to become pregnant
  • if you are not using any effective method of contraception (see Pregnancy, Contraception and Breastfeeding)
  • if you are breast-feeding.

Do not take this medicine if any of the above conditions apply to you. If you are unsure, talk to your doctor or pharmacist before taking CellCept.

Precautions for use What you need to know before taking Cellcept

Tell your doctor immediately before taking CellCept:

  • if you have signs of infection such as fever or sore throat
  • in case of unexpected bruising or bleeding
  • if you have ever suffered from a digestive disorder, such as a 'stomach ulcer
  • if you are planning to become pregnant or become pregnant while being treated with CellCept.

If any of the above apply to you (or you are unsure), tell your doctor immediately before taking CellCept.

Interactions Which drugs or foods can change the effect of Cellcept

Talk to your doctor or pharmacist if you are taking or have recently taken any other medicines including those obtained without a prescription and herbal medicines. CellCept can alter the activity of other medicines. Other medicines can also alter the activity of CellCept.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines before taking CellCept:

  • azathioprine or other medicines that suppress the immune system, prescribed after an organ transplant
  • cholestyramine - used to treat high cholesterol
  • rifampicin - an antibiotic used to prevent and treat infections such as tuberculosis (TB)
  • antacids or proton pump inhibitors - used for stomach acid problems such as indigestion
  • phosphate binders - used in patients with chronic renal failure to reduce the amount of phosphate absorbed from the blood.

Vaccines

If you are due to have a vaccination (live vaccine) while being treated with CellCept, please tell your doctor or pharmacist first. Your doctor will advise you which vaccine is suitable for you.

You should not donate blood during CellCept treatment and for at least 6 weeks after stopping treatment. Men should not donate sperm during CellCept treatment and for at least 90 days after stopping treatment.

CellCept with food and drink

Consumption of food and drink has no effect on CellCept treatment.

Warnings It is important to know that:

Effects of sunlight

CellCept lowers the body's defenses resulting in a greater risk of skin cancer. Limit exposure to the sun and UV rays by:

  • the use of protective clothing that covers her head, neck, arms and legs
  • the use of products with a high protection factor.

Pregnancy, contraception and breastfeeding

Contraception in women taking CellCept

If you are a woman capable of becoming pregnant you should always use two effective methods of contraception with CellCept. By this we mean:

  • before you start taking CellCept
  • during the entire CellCept treatment
  • for 6 weeks after stopping CellCept treatment.

Talk to your doctor about which contraceptive method is best for you. This will depend on the individual situation. Contact your doctor as soon as possible if you think that the contraceptive you used may not have worked or if you have forgotten to take the birth control pill.

You are a woman who is unable to have children if any of the following apply to you:

  • you are in menopause, that is, you are at least 50 years of age and your last menstrual period was more than a year ago (if your menstrual cycle has stopped because you have undergone anticancer treatment, there is still the possibility that you may start a pregnancy).
  • the fallopian tubes and both ovaries were surgically removed (bilateral salpingoovariectomy).
  • the uterus was surgically removed (hysterectomy)
  • your ovaries no longer work (premature ovarian failure, which has been confirmed by a gynecologist specialist).
  • was born with one of the following rare conditions that make pregnancy impossible: XY genotype, Turner syndrome, or uterine agenesis.
  • is a girl or teenager who has not yet had her first period.

Contraception in men taking CellCept

You must always use a condom during treatment and for 90 days after stopping CellCept therapy.

If you are planning to become pregnant, your doctor will explain the risks and alternative treatments you can undergo to prevent rejection of the transplanted organ.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will discuss with you the risks of becoming pregnant and the alternative treatments you can undergo to prevent rejection of the transplanted organ if:

  • is planning a pregnancy
  • miss or think you have missed a period, have unusual menstrual bleeding or suspect pregnancy
  • have had sex without using effective contraception.

If you become pregnant while taking mycophenolate, you must inform your doctor immediately. In any case, keep taking CellCept until you see your doctor.

Pregnancy

Mycophenolate very frequently causes miscarriage (50%) and severe birth defects (23-27%) in the unborn child. Congenital defects reported include abnormalities of the ears, eyes, face (cheiloschisis / cleft palate), development of the fingers, heart, esophagus (tubular organ that connects the throat and stomach), kidneys and nervous system ( for example spina bifida [where the bones of the spine are not fully developed]) The child may have one or more of these defects.

If you are a woman capable of having children, you must have a negative pregnancy test before starting treatment and follow your doctor's advice on contraception. Your doctor may take more than one test to make sure you are not pregnant before starting treatment.

Feeding time

Do not take CellCept if you are breast-feeding. Small amounts of the medicine can pass into breast milk.

Driving and using machines:

CellCept is not expected to affect the ability to drive or use any tools or machines.

Dose, Method and Time of Administration How to use Cellcept: Posology

Always take CellCept exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

How much to take

The amount you need to take depends on the type of transplant you have received. Usual doses are indicated below. Treatment will continue as long as it is necessary to prevent rejection of the transplanted organ.

Kidney transplant

Adults

  • The first dose is given within 3 days following the transplant surgery.
  • The daily dose is 8 capsules (2 g of medicine), divided into 2 separate doses.
  • Take 4 capsules in the morning and 4 capsules in the evening.

Children (aged 2-18 years)

  • The dose to be administered will depend on the child's body surface.
  • Your doctor will decide the most appropriate dose based on the child's height and weight (body surface area - measured in square meters or "m2"). The recommended dose is 600 mg / m2 administered twice a day.

Heart transplant

Adults

  • The first dose is given within 5 days of the transplant surgery.
  • The daily dose is 12 capsules (3 g of medicine), divided into 2 doses.
  • Take 6 capsules in the morning and 6 capsules in the evening.

Children

  • There is no information on the use of CellCept in children with a heart transplant.

Liver transplantation

Adults

  • The first dose of oral CellCept will be given to you at least 4 days after your transplant surgery and when you are able to swallow medicines by mouth.
  • The daily dose is 12 capsules (3 g of medicine), divided into 2 separate doses.
  • Take 6 capsules in the morning and 6 capsules in the evening.

Children

  • There is no information on the use of CellCept in children with a liver transplant.

Taking the medicine

Swallow the capsules whole with a glass of water

  • Do not break or crush the capsules
  • Do not take broken or opened capsules.

Take care to avoid contact between the powder escaping from the damaged capsules and your eyes or mouth.

  • If so, rinse with plenty of running water.

Take care to avoid contact between the powder escaping from the damaged capsules and your skin.

  • If so, wash the area thoroughly with soap and water.

If you forget to take CellCept

If you forget to take your medicine, take it as soon as you remember, then continue taking it as usual.

Do not take a double dose to make up for a forgotten dose.

If you stop taking CellCept

Do not stop taking CellCept unless your doctor tells you to. Discontinuing treatment could increase the risk of organ rejection.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Cellcept

If you take more CellCept than you should, tell a doctor or go to a hospital straight away. Do the same if someone else accidentally takes the medicine. Take the medicine pack with you.

Side Effects What are the side effects of Cellcept

Like all medicines, CellCept can cause side effects, although not everybody gets them.

Talk to a doctor immediately if you notice any of the following serious side effects; you may need urgent medical treatment:

  • have signs of infection such as fever or sore throat
  • have unexpected bruising or bleeding
  • have a rash, swelling of the face, lips, tongue or throat, with difficulty in breathing; you may have a severe allergic reaction to the medicine (such as anaphylaxis, angioedema).

Common problems

Some of the most common complaints are diarrhea, decreased white or red blood cells, infections and vomiting. Your doctor will do regular blood tests to check for any changes:

  • the number of blood cells
  • the blood level of certain substances such as sugar, fat or cholesterol.

Children may be more likely than adults to develop some side effects.

These include diarrhea, infections and decreased white and red blood cells in the blood.

Fighting Infections

CellCept lowers the body's defenses to prevent it from rejecting the transplant. As a result, the body will not be able to fight infections as effectively as it would under normal conditions. This means that you may experience infections more frequently, such as infections affecting the brain, skin, mouth, stomach and intestines, lungs and urinary tract.

Tumors of the lymphatic system and skin

As can happen with other substances of this type (immunosuppressants), a very small number of patients taking CellCept have developed cancers of the lymphatic system and of the skin.

Undesirable effects of a general nature

It may have undesirable effects affecting the body in general. These include severe allergic reactions (such as anaphylaxis, angioedema), fever, feeling tired, sleep disturbances, pains (in the stomach, chest, muscles or joints at the time of urinating), headache, flu symptoms and swelling.

Other side effects can include:

Skin disorders such as:

  • acne, cold sores, shingles, skin hypertrophy, hair loss, rash and itching.

Disorders of the urinary system such as:

  • kidney problems or an urgent need to urinate.

Disorders of the digestive system and mouth such as:

  • swelling of the gums and mouth ulcers
  • inflammation of the pancreas, colon or stomach
  • intestinal disorders including bleeding, liver problems
  • constipation, feeling sick (nausea), indigestion, loss of appetite and flatulence.

Nervous system disorders such as:

  • feeling dizzy, sleepy or paresthesia
  • tremors, muscle spasms, convulsions
  • feeling anxious or depressed, altered mood and thinking.

Heart and blood vessel disorders such as:

  • changes in blood pressure, abnormal heart beat and dilation of blood vessels.

Lung disorders such as:

  • pneumonia, bronchitis
  • shortness of breath, cough, which may be caused by bronchiectasis (a condition in which the airways in the lungs are abnormally dilated) or pulmonary fibrosis (scarring of the lung tissue). Contact your doctor if you have a persistent cough or breathlessness
  • accumulation of fluid in the lungs or chest
  • sinusitis.

Other ailments such as:

  • weight loss, gout, high blood sugar, bleeding and bruising.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.

Expiry and Retention

  • Keep out of the sight and reach of children.
  • Do not use the capsules after the expiry date which is stated on the carton (EXP).
  • Do not store above 30 ° C.
  • Store in the original package to protect from moisture.
  • Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What CellCept contains

  • The active ingredient is mycophenolate mofetil.
  • The other ingredients are:
    • CellCept capsules: corn starch in pregelatinized form, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone (K-90), magnesium stearate
    • capsule shell: gelatin, indigo carmine (E132), yellow iron oxide (E172), red iron oxide (E172), titanium dioxide (E171), black iron oxide (E172), potassium hydroxide, shellac.

What CellCept looks like and contents of the pack

  • CellCept capsules are oblong in shape with one end blue and the other brown. The wording "CellCept 250" is printed in black on the top, while the name "Roche" is printed in black on the bottom.
  • They are available in packs of 100 or 300 capsules (both in blisters of 10 capsules).

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Cellcept can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

CELLCEPT 250 MG CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each capsule contains 250 mg of mycophenolate mofetil.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Hard capsules.

CellCept capsules: oblong, blue and brown in color with black printed on the top "CellCept 250" and the name "Roche" on the bottom.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

CellCept is indicated for the prophylaxis of acute rejection in patients receiving a renal, cardiac or hepatic allograft in combination with cyclosporine and corticosteroids.

04.2 Posology and method of administration -

CellCept treatment should be initiated and continued by appropriately qualified transplant specialists.

Dosage

Use in kidney transplantation

Adults

Administration of oral CellCept should commence within the first 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Pediatric population aged 2 to 18 years

The recommended dose of mycophenolate mofetil is 600 mg / m² administered orally twice daily (up to a maximum of 2 g per day). CellCept capsules should only be prescribed to patients with a body surface area of ​​at least 1.25 m². For patients with a body surface area between 1.25 and 1.5 m² CellCept capsules may be prescribed at a dose of 750 mg twice daily (1.5 g daily dose). For patients with a body surface area greater than 1.5 m² CellCept capsules may be prescribed at a dose of 1 g twice a day (2 g daily dose). As some adverse reactions occur more frequently in this age group than in adults (see section 4.8), a temporary dose reduction or discontinuation of treatment may be required; in these cases relevant clinical factors should be taken into account, including the severity of the reaction.

Pediatric population less than 2 years of age

There are limited safety and efficacy data in children less than 2 years of age. These data are insufficient to make dosing recommendations; therefore it is not recommended to use the medicine in this age group.

Use in heart transplantation

Adults

Administration of oral CellCept should commence within the first 5 days following transplantation. The recommended dose for heart transplant patients is 1.5 g administered twice daily (3 g daily dose).

Pediatric population

No data are available for pediatric heart transplant patients.

Use in liver transplantation

Adults

CellCept i.v. it must be administered for the first four days after liver transplantation; administration of oral CellCept will commence soon thereafter when it can be tolerated. The recommended oral dose for liver transplant patients is 1.5 g administered twice daily (3 g daily dose).

Pediatric population

No data are available in pediatric patients with hepatic transplantation.

Use in particular populations

Senior citizens

For the elderly, the recommended dose of 1 g administered twice daily for renal transplant patients and the 1.5 g dose administered twice daily for cardiac or hepatic transplant patients.

Renal impairment

In renal transplant patients with severe chronic renal impairment (kidney glomerular filtration after transplantation no dose adjustment is required (see section 5.2). No data are available in cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment

No dose adjustments are required for renal transplant patients with severe liver parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not cause changes in MPA pharmacokinetics; no dose reductions or interruptions of CellCept therapy are required. There are no reasons for CellCept dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Method of administration

Oral administration

Precautions to be taken before handling or administering the medicinal product

Since mycophenolate mofetil has been shown to exert teratogenic effects on rats and rabbits, CellCept capsules should therefore not be opened or broken to avoid inhalation of the powder contained in the medicine capsules or direct contact between the latter and the skin or the mucous membranes. In this case, wash the affected area thoroughly with soap and water and rinse your eyes with running water.

04.3 Contraindications -

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

• CellCept must not be administered to women of childbearing potential who are not using highly effective contraceptive measures (see section 4.6).

• In women of childbearing potential, treatment with CellCept should only be initiated in the presence of a pregnancy test result, in order to exclude inadvertent use of the medicinal product during pregnancy (see section 4.6).

• CellCept should not be used during pregnancy unless there is no suitable alternative treatment for the prevention of transplant rejection (see section 4.6).

• CellCept must not be given to women who are breastfeeding (see section 4.6).

04.4 Special warnings and appropriate precautions for use -

Neoplasms

Patients receiving combination immunosuppressive therapy including CellCept are at increased risk for the development of lymphomas and other malignancies, especially of the skin (see section 4.8). The risk seems to depend on the intensity and duration of the treatment, rather than on the use of a specific product.

As a general precaution to minimize the risk of skin cancer, exposure to sunlight and UV rays should be limited by the use of protective clothing and high-protection sunscreen.

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 reactivation of latent viruses such as hepatitis B virus or hepatitis C virus and infections caused by polyomaviruses (BK virus associated nephropathy and progressive multifocal leukoencephalopathy, PML, John Cunningham virus associated, JC). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C virus have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and can lead to serious or fatal conditions that physicians should consider in the differential diagnosis of immunosuppressed patients with impaired renal function or neurological symptoms.

There have been reports of hypogammaglobulinemia in association with recurrent infections in patients taking CellCept in combination with other immunosuppressants. In some of these cases, switching from CellCept to an alternative immunosuppressant resulted in a return of serum IgG levels to normal. In patients treated with CellCept who develop recurrent infections, serum immunoglobulins should be measured. In case of clinically relevant prolonged hypogammaglobulinemia, an appropriate clinical action should be evaluated taking into account the potent cytostatic effects that mycophenolic acid exerts on B and T lymphocytes.

There have been published reports of bronchiectasis in adults and children who have taken CellCept in combination with other immunosuppressants. In some of these cases, switching from CellCept to another immunosuppressant resulted in improved respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinemia or 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 be investigated if they develop persistent pulmonary symptoms such as cough and dyspnoea.

Blood and lymphatic and immune system

Patients treated with CellCept should be monitored for neutropenia, which may be linked to CellCept itself, concomitant medications, viral infections, or a combination of these causes. CellCept-treated patients should have a complete blood count every week in the first month of therapy, twice a month during the second and third months, and once a month for the first year. In case of development of neutropenia (absolute neutrophil count

Cases of Pure Red Cell Aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressive drugs. The mechanism by which mycophenolate mofetil induced PRCA is not known. PRCA may resolve with dose reduction or discontinuation of CellCept therapy. Changes to CellCept treatment in transplant patients should only be made under appropriate clinical supervision in order to minimize the risk of rejection (see section 4.8. ).

Patients treated with CellCept should be advised to report immediately any evidence of infection, unexpected bruising or bleeding, or any other manifestation of myelosuppression.

Patients should be advised that vaccinations may be less effective during treatment with CellCept, and that the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may be helpful. reference to national guidelines.

Gastrointestinal system

CellCept has been associated with an "increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal ulceration, haemorrhage and perforation. CellCept should be administered with caution to patients with active severe digestive system disease.

CellCept is an inhibitor of the enzyme Inosine Monophosphate Dehydrogenase (IMPDH). It should therefore be avoided in patients suffering from rare hereditary diseases involving a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), such as Lesch syndrome. -Nyhan and Kelley-Seegmiller syndrome.

Interactions

Caution should be exercised when switching from combination therapy containing immunosuppressants that interfere with the enterohepatic circulation of MPA (e.g. cyclosporine) to other treatments that do not exert this effect (e.g. sirolimus or belatacept) and vice versa, as the change in therapy could lead to changes in MPA exposure. Medicines from other categories that interfere with the enterohepatic circulation of MPA, eg cholestyramine, should be used with caution as they may lead to decreased plasma levels and the efficacy of CellCept (see also paragraph 4.5).

It is recommended not to administer CellCept in combination with azathioprine, as the concomitant administration of the two medicinal products has not been investigated.

The benefit / risk balance 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 greater risk of adverse events, e.g. certain infections (including cytomegalovirus invasive tissue disease) and possible gastrointestinal haemorrhage and pulmonary edema (see section 4.8), compared to younger subjects.

Teratogenic effects

Mycophenolate is a potent teratogen in humans. Spontaneous abortions (rate 45-49%) and congenital malformations (estimated rate 23-27%) have been reported following exposure to MMF during pregnancy. CellCept is therefore contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Women and men of childbearing potential should be informed of the risks and follow the recommendations given in section 4.6 (e.g. contraceptive methods, pregnancy tests) before, during and after CellCept therapy. Physicians should ensure that women and men being treated with mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to seek immediate medical attention if there is a possibility of pregnancy.

Contraception (see section 4.6)

Due to the genotoxic and teratogenic potential of CellCept, women of childbearing potential must use two reliable methods of contraception at the same time before starting CellCept therapy, during it and for six weeks after stopping treatment, unless abstinence. is not the method of contraception of choice (see section 4.5).

Sexually active men are recommended to use condoms during treatment and for at least 90 days after stopping therapy. Condoms should be used by both fertile men and those undergoing vasectomy, as the risks associated with semen transfer also apply to men who have undergone 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 material

In order to help patients avoid fetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorization Holder will provide educational material to healthcare professionals. The educational material will reiterate the warnings on the teratogenicity of the mycophenolate, will advise on contraception before starting therapy and on the need to carry out pregnancy tests. The physician should provide all patient information regarding teratogenic risk and pregnancy prevention methods to women of childbearing potential and, if applicable, to male patients.

Additional Precautions

Patients should not donate blood during therapy or for at least 6 weeks after stopping mycophenolate. Men should not donate sperm during therapy or for 90 days after stopping mycophenolate.

04.5 Interactions with other medicinal products and other forms of interaction -

Acyclovir

When the combination of mycophenolate mofetil and aciclovir was administered, increased plasma concentrations of aciclovir were observed compared to administration of aciclovir alone. Changes in the pharmacokinetics of the phenolic glucuronide of MPA (MPAG) were minimal (increased "MPAG of 8%) and were not considered clinically relevant. Since both MPAG and aciclovir plasma concentrations are increased in the presence of renal impairment, it is possible that mycophenolate mofetil and aciclovir or its prodrugs, eg valaciclovir, compete for excretion in the renal tubules, increasing the concentration of the two substances.

Antacids and Proton Pump Inhibitors (PPIs)

A reduction in MPA exposure has been observed with administration of CellCept with antacids such as magnesium and aluminum hydroxide or with proton pump inhibitors, including lansoprazole and pantoprazole. graft loss in patients taking CellCept and proton pump inhibitors versus patients taking CellCept but not proton pump inhibitors. magnesium or aluminum hydroxide is significantly lower than when CellCept is administered with proton pump inhibitors.

Cholestyramine

Following administration of a single 1.5 g dose of mycophenolate mofetil to healthy subjects previously treated with cholestyramine at 4 g three times daily for 4 days, a 40% reduction in MPA AUC was observed. (see sections 4.4 and 5.2). Caution should be exercised in concomitant use as the efficacy of CellCept may be impaired.

Medicines that can interfere with the enterohepatic circulation

Caution should be exercised with medicinal products that interfere with the enterohepatic circulation as the efficacy of CellCept may be impaired.

Ciclosporin A

The pharmacokinetics of cyclosporine A (CsA) are not affected by mycophenolate mofetil.

Conversely, if concomitant cyclosporine treatment is discontinued, an increase in MPA AUC of approximately 30% should be expected. CsA interferes with the enterohepatic circulation of MPA, resulting in a 30-50% reduction in MPA exposure in renal transplant patients treated with CellCept and CsA compared to that observed in subjects treated with sirolimus or belatacept and similar doses of CellCept (See also section 4.4) Conversely, changes in MPA exposure should be expected in patients switching from CsA treatment to immunosuppressants that do not interfere with the enterohepatic circulation of MPA.

Telmisartan

Concomitant administration of telmisartan and CellCept resulted in an approximately 30% reduction in MPA concentrations. Telmisartan affects the elimination of MPA by enhancing the expression of the peroxisome proliferator-activated receptor gamma (PPAR-gamma), which in turn results in an increase in the expression and activity of UGT1A9.Comparison of transplant organ rejection rates, transplant failure rates or adverse event profiles for patients treated with CellCept in combination or not with telmisartan did not reveal any clinical consequences on pharmacokinetic drug interactions.

Ganciclovir

Based on the results of a single-dose study of the recommended dose of oral mycophenolate and iv ganciclovir, and the known effects of renal impairment on the pharmacokinetics of CellCept (see section 4.2) and ganciclovir, co-administration of these two agents is expected (competing for the same tubular secretion mechanism) will give rise to an increase in the concentration of MPAG and ganciclovir. No substantial changes in MPA pharmacokinetics are expected and no dose adjustments of CellCept are required. In patients with renal impairment co-administered with CellCept and ganciclovir or its prodrugs, eg valganciclovir, dose recommendations should be observed. ganciclovir and patients should be closely monitored.

Oral contraceptives

The pharmacokinetics and pharmacodynamics of oral contraceptives were not affected by the co-administration of CellCept (see also section 5.2).

Rifampicin

In patients not also taking cyclosporine, concomitant administration of CellCept and rifampicin resulted in a reduction in MPA exposure (AUC0-12h) of 18% -70%. It is recommended that MPA exposure levels be monitored and the CellCept dose adjusted accordingly in order to maintain clinical efficacy when rifampicin is administered concomitantly.

Sevelamer

When CellCept was administered concomitantly with sevelamer, a decrease in MPA Cmax and AUC (0-12h) was observed by 30% and 25%, respectively, without any clinical consequences (eg graft rejection). However, it is recommended that CellCept be administered at least one hour before or three hours after sevelamer intake in order to minimize the effect on MPA absorption. No data are available for CellCept with other phosphate binders other than sevelamer. .

Trimethoprim / sulfamethoxazole

There was no effect on the bioavailability of MPA.

Norfloxacin and metronidazole

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

Ciprofloxacin and amoxicillin plus clavulanic acid

Approximately 50% reductions in trough (trough) MPA concentrations have been reported in subjects who received a kidney transplant in the days immediately following the initiation of oral therapy with ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic therapy and ceased within a few days of stopping it. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, changes in MPA are not usually indicated. CellCept dose in the absence of clinical signs of graft impairment. However, close clinical monitoring should be performed during use of the combination and immediately after antibiotic treatment.

Tacrolimus

In hepatic transplant patients who initiated CellCept and tacrolimus therapy, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by co-administration with tacrolimus. In contrast, the AUC of tacrolimus increased by approximately 20% when multiple doses of CellCept (1.5 g twice daily) were administered to liver transplant patients treated with tacrolimus. However, in patients with kidney transplant, tacrolimus concentration does not appear to be altered by CellCept (see also section 4.4).

Other interactions

Co-administration of probenecid and mycophenolate mofetil in monkeys triples the plasma AUC of MPAG. Other substances known to be eliminated by the kidney can also compete with MPAG thereby increasing the plasma concentrations of MPAG or the other substance that is secreted through the renal tubules.

Live vaccines

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

Pediatric population

Interaction studies were conducted in adults only.

04.6 Pregnancy and breastfeeding -

Male and female contraception

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

Due to the genotoxic and teratogenic potential of CellCept, women of childbearing potential must use two reliable methods of contraception at the same time before starting CellCept therapy, during it and for six weeks after stopping treatment, unless abstinence. is not the method of contraception of choice (see section 4.5).

Sexually active men are recommended to use condoms during treatment and for at least 90 days after stopping therapy. Condoms should be used by both fertile men and those undergoing vasectomy, as the risks associated with semen transfer also apply to men who have undergone 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. Therapy should only be initiated in the presence of a negative pregnancy test result, in order to exclude inadvertent use of the drug during pregnancy.

At the start of treatment, women and men of childbearing potential should be informed of the increased risk of pregnancy loss and congenital malformations, as well as of pregnancy planning and prevention.

Before starting treatment with CellCept, women of childbearing potential must have undergone a pregnancy test in order to rule out unintentional exposure of the embryo to mycophenolate. Two serum or urine pregnancy tests are recommended, with a sensitivity of at least 25 mIU / ml; the second test should be performed 8 - 10 days after the first and immediately before starting mycophenolate mofetil therapy. Pregnancy tests should be repeated as needed (eg after a "discontinuation in contraception" has been reported. The results of all pregnancy tests should be discussed with the patient. Patients should be advised to consult immediately your doctor if you are pregnant.

Mycophenolate is a potent teratogen in humans, and leads to an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy.

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

• As reported in the medical literature, malformations emerged in 23-27% of live births from mothers exposed to mycophenolate mofetil during pregnancy (compared to 2-3% of live births in the overall population and approximately 4-5% of live births from subjects undergoing solid organ transplantation treated with immunosuppressants other than mycophenolate mofetil).

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

• ear abnormalities (eg malformed or absent outer / middle ear), atresia of the external auditory canal;

• congenital heart disease, such as atrial and ventricular septal defects;

• facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the eye sockets;

• eye abnormalities (eg coloboma);

• finger malformations (eg polydactyly, syndactyly);

• tracheo-oesophageal malformations (eg esophageal atresia);

• malformations of the nervous system, such as spina bifida;

• kidney abnormalities.

In addition, isolated cases of the following malformations have been reported:

• microphthalmia;

• congenital cyst of the choroid plexus;

• agenesis of the pellucid septum;

• agenesis of the olfactory nerve.

Animal studies have shown reproductive toxicity (see section 5.3).

Feeding time

Mycophenolate mofetil has been shown to be excreted in the breast milk of rats. It is not known whether this also occurs in women. Since mycophenolate mofetil can cause serious adverse reactions in infants, CellCept is contraindicated in breastfeeding women (see section 4.3).

04.7 Effects on ability to drive and use machines -

No studies on the ability to drive and use machines have been performed. The pharmacodynamic profile and adverse reactions reported make such an effect unlikely.

04.8 Undesirable effects -

The following undesirable effects include adverse reactions from clinical studies

The main adverse reactions associated with the administration of CellCept in combination with cyclosporine and corticosteroids include diarrhea, leukopenia, sepsis and vomiting; in addition, there is an increase in the frequency of certain types of infections (see section 4.4).

Neoplasms malignant

Patients receiving combination immunosuppressive therapy including CellCept are at increased risk for the development of lymphomas and other malignancies, especially of the skin (see section 4.4). Lymphoproliferative disorders or lymphomas developed in 0.6% of patients who received CellCept (at a daily dose of 2 or 3 g) in combination with other immunosuppressants in controlled clinical trials in renal transplant patients (dose-related data of 2 g daily), cardiac and hepatic followed for at least 1 year. Non-melanoma skin cancers occurred in 3.6% of patients; other types of malignancies occurred in 1.1% of patients. Safety data from 3 years of treatment in renal or cardiac transplant patients showed no unexpected difference in cancer incidence compared to 1 year data. Hepatic transplant patients were followed for at least 1 year but for less than 3 years.

Opportunistic infections

All transplant patients have an increased risk of opportunistic infections; the risk increases with the total immunosuppressive burden (see section 4.4). The most frequent opportunistic infections in patients treated with CellCept (at a dose of 2 or 3 g daily) in combination with other immunosuppressants in controlled clinical trials in renal transplant patients (data relating to a dose of 2 g daily), cardiac and followed for at least one year were mucocutaneous candida, CMV viraemia / syndrome and herpes simplex. The proportion of patients with CMV viraemia / syndrome was 13.5%.

Pediatric population

In a clinical study enrolling 92 pediatric patients aged 2 to 18 years who received oral mycophenolate mofetil at a dose of 600 mg / m² twice daily, the type and frequency of adverse reactions were generally similar to those seen in adult patients given CellCept 1 g twice daily. However, the following treatment-related adverse events were more frequent in the pediatric population than in the adult population, particularly in children under 6 years of age: diarrhea, sepsis, leukopenia, anemia and infections.

Senior citizens

Elderly people (≥ 65 years old) are generally at increased risk of developing adverse reactions due to immunosuppression. Elderly people who receive CellCept as part of a combination immunosuppressive regimen are at increased risk of developing certain types of infections (including illness invasive cytomegalovirus) and possibly gastrointestinal bleeding and pulmonary edema, compared to younger individuals.

Other adverse reactions

The following table shows the adverse reactions, more or less likely related to taking CellCept, reported in 1 out of 10 patients or more and between 1 out of 100 patients and less than 1 out of 10 patients treated with CellCept in controlled clinical trials in patients with renal transplant (data relating to a dose of 2 g daily), cardiac and hepatic.

Adverse reactions more or less likely related to taking CellCept reported in patients treated with CellCept in clinical studies in renal, cardiac and hepatic transplantation when used in combination with cyclosporine and corticosteroids

Within the system organ class, undesirable effects are grouped by frequency classes, using the following categories: very common (≥1 / 10); common (≥1 / 100 to

System and organ classification 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, skin fungal infection, skin candidiasis, vaginal candidiasis, rhinitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Very common - common Skin cancer, benign skin neoplasm Disorders of the blood and lymphatic system Very common Leukopenia, thrombocytopenia, anemia common Pancytopenia, leukocytosis Metabolism and nutrition disorders Very common - common Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcemia, hypercholesterolemia, hyperlipemia, hypophosphataemia, hyperuricaemia, gout, anorexia Psychiatric disorders Very common - common Agitation, confusion, depression, anxiety, altered thinking, insomnia Nervous system disorders Very common - common Convulsions, hypertonia, tremor, somnolence, myasthenia, dizziness, headache, paraesthesia, dysgeusia Cardiac pathologies Very common - common Tachycardia Vascular pathologies Very common - common Hypotension, hypertension, vasodilation Respiratory, thoracic and mediastinal disorders Very common - common Pleural effusions, dyspnoea, cough Gastrointestinal disorders Very common Vomiting, abdominal pain, diarrhea, nausea common Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, esophagitis, stomatitis, constipation, dyspepsia, flatulence, belching Hepatobiliary disorders Very common - common Hepatitis, jaundice, hyperbilirubinemia Skin and subcutaneous tissue disorders Very common - common Skin hypertrophy, rash, acne, alopecia Musculoskeletal and connective tissue disorders Very common - common Arthralgia Renal and urinary disorders Very common - common Renal impairment General disorders and administration site conditions Very common - common Edema, fever, chills, pain, malaise, asthenia Diagnostic tests Very common - common Increased liver enzymes, increased blood creatinine, increased blood lactic dehydrogenase, increased blood urea, increased blood alkaline phosphatase, weight loss

Note: In the phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, 501 (2 g of CellCept per day), 289 (3 g of CellCept per day) and 277 (2 g of CellCept per day) were treated, respectively. iv / oral 3 g of CellCept per day) patients.

The following undesirable effects include adverse reactions that occurred in post-marketing experience

The types of adverse reactions reported post-marketing of CellCept are similar to those seen in controlled clinical trials in renal, cardiac and hepatic transplantation. Additional adverse reactions are listed below with frequencies listed in parentheses if known.

Gastrointestinal system

Gingival hyperplasia (≥1 / 100 to pancreatitis (≥1 / 100 to intestinal villi.

Infections

Severe 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 leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept.

Agranulocytosis (≥1 / 1,000 to aplastic anemia and bone marrow depression have been reported in patients treated with CellCept, some of which were fatal.

Disorders of the blood and lymphatic system

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

Isolated cases of morphological abnormalities of neutrophils, including the acquired Pelger-Huet abnormality, have been reported in patients treated with CellCept. However, these changes are not associated with impaired neutrophil function. left shift maturation of neutrophils, which can be misinterpreted as a sign of infection in immunosuppressed patients such as those treated with CellCept.

Hypersensitivity

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

Pregnancy, puerperium and perinatal conditions

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

Congenital pathologies

Post-marketing congenital malformations have been observed in children of patients administered CellCept in combination with other immunosuppressants; see section 4.6.

Respiratory, thoracic and mediastinal disorders

Isolated cases of interstitial lung disease and pulmonary fibrosis have occurred in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal. There have been cases of bronchiectasis in adults and children (frequency not known).

Disorders of the immune system

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

Reported cases of overdose with mycophenolate mofetil were collected in clinical studies and during post-marketing experience. In many of these cases no adverse events were reported. In those cases of overdose in which adverse events were reported, such events they are within the known safety profile of the medicine.

An overdose of mycophenolate mofetil could lead to over-suppression of the immune system and increased susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, administration of CellCept should be discontinued or the dosage reduced (see section 4.4).

Hemodialysis is very unlikely to remove clinically significant amounts of MPA or MPAG. Bile acid-sequestering drugs, such as cholestyramine, can remove MPA by decreasing enterohepatic recirculation of the drug (see section 5.2).

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "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, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase; it inhibits, without being incorporated into DNA, the synthesis de novo of the guanosine nucleotide. Since the synthesis de novo of purines is essential for the proliferation of T and B lymphocytes, while other cell types can use the purine reuse mechanism, MPA exerts a greater cytostatic effect on lymphocytes than on other cells.

05.2 "Pharmacokinetic properties -

Absorption

Following oral administration, mycophenolate mofetil is rapidly and extensively absorbed and completely transformed, by a presystemic metabolic process, into its active form MPA. As demonstrated by the suppression of acute rejection after renal transplantation, the immunosuppressive activity of CellCept is related to the concentration of MPA. Based on MPA AUC, the mean bioavailability of orally administered mycophenolate mofetil is 94% compared to intravenously administered mycophenolate mofetil. Food intake was shown to have no effect on the absorption of mycophenolate mofetil (MPA AUC), administered at a dose of 1.5 g twice daily to renal transplant patients. However, MPA Cmax was decreased. 40% in the presence of food. Mycophenolate mofetil cannot be systematically determined in plasma after oral administration.

Distribution

As a consequence of the enterohepatic circulation, secondary increases in plasma MPA concentration are usually observed approximately 6-12 hours after drug administration. The combination of cholestyramine (4 g three times a day) leads to a reduction in the AUC of "MPA of about 40%, indicating the importance of the enterohepatic circulation." MPA at clinically relevant concentrations is 97% bound to plasma albumin.

Biotransformation

MPA is metabolised primarily by glucuronyltransferase (UGT1A9 isoform) to the inactive MPA phenolic glucuronide (MPAG). In vivo MPAG is converted back into free MPA through the enterohepatic circulation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some undesirable effects of mycophenolate mofetil (diarrhea, leukopenia).

Elimination

A small amount is excreted in the urine in the form of MPA (faeces. Most (approximately 87%) of the administered dose is excreted in the urine as MPAG.

At the concentrations used in the clinic, MPA and MPAG are not eliminated by hemodialysis. However, for high plasma MPAG concentrations (> 100 mcg / ml) small amounts of MPAG are eliminated. By interfering with the enterohepatic circulation of the drug, the bile acid sequestrants, such as cholestyramine, cause a reduction in the AUC of MPA (see section 4.9).

The absorption, distribution, metabolism and excretion of MPA depend on different transporters. These processes involve the organic anion-carrying polypeptides (OATP) and the multi-drug resistance associated protein 2 (MRP2); the isoforms of OATP , MRP2 and breast cancer resistance protein (BCRP) are transporters associated with biliary excretion of glucuronides. Multi-drug resistance-associated protein 1 (MDR1) is also capable of carrying MPA, but its contribution appears limited to the absorption process. In the kidney, MPA and its metabolites may interact with kidney organic anion transporters.

In the immediate post-transplant period (less than 40 days post-transplant), renal, cardiac and hepatic transplant patients had an average MPA AUC about 30% lower and a Cmax about 40% lower than the values ​​observed long after transplantation (3-6 months after transplantation).

Special populations

Renal impairment

In a single dose study (6 subjects / group) the mean AUC of plasma MPA concentration in patients with severe chronic renal impairment (glomerular filtration

Delayed resumption of renal function

In patients in whom the transplanted renal organ begins to function with delay, the mean AUC0-12 of MPA was comparable to the values ​​recorded in patients in whom the functions of the transplanted organ are established without delay and the area under the curve of the mean plasma MPAG concentration (AUC0-12) was 2-3 times higher. There may be a transient increase in plasma MPA free fraction and concentration in patients with delayed organ function. No dose adjustment of CellCept appears to be necessary.

Hepatic impairment

In volunteers with alcoholic cirrhosis, the alteration of the liver parenchyma did not greatly influence the hepatic processes of glucuronidation of MPA. The effects of liver disease on this process are likely to depend on the particular disease. However, liver disease with damage mainly to the biliary tract, such as primary biliary cirrhosis, can have a different effect on drug metabolism.

Pediatric population

Pharmacokinetic parameters were evaluated in 49 pediatric renal transplant patients (aged 2 to 18 years) treated with oral mycophenolate mofetil 600 mg / m² twice daily. With this dose, MPA AUC values ​​similar to those observed in adult renal transplant patients treated with CellCept at a dose of 1 g twice daily were achieved immediately after transplant and in the subsequent period. MPA in the different age groups were similar immediately after transplant and in the subsequent period.

Senior citizens

The pharmacokinetic behavior of CellCept in the elderly (≥ 65 years) has not been formally assessed.

Patients taking oral contraceptives

The pharmacokinetics of oral contraceptives were not affected by the co-administration of CellCept (see also section 4.5). A study on co-administration of CellCept (1 g twice daily) and combinations of 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 gestoden (0.05 mg to 0.10 mg), conducted in 18 non-transplant women (who were not receiving other immunosuppressants) over 3 consecutive menstrual cycles showed no clinical influence of CellCept on the suppressive action of ovulation by oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected.

05.3 Preclinical safety data -

In experimental models, mycophenolate mofetil was not carcinogenic. The maximum dose tested in animal carcinogenicity studies resulted in a "systemic exposure (AUC or Cmax) approximately 2-3 times that observed in renal transplant patients treated at the recommended dose of 2 g / day and a" systemic exposure (AUC or Cmax) approximately 1.3-2 times that observed in heart transplant patients treated at the recommended dose of 3 g / day.

Two genotoxicity assays (the in vitro on lymphoma in mice and the test in vivo on medullary micronuclei in mice) showed that mycophenolate mofetil can cause chromosomal aberrations. These effects can be related to the pharmacodynamic activity, in particular to the inhibition of nucleotide synthesis in sensitive cells. Other tests in vitro for the evaluation of the gene mutation they did not show genotoxic activity.

In oral doses up to 20 mg / kg / day mycophenolate mofetil showed no effect on the fertility of male rats. This dose resulted in a systemic exposure of 2-3 times that observed in the clinic using the recommended dose of 2 g / day in renal transplant patients and a systemic exposure of 1.3-2 times that observed in the clinic using the recommended dose of 3 g / day in heart transplant patients. In a fertility and reproduction study in female rats, oral doses of 4.5 mg / kg / day, although non-maternal toxic, caused malformations in first generation offspring (including anophthalmia, missing jaw and hydrocephalus). . This dose resulted in a "systemic exposure of approximately 0.5 times that observed in the clinic using the recommended dose of 2 g / day in renal transplant patients and a" systemic exposure of approximately 0.3 times that observed in the clinic using the recommended dose of 3 g / day in heart transplant patients. There was no evidence of any effects on fertility and reproduction in first generation or later generation females.

In teratology studies in rats and rabbits, absorption and fetal malformations were observed in the rat at a dose of 6 mg / kg / day (including anophthalmia, lack of jaw and hydrocephalus) and in the rabbit at a dose of 90 mg / kg. / day (including cardiovascular and renal abnormalities, such as cardiac ectopy and renal ectopy, diaphragmatic and umbilical hernias), in the absence of maternal toxicity. This dose resulted in a systemic exposure of approximately 0.5 times or less than that observed in the clinic using the recommended dose of 2 g / day in renal transplant patients and a systemic exposure of approximately 0.3 times that observed in the clinic using the recommended dose of 3 g / day in heart transplant patients (see section 4.6) .

In toxicological studies conducted with mycophenolate mofetil in rats, mice, dogs and monkeys, the main organs affected were the haematopoietic and lymphoid systems. These effects occurred at exposure levels equivalent to or lower than those seen in the clinic using the recommended dose of 2 g / day in renal transplant patients. Gastrointestinal undesirable effects were observed in dogs at exposure levels equivalent to or lower than those seen in the clinic using the recommended dose. In monkeys, gastrointestinal and renal undesirable effects involving dehydration were also observed at higher doses (for systemic exposure levels equivalent to or greater than those observed in the clinic). The toxicity profile of mycophenolate mofetil in experimental studies appears to be compatible with the undesirable effects of human clinical studies, which currently provide more relevant tolerability data for patients (see section 4.8).

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

CellCept capsules

corn starch in pregelatinized form;

cross-linked sodium carboxymethylcellulose;

polyvinylpyrrolidone (K-90);

magnesium stearate.

Capsule operculum

Jelly;

indigo carmine (E132);

yellow iron oxide (E172);

red iron oxide (E172);

titanium dioxide (E171);

black iron oxide (E172);

potassium hydroxide;

shellac rubber.

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

3 years.

06.4 Special precautions for storage -

Do not store above 30 ° C. Store in the original package in order to protect from moisture.

06.5 Nature of the immediate packaging and contents of the package -

CellCept 250 mg capsules: 1 box contains 100 capsules (in blisters of 10 capsules);

1 box contains 300 capsules (in blisters of 10 capsules).

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

The unused product and the waste derived from this medicinal product must be disposed of in accordance with local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

UK

08.0 MARKETING AUTHORIZATION NUMBER -

EU / 1/96/005/001 CellCept (100 capsules)

029796012

EU / 1/96/005/003 CellCept (300 capsules)

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 14 February 1996

Date of last renewal: March 13, 2006

10.0 DATE OF REVISION OF THE TEXT -

November 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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