Active ingredients: Mycophenolic acid (sodium mycophenolate)
Myfortic 180 mg gastro-resistant tablets
Myfortic package inserts are available for pack sizes:- Myfortic 180 mg gastro-resistant tablets
- Myfortic 360 mg gastro-resistant tablets
Indications Why is Myfortic used? What is it for?
Myfortic contains a substance called mycophenolic acid. It belongs to a group of medicines called immunosuppressants.
Myfortic is used to prevent the immune system from rejecting the transplanted kidney. It is used in combination with other medicines containing cyclosporine and corticosteroids.
Contraindications When Myfortic should not be used
Mycophenolate causes birth defects and miscarriages. If you are a woman of childbearing age, you must provide a negative pregnancy test before starting treatment and you must follow the advice on contraception provided by your doctor.
Your doctor will talk to you and give you written information, especially on the effects of mycophenolate on the unborn child. Read the information carefully and follow the instructions.
If you do not fully understand the instructions, ask your doctor to explain them again before taking mycophenolate. You can find more information in this section under "Warnings and precautions" and "Pregnancy and breastfeeding".
Do not take Myfortic:
- if you are allergic (hypersensitive) to mycophenolic acid, mycophenolate sodium, mycophenolate mofetil or any of the other ingredients of this medicine
- if you are a woman of childbearing age (who may become pregnant) and have not provided a negative pregnancy test prior to the first prescription as mycophenolate causes birth defects and miscarriage
- if you are pregnant or planning to become pregnant or think you may be pregnant
- if you are not using effective contraception (see Contraception in women and men)
- if you are breastfeeding (see also "Pregnancy and breastfeeding").
If this applies to you, tell your doctor without taking Myfortic.
Precautions for use What you need to know before taking Myfortic
Talk to your doctor or pharmacist before taking Myfortic:
- if you have or have ever had severe digestive disorders, such as stomach ulcer.
- if you have a rare hereditary deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT), such as Lesch-Nyhan syndrome and Kelley-Seegmille syndrome.
He must also be informed that:
- Myfortic reduces the level of protection of the epidermis from the sun. This increases the risk of skin cancer. It must limit exposure to the sun and ultraviolet rays (UV) by protecting the exposed areas as much as possible and by regularly applying high protection sun creams . Ask your doctor for advice on how to protect yourself from the sun.
- If you have already had hepatitis B or C, Myfortic can increase the risk of these diseases by causing them to come back. Your doctor may perform blood tests and check the symptoms of these diseases. If you have any symptoms (yellow eyes and skin, nausea, loss of appetite, dark urine) you must inform your doctor immediately.
- If you have a persistent cough or shortness of breath, especially when taking other immunosuppressants, you should tell your doctor immediately.
- Your doctor may ask you to check the levels of antibodies in your blood during treatment with Myfortc particularly when infections recur, especially if you are also being treated with other immunosuppressants, and will inform you if you can continue treatment with Myfortic.
- If you have any signs of infection (such as fever or sore throat) or if you experience any unexpected bruising or bleeding you should tell your doctor immediately.
- Your doctor may ask you to check your white blood cell values during treatment with Myfortic and will inform you if you can continue treatment with Myfortic.
- The active substance, mycophenolic acid, is different from that of other medicines with a similar name such as mycophenolate mofetil. You should not switch between medicines unless your doctor tells you to.
- The use of Myfortic in pregnancy may be harmful to the fetus (see also "Pregnancy and breastfeeding") and may increase the risk of pregnancy loss (miscarriage).
Interactions Which drugs or foods may change the effect of Myfortic
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, even those obtained without a prescription. In particular, you should tell your doctor if you are taking any of the following medicines:
- other immunosuppressive medicines such as azathioprine or tacrolimus.
- medicines used to treat high blood cholesterol levels such as cholestyramine.
- activated charcoal used to treat digestive disorders such as diarrhea, stomach upset and bloating.
- antacids that contain magnesium and aluminum.
- medicines used to treat viral infections such as aciclovir or ganciclovir.
You should also tell your doctor if you intend to have any vaccinations.
You should not donate blood during treatment with Myfortic and for at least 6 weeks after stopping treatment. Men should not donate sperm during treatment with Myfortic and for at least 90 days after stopping treatment.
Myfortic can be taken with or without food. You must choose whether to take the tablets with or without food and then continue to take them in the same way every day. This way it is safe to absorb the same amount of medicine every day.
Warnings It is important to know that:
Senior citizens
Elderly people (aged 65 years and over) can take Myfortic without needing to adjust the usual recommended dose.
Pediatric and adolescent population
Due to the lack of data, the use of Myfortic in children and adolescents is not recommended.
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 talk to you about the risks of becoming pregnant and about alternative therapies you can take to prevent rejection of the transplanted organ if:
- plan a pregnancy.
- you have missed or think you have missed a period or notice unusual menstrual bleeding or suspect that you are pregnant.
- have sex without using an effective method of contraception.
If you become pregnant while taking mycophenolate, you should inform your doctor immediately. However, continue taking mycophenolate until you have seen your doctor.
Pregnancy
Mycophenolate causes a very high frequency of spontaneous abortions (50%) and severe birth defects (23 - 27%) in the unborn child. Birth defects that have been reported include abnormalities of the ears, eyes, face (cleft of the lip / palate), development of the fingers, heart, esophagus (the tract that connects the throat to the stomach), kidneys and nervous system (for example spina bifida (where the bones of the spine are not properly developed). One or more of these may affect your baby.
If you are a woman of childbearing age, you must provide a negative pregnancy test before starting treatment and you must follow the advice on contraception provided by your doctor. Your doctor may request more than one test to make sure you are not pregnant before starting treatment.
Feeding time
Do not take Myfortic if you are breastfeeding. This is because small amounts of the medicine can pass into breast milk.
Contraception in women taking Myfortic
If you are a woman of childbearing age, you should always use two effective methods of contraception with Myfortic. This includes:
- Before starting treatment with Myfortic
- Throughout the period of treatment with Myfortic
- For 6 weeks after stopping treatment with Myfortic.
Talk to your doctor about the most suitable method of contraception for you. This will depend on your personal situation. Contact your doctor as soon as possible if you think the contraceptive method may not be effective and if you have forgotten to take the contraceptive pill.
If any of the following applies to you, you can consider yourself an infertile woman:
- She is postmenopausal, ie she is at least 50 years old and the last menstruation occurred more than a year ago (if her period was stopped because she received cancer treatment, there is still the possibility that she may remain pregnant )
- Her fallopian tubes and both ovaries were surgically removed (bilateral salpingoovariectomy)
- Her uterus was surgically removed (hysterectomy)
- Your ovaries are no longer functioning (early ovarian failure confirmed by a gynecologist specialist)
- She was born with one of the following rare conditions that make pregnancy impossible: the XY genotype, Turner syndrome or uterine agenesis.
- It is a "girl or a" teenager who has not yet had her first period.
Contraception in men taking Myfortic
You must always use a condom during treatment and for at least 90 days after stopping Myfortic
If you are planning to have a baby, your doctor will inform you about the risks and alternative treatments you can take to prevent rejection of the transplanted organ.
Driving and using machines
Myfortic does not appear to affect the ability to drive or use machines.
Myfortic contains lactose
If you have been told by your doctor that you have "intolerance to some sugars (including lactose, galactose or glucose), contact your doctor before taking Myfortic.
Dose, Method and Time of Administration How to use Myfortic: Posology
Always take Myfortic exactly as your doctor has told you. Myfortic will only be prescribed to you by doctors who have experience in treating transplant patients. If in doubt, consult your doctor or pharmacist.
What dose to take
The recommended daily dose of Myfortic is 1440 mg (8 tablets of Myfortic 180 mg). They are taken in 2 separate doses of 720 mg each (4 Myfortic 180 mg tablets). Take the tablets in the morning and in the evening.
The first dose of 720 mg will be given to you within 72 hours of the transplant.
If you have severe kidney problems
The daily dose should not exceed 1440 mg (8 tablets of Myfortic 180 mg).
Taking Myfortic
Swallow the tablets whole with a glass of water.
The tablets should not be broken or crushed.
Do not take any broken or split tablets
Treatment will continue as long as immunosuppression is needed to avoid rejection of the transplanted organ.
If you forget to take Myfortic
If you forget to take Myfortic, take it as soon as you remember unless it is almost time for your next dose. Then take your next dose when you are expected to take it. Ask your doctor for advice. Do not take a double dose to make up for a forgotten dose.
If you stop taking Myfortic
Do not stop taking Myfortic unless your doctor tells you to. Stopping treatment with Myfortic may increase the risk of rejection of a transplanted kidney.
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 Myfortic
If you have taken more Myfortic than you were told to take or if someone else has taken your tablets, contact your doctor and go to a hospital immediately. Medical treatment may be required. Take the tablets with you and show them to your doctor or hospital staff. If you have run out of tablets, take the empty pack with you.
Side Effects What are the side effects of Myfortic
Like all medicines, Myfortic can cause side effects, although not everybody gets them. Elderly patients may experience more side effects due to a reduced immune defense.
Immunosuppressants, including Myfortic, reduce your body's defense mechanisms to keep you from rejecting your transplanted organ. As a result, your body will not be able to defend itself against infections as it would under normal conditions. Therefore, if you are taking Myfortic, you may get more infections than usual such as infections of the brain, skin, mouth, stomach and intestines, lung and urinary tract.
Your doctor will have regular blood tests to check for changes in the number of blood cells or the levels of substances carried in the blood, such as sugar, fat and cholesterol.
Some side effects can be serious:
- signs of infection including fever, chills, sweating, feeling tired, sleepy or lack of energy. If you are taking Myfortic you may have viral, bacterial and fungal infections more frequently than usual. These infections can affect different parts of the body but most commonly the kidneys, bladder, upper and / or lower airways.
- haemorrhagic vomiting, dark or bloody stools, stomach or intestinal ulcer.
- swelling of the glands, proliferation of new skin formations, increase in the volume of existing formations or alterations of an already existing formation. As may occur in patients being treated with immunosuppressants, a very small number of patients taking Myfortic have developed cancer of the skin or lymph nodes.
If you have experienced any of the above side effects after taking Myfortic, please contact your doctor immediately.
Other side effects may include:
Very common (affecting more than 1 in 10 patients)
- low levels of white blood cells.
- low levels of calcium in the blood (hypocalcaemia)
- low levels of potassium in the blood (hypokalaemia)
- high levels of uric acid in the blood (hyperuricaemia)
- high blood pressure (hypertension)
- anxiety
- diarrhea
- joint pain (arthralgia)
Common (affecting less than 1 in 10 patients)
- low levels of red blood cells which can cause tiredness, shortness of breath and paleness (anemia)
- low levels of platelets in the blood which can cause unexpected bleeding and bruising (thrombocytopenia)
- high levels of potassium in the blood (hyperkalaemia)
- low levels of magnesium in the blood (hypomagnesaemia)
- dizziness
- headache
- cough
- low blood pressure (hypotension)
- shortness of breath (dyspnoea)
- pain in the abdomen or stomach, inflammation of the stomach wall, bloating, constipation, dyspepsia, flatulence, loose stools, nausea, vomiting
- fatigue, fever
- abnormal results of liver and kidney function tests
- respiratory infections
- acne
- weakness (asthenia)
- muscle pain (myalgia)
- swelling of the hands, ankles or feet (peripheral edema)
- itch
Uncommon (affecting less than 1 in 100 patients)
- fast (tachycardia) or irregular heartbeat (ventricular extrasystoles), fluid in the lungs (pulmonary edema)
- fluid-containing cyst-like skin formation (lymphocele)
- tremor, difficulty sleeping
- redness and swelling of the eyes (conjunctivitis), blurred vision
- wheezing
- belching, difficulty breathing, intestinal blockage (ileus), ulceration of the lips, heartburn, discolouration of the tongue, dry mouth, inflammation of the gums, inflammation of the pancreas causing severe upper stomach pain (pancreatitis), blockage of the salivary glands, inflammation of the inner wall of the abdomen (peritonitis)
- infection of the bones, blood and skin
- blood in the urine, kidney damage, pain and difficulty passing urine
- hair loss, bruising
- joint inflammation (arthritis), back pain, muscle cramps
- loss of appetite, increased lipid levels (hyperlipidaemia), sugar (diabetes), cholesterol (hypercholesterolemia) or decreased blood phosphate levels (hypophosphataemia)
- flu signs (such as tiredness, chills, sore throat, joint or muscle pain), swelling of ankles and feet, pain, stiffness, thirst or weakness
- abnormal dreams, sense of disappointment
- inability to have or maintain an erection
- cough, difficulty in breathing, painful breathing (possible symptoms of interstitial lung disease).
Not known (frequency cannot be estimated from the available data)
- rash
- fever, sore throat, frequent infections (possible symptoms of lack of white blood cells) (agranulocytosis)
Other side effects reported with medicines similar to Myfortic
Additional side effects have been reported with the group of medicines to which Myfortic belongs: inflammation of the colon (large intestine), inflammation of the stomach walls caused by cytomegalovirus, formation of a lesion in the intestinal wall which causes severe pain in the abdomen with the possibility bleeding, stomach or duodenal ulcer, low levels of white blood cells specifically or of all blood cells, severe infections such as inflammation of the heart and heart valves and membranes lining the brain and spinal cord, shortness of breath, cough which may be caused by bronchiectasis (a condition in which the airways in the lungs are abnormally dilated) and other less common bacterial infections that usually cause severe lung problems (tuberculosis and atypical mycobacterial infections). Contact your doctor if you have a persistent cough or shortness of breath.
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 at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use Myfortic after the expiry date which is stated on the carton. The expiry date refers to the last day of the month.
Do not store above 30 ° C.
Store Myfortic in the original package to protect from moisture. Do not use Myfortic if you notice that the package is damaged or shows signs of tampering.
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.
Other Information
What Myfortic contains
- The active ingredient is mycophenolic acid (as mycophenolate sodium). Each tablet of Myfortic contains 180 mg of mycophenolic acid.
- The excipients are:
- Core tablet: corn starch, povidone, crospovidone, anhydrous lactose, anhydrous colloidal silica, magnesium stearate.
- Tablet coating: hypromellose phthalate, titanium dioxide (E 171), yellow iron oxide (E 172), indigo carmine (E 132).
What Myfortic looks like and contents of the pack
Myfortic 180 mg gastro-resistant tablets are yellowish green, film-coated, round shaped and debossed with "C" on one side. Myfortic 180 mg gastro-resistant tablets are available in blister packs containing 20, 50, 100, 120 or 250 tablets.
Not all pack sizes may be marketed.
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.
01.0 NAME OF THE MEDICINAL PRODUCT
MYFORTIC 180 MG FOOD-RESISTANT TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each gastro-resistant tablet contains 180 mg of mycophenolic acid (as mycophenolate sodium).
Excipients:
Anhydrous lactose: 45 mg per tablet.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Gastro-resistant tablet.
Round shaped, yellowish green film-coated tablets with beveled corners debossed with "C" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Myfortic is indicated in combination with cyclosporine and corticosteroids, for the prophylaxis of acute rejection, in adult patients receiving an allogeneic kidney transplant.
04.2 Posology and method of administration
Treatment with Myfortic should be initiated and continued by appropriately qualified transplant physicians.
The recommended dose is 720 mg twice daily (1440 mg daily dose). In terms of mycophenolic acid (MPA) content, this sodium mycophenolate dose corresponds to 1 g of mycophenolate mofetil taken twice a day (2 g daily dose).
For further information on the matching of therapeutic doses of mycophenolate sodium and mycophenolate mofetil, see sections 4.4 and 5.2.
In transplant patients de-novo Myfortic administration should be started within 72 hours following the transplant surgery.
Myfortic can be taken with or between meals. Patients can choose one of the two modes of administration but will have to keep it for the entire period of taking the drug (see section 5.2).
Myfortic tablets should not be crushed to keep the enteric coating intact. In cases where crushing of Myfortic tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membranes. If contact occurs, wash thoroughly with soap and water; rinse eyes with only natural water This is due to the teratogenic effects of mycophenolate.
Pediatric and adolescent population
There are insufficient data available to document the efficacy and safety of Myfortic in children and adolescents. Limited pharmacokinetic data are available in pediatric renal transplant patients (see section 5.2).
Senior citizens
The recommended dose in elderly patients is 720 mg twice a day.
Patients with renal impairment
No dosage adjustment is required in patients with delayed renal function after transplantation (see section 5.2).
However, patients with severe renal impairment (glomerular filtration rate
Patients with hepatic impairment
No dose adjustments are required in patients with kidney transplantation and severe hepatic impairment.
Treatment during rejection episodes
No changes in mycophenolic acid (MPA) pharmacokinetics have been observed during rejection episodes following renal transplantation; therefore no dosage adjustment or discontinuation of Myfortic therapy is required.
04.3 Contraindications
Myfortic should not be used in patients with hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil or any of the excipients (see section 6.1).
Myfortic should not be used in women who are breastfeeding and in women of childbearing potential who are not using highly effective methods of contraception and should not be started without a pregnancy test in order to rule out inadvertent use of the medicine in pregnancy ( see section 4.6).
Myfortic should not be used in pregnancy unless there is a suitable alternative treatment to prevent organ rejection (see section 4.6).
Myfortic must not be administered to breastfeeding women (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Patients receiving immunosuppressive therapy based on a combination of drugs, including Myfortic, have an increased risk of developing lymphomas or other malignancies, especially of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppressive treatment rather than to the use of a specific product. As a general warning, in order to reduce the risk of skin cancer, it is necessary to limit exposure to sunlight and UV rays by using protective clothing and sun creams with a high protection factor.
Patients treated with Myfortic should be instructed on the need to immediately report any signs of infection or the presence of unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including Myfortic, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Opportunistic infections include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often due to a high total immunosuppressive burden and can lead to serious or fatal conditions that physicians should consider when making differential diagnosis in immunosuppressed patients with worsening renal function or neurological symptoms.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Myfortic in combination with other immunosuppressants. In some of these cases, switching from MPA derivatives to an alternative immunosuppressant resulted in serum IgG levels returning to normal. In patients treated with Myfortic who develop recurrent infections, serum immunoglobulins should be measured. In cases of persistent clinically relevant hypogammaglobulinemia, appropriate clinical intervention should be considered taking into account the potent cytostatic effects of mycophenolic acid on T and B lymphocytes.
There have been reports of bronchiectasis in patients treated with Myfortic in combination with other immunosuppressants. In some of these cases, switching from MPA derivatives to another immunosuppressant led to improvement in respiratory symptoms. The risk of bronchiectasis may be related to hypogammaglobulinemia or a direct effect on the lung. There have also been isolated reports of interstitial lung disease (see section 4.8). It is recommended that patients who develop persistent respiratory symptoms, such as cough and dyspnoea, are studied for any evidence of underlying interstitial lung disease.
Reactivation of hepatitis B (HBV) or hepatitis C (HCV) has been reported in patients treated with immunosuppressants, including myfortic mycophenolic acid (MPA) derivatives and mycophenolate mofetil (MMF). Monitoring of patients is recommended. infected for clinical and laboratory signs of active HBV or HCV infection.
Cases of Pure Red Cell Aplasia (PRCA) have been reported in patients treated with mycophenolic acid derivatives (which include mycophenolate mofetil and sodium mycophenolate) in combination with other immunosuppressive drugs. mycophenolic induced PRCA is not known. PRCA may resolve with dose reduction or discontinuation of therapy. Treatment changes with Myfortic 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 Myfortic should be monitored for blood disorders (e.g. neutropenia or anemia - see section 4.8), which may be related to mycophenolic acid itself, concomitant medications, viral infections, or combinations of these causes. Patients treated with Myfortic should therefore have a complete blood count every week during the first month of therapy, twice a month during the second and third months, and then monthly until the end of the first year of therapy. In case of blood disorders (eg: neutropenia with absolute neutrophil count
Patients should be advised that vaccinations may be less effective during treatment with mycophenolic acid, while vaccinations with live attenuated vaccines should be avoided (see section 4.5). However, influenza vaccination can be helpful; physicians should refer to national influenza vaccination guidelines.
Since mycophenolic acid derivatives have been associated with an increased incidence of adverse events affecting the digestive system, including infrequent cases of gastrointestinal ulcer, haemorrhage and perforation, Myfortic should be administered with caution in patients with severe illness. in the active phase of the digestive system.
It is recommended not to administer Myfortic concurrently with azathioprine as co-administration of these drugs has not been studied.
Due to the different pharmacokinetic profile, mycophenolic acid (as sodium salt) and mycophenolate mofetil should not be interchanged or substituted indiscriminately. Myfortic was administered in combination with cyclosporine and corticosteroids.
Experience of drug administration with induction therapies such as anti-lymphocyte-T globulin or basiliximab is limited. The efficacy and safety of Myfortic in combination with other immunosuppressive agents (eg tacrolimus) have not been studied.
Myfortic contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-Lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Administration of Myfortic concomitantly with drugs that interfere with the enterohepatic circulation, such as cholestyramine and activated charcoal, may result in systemic exposure to MPA below therapeutic levels and consequently in reduced efficacy.
Myfortic is an inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH). For this reason it should not be used in patients with rare hereditary conditions involving a deficiency of the enzyme hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT), such as the syndrome of Lesch-Nyhan and Kelley-Seegmiller syndrome.
Myfortic therapy should not be started before obtaining a negative pregnancy test.An effective method of contraception should be used prior to initiating therapy with Myfortic, during therapy and for six weeks after discontinuation (see section 4.6).
Teratogenic effects
Mycophenolate is a potent human teratogen. Spontaneous abortions (rate 45-49%) and congenital malformations (estimated rate 23-27%) have been reported following exposure to mycophenolate mofetil during pregnancy. Therefore Myfortic is contraindicated in pregnancy unless there are adequate alternative treatments to prevent transplant rejection. Female and male patients of childbearing potential should be informed of the risks and follow the recommendations given in section 4.6 (eg contraceptive methods, pregnancy tests) before, during and after Myfortic therapy. Physicians should ensure that both women and men taking mycophenolate understand the risk of harm to the fetus and the need for effective contraception and seek immediate medical attention if there is a possibility of pregnancy.
Contraception (see section 4.6)
Due to the genotoxic and teratogenic potential of Myfortic, women of childbearing potential should use two reliable methods of contraception at the same time before starting Myfortic therapy, during it and for six weeks after stopping treatment; unless the method is used. contraceptive chosen is not abstinence.
Sexually active men are recommended to use condoms during treatment and for at least 90 days after stopping treatment. The use of condoms is valid for both fertile men and for those undergoing vasectomy as the risks associated with the passage of seminal fluid also apply to men who have undergone a vasectomy. In addition, women partners of patients treated with Myfortic are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of Myfortic.
Educational materials
To help patients avoid fetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorization Holder will provide educational materials to healthcare professionals. The educational materials will reinforce warnings on the teratogenicity of mycophenolate and they will provide advice on contraception before starting therapy and guidance on the need for a pregnancy test. Complete patient information on teratogenic risk and pregnancy prevention methods should be provided by the physician to women of childbearing potential and, where relevant, 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
The following interactions between mycophenolic acid and other medicinal products have been reported:
Aciclovir and Ganciclovir
The potential for myelosuppression in patients taking Myfortic in combination with aciclovir or ganciclovir has not been studied. If Myfortic is given in combination with aciclovir / ganciclovir, increased levels of MPAG (mycophenolic acid glucuronate metabolite) and aciclovir / ganciclovir can be expected, possibly due to competition for the tubular secretion mechanism. changes in MPAG pharmacokinetics are of clinical relevance in patients with adequate renal function. In the presence of renal impairment, there is a potential for increased plasma concentrations of MPAG and aciclovir / ganciclovir; in this case, patients should be carefully monitored and follow dosing recommendations for aciclovir / ganciclovir.
Gastroprotectors:
Antacids based on magnesium and aluminum:
A decrease in mycophenolic acid AUC and Cmax of approximately 37% and 25% respectively was observed when Myfortic is administered in combination with a single dose of magnesium-aluminum antacid. Magnesium-aluminum antacids may be used occasionally to treat occasional dyspepsia. However, the daily chronic use of magnesium-aluminum antacids in combination with Myfortic is not recommended due to their potential to decrease exposure to mycophenolic acid and consequently reduce its efficacy.
Proton pump inhibitors:
In healthy volunteers, no changes in MPA pharmacokinetics were observed following concomitant administration of Myfortic and pantoprazole at a dose of 40 mg twice daily within the previous four days. No data are available on other proton pump inhibitors given in high doses.
Oral contraceptives
Interaction studies conducted with MMF (mycophenolate mofetil) and oral contraceptives have shown no interactions between these drugs. Based on the metabolic profile of MPA, no interactions are foreseeable between Myfortic and oral contraceptives.
Cholestyramine and drugs that bind to bile acids
Attention should be paid to the concomitant use of drugs or therapies that can bind to bile acids, such as bile acid sequestrants or oral activated charcoal, due to their potential to decrease MPA exposure and thereby reduce the "efficacy of Myfortic.
Cyclosporine
The pharmacokinetics of cyclosporine, studied in stable renal transplant patients, were not affected by steady-state administration of Myfortic dosing. Conversely, it is known that the administration of cyclosporine concomitantly with mycophenolate mofetil reduces exposure to mycophenolic acid. It is therefore believed that cyclosporine, administered with Myfortic, may similarly decrease blood concentrations of mycophenolic acid (approximately 20%, based on data obtained with mycophenolate mofetil) but the precise extent of this decrease is not known as this interaction is not known. has been studied. However, as all efficacy studies were conducted in combination with cyclosporine, this interaction does not change the recommended dosage of Myfortic. If ciclosporin treatment is interrupted or discontinued, the Myfortic dosage should be re-evaluated according to the immunosuppressive regimen.
Tacrolimus
In a cross-over clinical study of calcineurin in stable kidney transplant patients, steady-state pharmacokinetics of Myfortic were measured during treatment with both Neoral and tacrolimus. The mean value of the AUC of mycophenolic acid was greater than 19% (90% CI: - 3, +47) while the mean value of the AUC of the metabolite MPAG (phenolic glucuronide of mycophenolic acid) was about 30% (90% CI: 16, 42) during treatment with tacrolimus compared with Neoral. Furthermore, the variability in mycophenolic acid AUC observed within subjects was doubled after switching from Neoral to tacrolimus treatment. Clinicians should take into account both the increase in the AUC of mycophenolic acid and the variability, and the Myfortic dose adjustment should be dictated by the clinical situation. Close clinical monitoring should be made when planning to switch from one calcineurin inhibitor to another.
Live attenuated vaccines
Live vaccines should not be given to patients with impaired immune responses. The antibody response to vaccines of other types may be diminished.
04.6 Pregnancy and breastfeeding
Women of childbearing age
Do not start Myfortic therapy before taking a pregnancy test, which must be negative.
Contraception in men and women
Myfortic is contraindicated in women of childbearing potential who are not using highly effective methods of contraception.
Due to the genotoxic and teratogenic potential of Myfortic, women of childbearing potential should use two reliable methods of contraception at the same time before starting Myfortic therapy, during Myfortic therapy and for six weeks after the last dose of Myfortic, unless that the contraceptive method chosen is not abstinence.
Sexually active men are recommended to use condoms during treatment with Myfortic and for at least 90 days after stopping treatment. The use of condoms applies to both fertile and vasectomy men as the risks associated with passage of seminal fluid also apply to men who have undergone vasectomy. In addition, female companions of male patients treated with Myfortic are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of Myfortic.
Pregnancy
Myfortic is contraindicated in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be started without a pregnancy test result in order to rule out inadvertent use of the drug in pregnancy.
Female and male patients of childbearing potential should be advised of the increased risk of pregnancy loss and congenital malformations at the start of treatment and should be counseled on pregnancy prevention and planning.
Before starting treatment with Myfortic, women of childbearing potential should have a pregnancy test to rule out unintentional 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 (when appropriate) should be done 8 to 10 days after the first and immediately before starting Myfortic therapy. Pregnancy tests should be repeated as clinically needed (e.g. after each report of interruption in contraception). The results of all pregnancy tests should be discussed with the patient. Patients should be advised to consult their physician immediately if they are pregnant.
Mycophenolate is a potent teratogen in humans, with an increased risk of miscarriages and congenital malformations in case of exposure to the drug during pregnancy:
• Spontaneous abortions have also been reported in 45-49% of pregnant women exposed to mycophenolate mofetil, compared with a reported rate of 12 to 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil .
• According to literature, malformations occurred 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, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:
• Ear abnormalities (eg malformed or absent external / 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 anomalies (eg coloboma);
• Finger malformations (eg polydactyly, syndactyly);
• Tracheoesophageal malformations (eg esophageal atresia);
• Nervous system malformations such as spina bifida;
• Renal anomalies.
In addition, there have been isolated reports of the following malformations:
• Microphthalmia;
• Congenital cyst of the choroid plexus;
• Agenesis of the septum pellucidum;
• Agenesis of the olfactory nerve.
Studies in animals have shown reproductive toxicity (see section 5.3).
Feeding time
In rats, mycophenolic acid is excreted in human milk. It is not known whether Myfortic is also excreted in human milk, but as mycophenolic acid could potentially cause serious adverse reactions in the infant, administration of Myfortic is contraindicated during breastfeeding. breast (see section 4.3).
Fertility
No specific studies have been conducted with Myfortic in humans to evaluate its effects on fertility. In a male and female fertility study in rats, no effects were observed up to doses of 40 mg / kg and 20 mg / kg, respectively (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. The mechanism of action, the pharmacodynamic profile and the adverse reactions reported make such an effect unlikely.
04.8 Undesirable effects
The following undesirable effects refer to adverse drug reactions observed in clinical studies.
Neoplasms
Patients receiving immunosuppressive therapy consisting of a combination of drugs, including mycophenolic acid, are at increased risk of developing lymphomas or other malignancies, especially of the skin (see section 4.4). A lymphoproliferative disease or lymphoma has developed in 2 patients de-novo (0.9%) and in 2 maintenance patients (1.3%) who took Myfortic for one year. In 0.9% of patients de-novo and 1.8% of maintenance patients who took Myfortic for one year had non-melanoma skin cancer; other types of cancer were seen in 0.5% of patients de-novo and in 0.6% of patients in the maintenance phase.
Opportunistic infections
The risk of opportunistic infections increases in all transplant patients, the risk increases with the total immunosuppressive burden (see section 4.4). The most common opportunistic infections in renal transplant patients de-novo treated with Myfortic in combination with other immunosuppressants observed in controlled clinical trials of renal transplant patients followed for 1 year were CMV (cytomegalovirus), candidiasis and herpes simplex. CMV infections (serology, viraemia or disease established) were 21.6% in renal transplant patients de novo and 1.9% in maintenance therapy patients.
Senior citizens
In general, elderly patients may be at an increased risk of developing adverse reactions due to immunosuppression.
Other adverse drug reactions
The following table 1 lists the adverse reactions possibly or likely related to Myfortic, reported in controlled clinical trials in kidney transplant patients in which Myfortic was administered in combination with cyclosporine microemulsion and corticosteroids at a dose of 1440 mg / day. for 12 months The table was compiled according to the MedDRA system organ class classification.
Adverse reactions are listed according to the following categories:
Very common (≥ 1/10)
Common (> 1/100,
Uncommon (> 1 / 1,000,
Rare (> 1 / 10,000,
Very rare (
Table 1
* event reported in only one patient (out of 372).
Note: Kidney transplant patients were treated with Myfortic 1440 mg / day for up to one year. The adverse reaction profile is similar in patients de-novo and in the population in maintenance therapy after transplantation, even if the incidence of adverse reactions appears to be lower in the latter population.
From post-marketing experience, rash and agranulocytosis have been identified as adverse reactions.
The following additional adverse reactions have been attributed as a class effect to mycophenolic acid derivatives:
Infections and infestations:
Serious, life-threatening infections, including meningitis, infective 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 Myfortic (see section 4.4).
Disorders of the blood and lymphatic system:
Neutropenia, pancytopenia.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolic acid derivatives (see section 4.4).
Disorders of the immune system
Hypogammaglobulinaemia has been reported in patients receiving Myfortic in combination with other immunosuppressants.
Respiratory, thoracic and mediastinal disorders:
There have been isolated reports of interstitial lung disease in patients treated with Myfortic in combination with other immunosuppressants. There have also been reports of bronchiectasis in combination with other immunosuppressants.
Isolated cases of neutrophil morphological abnormalities, including the acquired Pelger-Huet anomaly, have been reported in patients treated with mycophenolic acid derivatives. However, these alterations are not associated with impaired functionality of neutrophils. These alterations can be suggestive of a phenomenon of left shift maturation of neutrophils, which may be misinterpreted as a sign of infection in immunosuppressed patients such as those treated with Myfortic.
Gastrointestinal disorders:
Colitis, CMV gastritis, intestinal perforation, gastric ulcer, duodenal ulcer.
Pregnancy, puerperium and perinatal conditions:
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mainly in the first trimester (see section 4.6).
Congenital disorders:
Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate in combination with other immunosuppressants (see section 4.6).
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
There have been reports of intentional or accidental overdoses with Myfortic although not all patients have experienced related adverse events.
In those cases of overdose for which adverse events have been reported, the events fall within the scope of the known safety profile of the class (mainly blood dyscrasias, sepsis ...) (see sections 4.4 and 4.8).
Although dialysis can be used to eliminate the inactive metabolite of mycophenolic acid MPAG, it is not expected to remove clinically significant amounts of the active part of mycophenolic acid. This is mainly due to the high binding of mycophenolic acid to plasma proteins. bile acid sequestering drugs such as cholestyramine, by interfering with the enterohepatic circulation of mycophenolic acid, can decrease systemic exposure to mycophenolic acid.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressants.
ATC code: L04 AA06.
Mycophenolic acid is a potent, selective, non-competitive and reversible inhibitor of the enzyme inosine monophosphate dehydrogenase; it inhibits the synthesis pathway de-novo of the guanosine nucleotide, without being incorporated into the DNA. The proliferation of T and B lymphocytes being critically dependent on synthesis de-novo of purines, unlike other cell types that can use an alternative mechanism, the cytostatic action of mycophenolic acid on lymphocytes is more powerful than that exerted on other cell types.
05.2 Pharmacokinetic properties
Absorption
After oral administration, mycophenolate sodium is extensively absorbed. Consistent with the characteristics of the gastroenteric formulation, the Tmax (time to reach maximum concentration) of mycophenolic acid is about 1.5 - 2 hours. About 10% of the pharmacokinetic profiles determined after morning administration showed a prolongation of the value of Tmax, some times of several hours, without any estimated influence on the exposure to mycophenolic acid in the 24 hours.
In stable kidney transplant patients receiving immunosuppressive treatment with cyclosporine, the gastrointestinal absorption of mycophenolic acid was 93% and the absolute bioavailability was 72%. The pharmacokinetics of Myfortic were dose proportional and linear over the dose range tested (180 - 2160 mg). Single dose administration of Myfortic (720 mg) with high fat foods (55 g fat, 1000 calories) did not change the AUC (the most important pharmacokinetic parameter correlated with efficacy) of mycophenolic acid compared to administration of the drug in fasted conditions; however, mycophenolic acid Cmax was reduced by 33%. In addition, a mean prolongation of tlag and Tmax values of 3-5 hours was observed, with Tmax values> 15 hours in many patients. "Food intake on the pharmacokinetics of Myfortic may therefore lead to overlap in absorption from one dose range to another." However, this effect did not show any clinical significance.
Distribution
The steady state volume of distribution of mycophenolic acid is 50 liters. Both mycophenolic acid and its glucuronate metabolite are strongly bound to plasma proteins (97% and 82%, respectively). The concentration of free mycophenolic acid may increase under conditions involving a decrease in protein binding sites (uremia, hepatic insufficiency, hypoalbuminemia, concomitant use of highly plasma protein binding drugs). This may lead to an increased risk of mycophenolic acid-related adverse events.
Biotransformation
Mycophenolic acid is metabolised by the enzyme glucuronyltransferase into phenolic glucuronide of mycophenolic acid (MPAG). MPAG is the major metabolite of mycophenolic acid and has no biological activity. In stable patients receiving ciclosporin after kidney transplantation, approximately 28% of the orally administered dose of Myfortic is metabolised to MPAG by presystemic metabolism. The half-life of this metabolite, longer than that of mycophenolic acid, is about 16 hours and its clearance is 0.45 L / h.
Elimination
The half-life of mycophenolic acid is approximately 12 hours and clearance is 8.6 l / hour. Although negligible amounts of mycophenolic acid are present in the urine (bile is available for deconjugation by the intestinal flora and the mycophenolic acid which is formed through this process can then be reabsorbed. Approximately 6-8 hours after administration of Myfortic it is possible in fact observe a second peak of concentration of mycophenolic acid, correlated to the reabsorption of the deconjugated mycophenolic acid. / ml) were observed in the morning in approximately 2% of patients treated with Myfortic. However, during studies, steady state AUC (0-12h) which is indicative of overall exposure, showed less variability than to that of the minimum plasma concentration (Ctrough).
Pharmacokinetics in renal transplant patients receiving immunosuppressive treatment with cyclosporine:
The following table 2 shows the mean pharmacokinetic parameters of mycophenolic acid after administration of Myfortic. In the period immediately following the transplant, the mean values of AUC and Cmax of mycophenolic acid were approximately half of the values determined six months after transplantation. .
Table 2 Pharmacokinetic parameters (mean and SD) for MPA following oral administration of Myfortic in kidney transplant patients receiving cyclosporine immunosuppression.
(* median values)
Renal impairment
The pharmacokinetics of mycophenolic acid appear to be unchanged from the stage of normal renal function up to renal failure. Conversely, exposure to the MPAG metabolite increases with decreased renal function, and is approximately 8 times higher in the presence of anuria. The clearance of mycophenolic acid and that of the MPAG metabolite were not affected by "hemodialysis. L" Free mycophenolic acid can also significantly increase in conditions of renal insufficiency, probably due to a decrease in the binding of mycophenolic acid to plasma proteins in the presence of high blood concentrations of urea.
Hepatic impairment
The hepatic glucuronidation of mycophenolic acid is scarcely altered by the presence of pathologies of the hepatic parenchyma, as observed in volunteers with alcoholic cirrhosis. The effects of liver disease on drug metabolism probably depend on the type of pathology: a liver disease with prevailing damage to the pathways. biliary, such as primary biliary cirrhosis, can have a different effect on the metabolism of mycophenolic acid.
Pediatric and adolescent population
Limited data are available on the use of Myfortic in children and adolescents. Table 2 above describes the mean (SD) pharmacokinetic parameters of mycophenolic acid in stable pediatric renal transplant patients aged 5-16 years undergoing therapy. immunosuppressive with cyclosporine. The mean AUC of mycophenolic acid at the dose of 450 mg / m2 was similar to the AUC determined in adults treated with Myfortic at the dose of 720 mg. The mean apparent clearance of mycophenolic acid was approximately 6.7 L / h / m2.
Type
There are no clinically significant gender differences in Myfortic pharmacokinetics.
Senior citizens
Pharmacokinetics in the elderly have not been evaluated in appropriate studies. Mycophenolic acid exposure does not appear to vary significantly with age.
05.3 Preclinical safety data
In repeat dose toxicity studies conducted with mycophenolate sodium in rats and mice, the major organs affected were the hematopoietic and lymphoid systems. Aplastic, regenerative anemia was identified as an expression of dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a marked decrease in erythroid cells (normoblasts and polychromatic erythroblasts), a dose-dependent "splenic hypertrophy and an increase of extra-medullary haematopoiesis. These effects occurred at systemic exposure levels equivalent to or lower than those observed in the clinical setting in renal transplant patients with the recommended Myfortic dose of 1.44 g / day.
Gastrointestinal effects were observed in dogs at systemic exposure levels equivalent to or lower than those observed in the clinical setting with the recommended dose.
The toxicological profile of mycophenolic acid (as sodium salt) resulting from preclinical studies is therefore consistent with the adverse events observed in clinical studies, which provide safety data of greater relevance to the patient population (see section 4.8).
In three genotoxicity tests (in vitro mouse lymphoma assay, Chinese hamster V79 cell micronuclei and in vivo mouse bone marrow micronuclei assay), mycophenolic acid showed the potential to cause chromosomal aberrations. It is possible that the observed effects are related to the pharmacodynamic mechanism of action, ie the inhibition of nucleotide synthesis in sensitive cells. In other in vitro tests aimed at evaluating the induction of genetic mutations, mycophenolic acid did not show genotoxic activity.
Mycophenolic acid (as sodium salt) was not carcinogenic in rats and mice. In animal carcinogenicity studies the maximum dose tested corresponds to a systemic exposure (AUC or Cmax) of approximately 0.6 - 5 times that observed in renal transplant patients treated with the recommended dose of Myfortic of 1.44 g / day.
Mycophenolic acid (as sodium salt), even at doses that have caused general toxicity and embryotoxicity, has no effect on the fertility of male and female rats.
In a rat teratogenic study with mycophenolic acid (as sodium salt) at a dose of 1 mg / kg, malformations in the progeny, including anophthalmia, exencephaly and umbilical hernia, were observed. The systemic exposure corresponding to this dose is equal 0.05 times the clinical exposure with the Myfortic dose of 1.44 mg / day (see section 4.6).
In a pre- and postnatal development study in the rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in the female and separation of the foreskin in the male) at the maximum dose of 3 mg / kg which also induces malformations. .
In an essay in vitro of phototoxicity 3T3 NRU mycophenolic acid (as sodium salt) showed phototoxic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nucleus:
Cornstarch
Povidone (K 30)
Crospovidone
Anhydrous lactose
Anhydrous colloidal silica
Magnesium stearate.
Coating:
Hypromellose phthalate
Titanium dioxide (E171)
Yellow iron oxide (E172)
Indigo carmine (E132)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
30 months.
06.4 Special precautions for storage
Do not store above 30 ° C.
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
The tablets are packaged in polyamide / aluminum / PVC / aluminum blisters, each containing 10 tablets, in quantities per box of 20, 50, 100, 120 and 250 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
In order to keep the enteric coating intact, Myfortic tablets must not be crushed (see section 4.2).
Mycophenolic acid has shown teratogenic effects (see section 4.6).
If crushing of Myfortic tablets is necessary, avoid inhalation or direct contact of the powder with the skin or mucous membrane.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Farma S.p.A
Largo Umberto Boccioni, 1
Origgio (Va)
08.0 MARKETING AUTHORIZATION NUMBER
180 mg gastro-resistant tablets - 20 tablets AIC n .: 036511018
180 mg gastro-resistant tablets - 50 tablets AIC n .: 036511020
180 mg gastro-resistant tablets - 100 tablets AIC n .: 036511032
180 mg gastro-resistant tablets - 120 tablets AIC n .: 036511044
180 mg gastro-resistant tablets - 250 tablets AIC n .: 036511057
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 13 June 2005
Renewal date: October 10, 2008
10.0 DATE OF REVISION OF THE TEXT
07/2016
