MMF 500 (Tablets) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Medis, S.A. (Tunisia)

ATC Code

L04AA06 (Mycophenolic acid)

Active Substance

Mycophenolate mofetil

Dosage Form

MMF 500

Film-coated tablets 500 mg: 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink in color, oval, biconvex, with the engraving “MMF 500” on one side and the engraving “MEDIS” on the other.

Excipients: microcrystalline cellulose – 250 mg, lactose monohydrate – 200 mg, croscarmellose sodium – 32.5 mg, colloidal silicon dioxide – 5 mg, magnesium stearate – 12.5 mg.

Film coating excipients Opadry (II) pink 85G34736 – 10 mg (polyvinyl alcohol 44%, titanium dioxide (E171) 19.3%, macrogol-4000 12.35%, talc 20%, soy lecithin 3.5%, dye Azorubine (E122) 0.85%), Opadry (II) white 85F18378 – 40 mg (polyvinyl alcohol 40%, titanium dioxide (E171) 25%, macrogol-4000 20.2%, talc 14.8%).

7 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agents

Pharmacological Action

Immunosuppressive agent. Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is a potent, selective, non-competitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which suppresses the de novo synthesis of guanosine nucleotides.

The mechanism by which MPA suppresses IMPDH enzyme activity appears to be related to MPA structurally mimicking both the nicotinamide dinucleotide phosphate co-factor and the catalytic water molecule. This prevents the oxidation of IMP to xanthosine-5-monophosphate, a crucial step in the de novo biosynthesis of guanosine nucleotides.

MPA has a more pronounced cytostatic effect on lymphocytes than on other cells because the proliferation of T and B lymphocytes is highly dependent on de novo purine synthesis, whereas other cell types can utilize salvage pathways.

Pharmacokinetics

After oral administration, MMF is rapidly and completely absorbed and undergoes complete presystemic metabolism to form the active metabolite, MPA. The bioavailability of MMF after oral administration, based on the MPA AUC value, averages 94% of that after its intravenous administration. After oral administration, MMF plasma concentrations are not detectable (below the quantification limit of 0.4 µg/ml).

In the early post-transplantation period (up to 40 days after kidney, heart, or liver transplantation), mean AUC values were approximately 30% lower and C_max was approximately 40% lower than in the late post-transplantation period (3-6 months after transplantation).

Food intake does not affect the extent of MMF absorption (MPA AUC) when administered at a dose of 1.5 g twice daily in kidney transplant patients. However, the C_max of MPA is reduced by 40% when mycophenolate mofetil is taken with food.

Typically, a secondary increase in MPA plasma concentration is observed about 6-12 hours after mycophenolate mofetil intake, indicating enterohepatic recirculation of MMF. With concurrent use of cholestyramine, the MPA AUC decreases by approximately 40%, indicating interruption of enterohepatic recirculation.

At clinically significant concentrations, MPA is 97% bound to plasma albumin.

MPA is metabolized primarily by glucuronyltransferase (UGT1A9 isoform) to form the pharmacologically inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG can be converted back to free MPA during enterohepatic recirculation, and an acyl glucuronide is also formed, which is pharmacologically active and may be responsible for some of MPA’s side effects (diarrhea, leukopenia).

After oral administration of radiolabeled MMF, 93% of the administered dose is excreted in the urine and 6% in the feces. The majority (about 87%) of the administered dose is excreted in the urine as MPAG. Minor amounts of MMF (<1% of the dose) are excreted in the urine as MPA.

Clinically significant concentrations of MPA and MPAG are not removed by hemodialysis. However, at higher MPAG concentrations (>100 µg/ml), some removal may occur. Bile acid sequestrants like cholestyramine reduce MPA AUC by interrupting enterohepatic recirculation.

The distribution of MPA involves several transporters: the organic anion transporter polypeptide (OATP) and the multidrug resistance-associated protein 2 (MRP2). OATP isoforms, MRP2, and the breast cancer resistance protein (BCRP) are transporters associated with the biliary excretion of the glucuronide. The multidrug resistance protein 1 (MDR1) may also be involved in MPA transport, but its role is limited to the absorption process. MPA and its metabolites may potentially interact with organic anion transporters in the kidneys.

Indications

Mycophenolate mofetil is used as part of combination therapy with cyclosporine and corticosteroids.

Adults and children with a body surface area >1.5 m² (approximately children over 14 years of age): prophylaxis of acute transplant rejection in patients after allogeneic kidney transplantation.

Adults: prophylaxis of acute transplant rejection in patients after allogeneic heart transplantation; prophylaxis of acute transplant rejection in patients after allogeneic liver transplantation.

ICD codes

Dosage Regimen

Administer orally as part of combination immunosuppressive therapy with cyclosporine and corticosteroids.

For adult kidney transplant recipients, the recommended dose is 1 g twice daily (two 500 mg tablets taken twice per day).

For adult heart transplant recipients, the recommended dose is 1.5 g twice daily (three 500 mg tablets taken twice per day).

For adult liver transplant recipients, the recommended dose is 1.5 g twice daily (three 500 mg tablets taken twice per day).

Initiate therapy within 24 hours following transplantation. The total daily dose should not exceed 3 g.

For pediatric patients (children with a body surface area greater than 1.5 m², approximately over 14 years of age) after kidney transplantation, the recommended dose is 600 mg/m² twice daily. The maximum daily dose is 2 g.

Take tablets on an empty stomach, at least 1 hour before or 2 hours after food intake, to ensure optimal absorption.

Do not crush or chew the tablets; swallow them whole with a glass of water.

In patients with severe chronic renal impairment (GFR less than 25 mL/min/1.73 m²) outside the immediate post-transplant period, avoid doses exceeding 1 g twice daily.

No dose adjustment is required for patients with delayed graft function, but close monitoring is essential.

If neutropenia develops (absolute neutrophil count less than 1.3×10³/µL), interrupt therapy or reduce the dosage. Perform regular monitoring of complete blood counts.

When switching from cyclosporine to other immunosuppressants (e.g., tacrolimus), monitor for potential changes in MPA exposure and adjust the dose if necessary.

Adverse Reactions

Hypersensitivity reactions: angioedema, anaphylactic reactions.

Infections and infestations: very common – sepsis, gastrointestinal candidiasis, urinary tract infections, herpes simplex, herpes zoster; common – pneumonia, influenza, respiratory tract infections, respiratory moniliasis, gastrointestinal infections, candidiasis, gastroenteritis, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candidiasis, vaginal candidiasis, rhinitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps) common – skin cancer, benign skin neoplasm.

Blood and lymphatic system disorders very common – leukopenia, thrombocytopenia, anemia; common – pancytopenia, leukocytosis.

Metabolism and nutrition disorders common – acidosis, hyperkalemia, hypokalemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypercholesterolemia, hyperlipidemia, hypophosphatemia, hyperuricemia, gout, anorexia.

Psychiatric disorders common – agitation, confusion, depression, anxiety, thinking abnormal, insomnia.

Nervous system disorders common – convulsions, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paresthesia, dysgeusia.

Cardiac disorders common – tachycardia, hypotension, hypertension, vasodilation.

Respiratory, thoracic and mediastinal disorders common – pleural effusion, dyspnea, cough.

Gastrointestinal disorders very common – vomiting, abdominal pain, diarrhea, nausea; common – gastrointestinal hemorrhage, peritonitis, intestinal obstruction, colitis, gastric ulcer, duodenal ulcer, gastritis, esophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation.

Hepatobiliary disorders common – hepatitis, jaundice, hyperbilirubinemia.

Skin and subcutaneous tissue disorders common – skin hypertrophy, rash, acne, alopecia.

Investigations: common – increased hepatic enzyme levels, increased blood creatinine, increased blood LDH, increased blood urea, increased blood alkaline phosphatase.

General disorders and administration site conditions arthralgia, renal failure, edema, pyrexia, chills, pain, malaise, asthenia, weight decreased.

Contraindications

Hypersensitivity to mycophenolate mofetil. Deficiency of hypoxanthine-guanine phosphoribosyltransferase (a rare genetic disorder caused by hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase – Lesch-Nyhan and Kelley-Seegmiller syndromes). Concurrent use with azathioprine. Children with a body surface area <1.5 m² (approximately children under 14 years of age). Pregnancy, breastfeeding period. Women of childbearing potential not using highly effective methods of contraception. Women of childbearing potential without a prior pregnancy test to rule out unintentional use of mycophenolate mofetil during pregnancy.

With caution: active gastrointestinal disease. Switching from combination therapy including immunosuppressants that affect the enterohepatic recirculation of MPA, such as cyclosporine, to therapy with drugs lacking this effect, such as tacrolimus, sirolimus, and belatacept, and vice versa. Concurrent use of drugs that affect the enterohepatic cycle of MPA, such as cholestyramine, sevelamer, antibiotics, and glucuronidation, such as isavuconazole.

Use in Pregnancy and Lactation

Contraindicated during pregnancy (due to the mutagenic and teratogenic potential of mycophenolate mofetil). The use of mycophenolate mofetil is contraindicated during breastfeeding due to the possibility of serious adverse reactions in breastfed infants.

The use of mycophenolate mofetil is contraindicated in women of childbearing potential not using highly effective methods of contraception. Before starting therapy, female patients with reproductive potential must be informed about the increased risk of fetal loss and congenital malformations; counseling on pregnancy prevention and planning should be provided.

Use in Renal Impairment

In patients who have undergone kidney transplantation with severe chronic renal impairment (glomerular filtration rate less than 25 ml/min/1.73 m²) outside the immediate post-transplantation period, doses higher than 1 g twice daily should be avoided.

Dose adjustment is not recommended for patients with delayed renal graft function, but such patients require careful medical supervision.

Pediatric Use

Contraindicated in children with a body surface area <1.5 m² (approximately children under 14 years of age). In children with a body surface area >1.5 m², Mycophenolate mofetil is used for the prophylaxis of acute transplant rejection after allogeneic kidney transplantation.

Geriatric Use

In elderly patients (≥65 years), the risk of adverse events, such as certain infections (including tissue-invasive forms of manifest cytomegalovirus infection), gastrointestinal bleeding, and pulmonary edema, may be increased compared to younger patients.

Special Precautions

Patients taking Mycophenolate mofetil have an increased risk of developing lymphomas and other malignancies, particularly skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using sunscreen with a high protection factor.

During treatment with mycophenolate mofetil, there is an increased risk of opportunistic infections (bacterial, fungal, viral, and protozoal), fatal infections, and sepsis. Such cases include reactivation of latent viral infections, such as hepatitis B or C, or infections caused by polyomaviruses (BK virus-associated nephropathy, JC virus-associated PML). Cases of hepatitis due to reactivation of hepatitis B or C viruses have been reported in carriers of hepatitis B or C viruses receiving immunosuppressive therapy. These infections are often associated with a high overall immunosuppressive burden and can lead to serious complications or be fatal, which should be considered in the differential diagnosis of immunocompromised patients with deteriorating renal function or neurological symptoms.

Cases of hypogammaglobulinemia have been observed in patients receiving mycophenolate mofetil in combination with other immunosuppressants, in the context of recurrent infections. In some of these cases, switching from mycophenolate mofetil to an alternative immunosuppressant led to normalization of serum IgG levels.

In patients with recurrent infections receiving Mycophenolate mofetil, serum immunoglobulin levels should be measured. In cases of persistent, clinically significant hypogammaglobulinemia, appropriate clinical measures should be taken, considering the possible cytostatic effects that MPA has on T and B lymphocytes.

There are reports of bronchiectasis developing in adults and children who received Mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching from mycophenolate mofetil to another immunosuppressant led to a reduction in respiratory symptoms. The risk of developing bronchiectasis may be associated with hypogammaglobulinemia or a direct effect on the lungs. There are isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. Patients with persistent pulmonary symptoms such as cough and dyspnea should be evaluated.

Cases of pure red cell aplasia (PRCA) have been observed in patients taking Mycophenolate mofetil in combination with other immunosuppressive drugs. The mechanism of PRCA development with mycophenolate mofetil use is unknown, as is the contribution of other immunosuppressants and their combination. In some cases, PRCA was reversible after reducing the dose of mycophenolate mofetil or discontinuing it. However, in transplant patients, reducing immunosuppression may compromise the graft.

Patients receiving MMF should be informed of the need to immediately report any signs of infection, unexpected bruising, bleeding, or other signs of bone marrow suppression to their doctor.

During treatment with MMF, a complete blood count should be determined weekly for the first month, twice a month during the second and third months of treatment, and then monthly during the first year. Particular attention should be paid to the possible development of neutropenia. Neutropenia may be associated with MMF intake, other medications, viral infections, or a combination of these causes. If neutropenia occurs (absolute neutrophil count <1.3×10³/µl), MMF treatment should be interrupted or the dose reduced, with careful monitoring of these patients.

Patients receiving Mycophenolate mofetil should not donate blood during treatment and for at least 6 weeks after the last dose.

During MMF treatment, vaccination may be less effective; the use of live attenuated vaccines should be avoided. Influenza vaccination can be administered according to national guidelines.

MMF administration may be accompanied by gastrointestinal side effects (gastrointestinal mucosal ulceration, gastrointestinal bleeding, gastrointestinal perforations). Caution should be exercised when using MMF in patients with active digestive tract diseases.

MMF is an inhibitor of IMPDH; it should not be used in patients with a rare genetically determined hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (Lesch-Nyhan and Kelley-Seegmiller syndromes).

Mycophenolate is a potent human teratogen. Cases of spontaneous abortions (with a frequency of 45% to 49%) and congenital malformations (estimated frequency of 23% to 27%) have been reported with MMF use during pregnancy.

The treating physician should ensure that a woman taking mycophenolate understands the risk of harm to the child, the need for effective contraception, and the need for immediate consultation with the treating physician if pregnancy is likely.

Women of childbearing potential should use at least one reliable method of contraception before starting, during treatment, and for 6 weeks after discontinuation of mycophenolate mofetil therapy, if abstinence is not possible. It is preferable to use two complementary methods of contraception simultaneously to minimize the possibility of contraceptive failure and unplanned pregnancy.

Sperm donation is not permitted during treatment and for 90 days after the last dose of mycophenolate mofetil.

Effect on ability to drive and use machines

During treatment, patients should avoid driving vehicles and engaging in other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

When MMF and acyclovir were used concomitantly, higher plasma concentrations of acyclovir were observed compared to acyclovir alone. Changes in the pharmacokinetic parameters (namely, an 8% increase in MPAG concentration) of MPAG (the phenolic glucuronide of MPA) were minimal and not considered clinically significant. Since plasma concentrations of both MPAG and acyclovir increase in renal failure, it is possible that MMF and acyclovir (or its prodrugs, e.g., valacyclovir) compete for tubular secretion, which could lead to a further increase in the concentration of both drugs.

When mycophenolate mofetil was co-administered with antacids (aluminum and magnesium hydroxide) and proton pump inhibitors (lansoprazole and pantoprazole), a decrease in MPA concentration was observed. However, there was no significant difference in the rates of transplant rejection between patients taking Mycophenolate mofetil concomitantly with proton pump inhibitors and those without. This conclusion theoretically extends to all antacids, since the administration of magnesium and aluminum hydroxide simultaneously with mycophenolate mofetil reduces MPA concentration to a much lesser extent than the concomitant administration of mycophenolate mofetil with proton pump inhibitors.

Caution should be exercised when using medicinal products that affect enterohepatic circulation (e.g., cholestyramine, cyclosporine, antibiotics) due to their potential to reduce the efficacy of mycophenolate mofetil.

Caution is advised with the concomitant use of cholestyramine due to the possibility of reduced efficacy of mycophenolate mofetil.

MMF does not affect the pharmacokinetics of cyclosporine. However, upon discontinuation of concomitant cyclosporine use, an increase in the MPA AUC of approximately 30% should be expected. Cyclosporine affects the enterohepatic recirculation of MPA, which may lead to a reduction in MPA exposure of approximately 30-50% in kidney transplant patients receiving Mycophenolate mofetil and cyclosporine. In contrast, when switching patients from cyclosporine therapy to immunosuppressants that do not affect the enterohepatic recirculation of MPA, a change in MPA exposure should be expected.

Antibiotics that lead to the elimination of bacteria producing β-glucuronidase in the intestine (e.g., antibiotics from the aminoglycoside, cephalosporin, fluoroquinolone, and penicillin groups) may disrupt the enterohepatic recirculation of MPAG/MPA, which, in turn, may lead to reduced systemic exposure to MPA.

When used concomitantly with drugs that inhibit the glucuronidation of MPA (isavuconazole and telmisartan), its exposure may increase.

In patients who were not taking cyclosporine, the concomitant administration of mycophenolate mofetil and rifampicin led to a reduction in MPA exposure of 18-70% (AUC_0-12). Monitoring of MPA exposure and dose adjustment of mycophenolate mofetil is recommended to maintain the clinical effect during concomitant use.

Concomitant administration of sevelamer and MMF in adults and children reduced the MPA C_max and AUC_0-12 by 30% and 25%, respectively, without any clinical consequences (e.g., graft rejection). Nevertheless, it is recommended to administer Mycophenolate mofetil at least 1 hour before or 3 hours after sevelamer intake to minimize the impact on MPA absorption. Data regarding the use of mycophenolate mofetil concomitantly with phosphate-binding agents other than sevelamer are not available.

In liver transplant patients initiating therapy with mycophenolate mofetil and tacrolimus, no significant effect on the AUC and C_max of MPA (the active metabolite of mycophenolate mofetil) was observed. In contrast, in liver transplant patients after multiple administrations of mycophenolate mofetil at a dose of 1.5 g twice daily, the tacrolimus AUC increased by approximately 20%. In kidney transplant patients, the use of mycophenolate mofetil did not appear to affect tacrolimus concentrations.

Live attenuated vaccines should not be administered to patients in an immunosuppressed state. Antibody formation in response to other vaccines may be reduced.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.