Mifenax
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIFENAX® (MYFENAX®)
Composition:
Active substance: mycophenolate mofetil;
1 capsule contains 250 mg of mycophenolate mofetil;
Excipients: pregelatinized starch, povidone, sodium croscarmellose, magnesium stearate;
Capsule shell: gelatin, indigocarmine (E 132), titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172).
Pharmaceutical form. Hard capsules.
Main physicochemical characteristics: hard gelatin capsules size №1, filled with white or almost white powder;
cap: opaque, blue, with a longitudinal inscription "М" printed in black ink;
body: opaque, brown, with a longitudinal inscription "250" printed in black ink.
Pharmacotherapeutic group.
Selective immunosuppressive agents. Mycophenolic acid. ATC code L04A A06.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action
Mycophenolate mofetil 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 de novo synthesis of guanosine nucleotides without incorporation into DNA. MPA exerts a more pronounced cytostatic effect on lymphocytes than on other cells, since proliferation of T- and B-lymphocytes is highly dependent on de novo purine synthesis, whereas other cell types can utilize salvage pathways of metabolism.
Pharmacokinetics.
Absorption
After oral administration, mycophenolate mofetil is rapidly and completely absorbed and undergoes complete presystemic metabolism to form the active metabolite MPA. Immunosuppressive effects of mycophenolate, as confirmed by suppression of acute rejection following kidney transplantation, correlate with MPA concentrations.
The mean oral bioavailability of mycophenolate mofetil, based on AUCMPA (area under the plasma concentration-time curve), is 94% relative to intravenous administration of mycophenolate mofetil. Food intake does not affect the extent of absorption (AUCMPA) of mycophenolate mofetil when administered at a dose of 1.5 g twice daily to kidney transplant patients. However, Cmax of MPA is reduced by 40% when the drug is taken with food. After oral administration, plasma concentrations of mycophenolate mofetil are not detectable systemically.
Distribution
Due to enterohepatic recirculation, a secondary peak in MPA plasma concentration is typically observed 6–12 hours after drug administration. When co-administered with cholestyramine (4 g three times daily), AUCMPA is reduced by approximately 40%, indicating significant enterohepatic recirculation.
MPA is approximately 97% bound to plasma albumin at clinically relevant concentrations.
Metabolism
MPA is primarily metabolized by glucuronosyltransferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA during enterohepatic recirculation. A minor acyl glucuronide metabolite (AcMPAG) is also formed, which is pharmacologically active and may contribute to some adverse effects of mycophenolate mofetil (e.g., diarrhea, leukopenia).
Excretion
Minimal amounts of the drug (<1% of dose) are excreted in urine as MPA. After oral administration of radiolabeled mycophenolate mofetil, the administered dose is completely eliminated; 93% of the dose is excreted in urine and 6% in feces. The majority (approximately 87%) of the administered dose is excreted in urine as MPAG.
At clinically observed concentrations, MPA and MPAG are not removed by hemodialysis. However, at higher concentrations of MPAG (>100 mcg/mL), a small amount may be removed. Bile acid sequestrants such as cholestyramine, by interrupting the enterohepatic recirculation of Myfenax®, reduce AUCMPA (see section "Overdose").
Pharmacokinetics (all phases except absorption) of mycophenolic acid depends on several transporters. Organic anion transporting polypeptide and multidrug resistance-associated protein 2 are involved in the pharmacokinetics (all phases except absorption) of mycophenolic acid; isoforms of organic anion transporting polypeptide, multidrug resistance-associated protein 2, and breast cancer resistance protein are transporters associated with biliary excretion of glucuronides. Multidrug resistance protein 1 may also transport mycophenolic acid, but its contribution appears limited to the absorption process. In the kidneys, mycophenolic acid and its metabolites strongly interact with renal organic anion transporters.
In the early post-transplant period (<40 days after transplantation), kidney, heart, and liver transplant patients have mean AUCMPA approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3–6 months after transplantation).
Special patient groups
Patients with renal impairment
In a single-dose study, mean AUCMPA in plasma was 28–75% higher in patients with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m²) compared to healthy volunteers and patients with milder renal dysfunction. However, after a single dose, mean AUC of phenolic glucuronide of mycophenolic acid was 3–6 times higher in patients with severe renal impairment than in patients with mild renal impairment and healthy volunteers, consistent with known renal excretion of the phenolic glucuronide of mycophenolic acid. Multiple-dose studies of mycophenolate mofetil in patients with severe renal impairment have not been conducted. There are no data in patients with severe chronic renal impairment following heart or liver transplantation.
Delayed graft function
In patients with delayed renal graft function after transplantation, the mean AUC0–12 for mycophenolic acid was comparable to that in patients whose graft functioned immediately after transplantation. The mean AUC0–12 for phenolic glucuronide of mycophenolic acid in plasma was 2–3 times higher than in patients whose graft functioned immediately. A transient increase in free fraction and plasma concentration of mycophenolic acid may occur in patients with delayed graft function. Dose adjustment of Myfenax® is not required in such cases.
Patients with hepatic impairment
In volunteers with alcoholic cirrhosis, parenchymal liver disease was found to have relatively little effect on glucuronidation of mycophenolic acid. The impact of liver disease on this process depends on the specific condition. However, in diseases affecting primarily the biliary tract (e.g., primary biliary cirrhosis), the effect may differ.
Children
Pharmacokinetic parameters were studied in children after kidney transplantation (aged 2 to 18 years) receiving mycophenolate mofetil at a dose of 600 mg/m² orally twice daily. At this dose, AUCMPA was similar to that in adult kidney transplant patients receiving Myfenax® 1 g twice daily in both early and late post-transplant periods. AUCMPA values were comparable across different age groups in both early and late post-transplant periods.
Elderly patients
No significant changes in the pharmacokinetics of mycophenolate mofetil and its metabolites have been observed in elderly patients (≥65 years) compared to younger patients after transplantation.
Patients taking oral contraceptives
Mycophenolate mofetil does not affect the pharmacokinetics of oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").
In a study involving 18 post-transplant women not receiving other immunosuppressants, co-administration of Myfenax® (1 g twice daily) with combined oral contraceptives containing ethinylestradiol (0.02–0.04 mg) and levonorgestrel (0.05–0.15 mg), desogestrel (0.15 mg), or gestodene (0.05–0.1 mg) did not show any clinically significant effect on the ovulation-suppressing effect of oral contraceptives. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone did not change significantly.
Clinical characteristics.
Indications.
Myfenax® is indicated in combination with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients receiving allogeneic kidney, heart, or liver transplantation.
Contraindications.
Hypersensitivity reactions to mycophenolate mofetil, mycophenolic acid, or any of the excipients. Hypersensitivity reactions have been observed during treatment with Myfenax® (see section "Adverse Reactions").
Myfenax® must not be administered to women of childbearing potential who are not using effective contraception (see section "Use in pregnancy or lactation").
Treatment with Myfenax® should not be initiated in women of childbearing potential who have not undergone a pregnancy test to avoid accidental exposure during pregnancy (see section "Use in pregnancy or lactation").
Myfenax® must not be used during pregnancy, except when no alternative therapy is available to prevent graft rejection (see section "Use in pregnancy or lactation").
Myfenax® must not be used during lactation (see section "Use in pregnancy or lactation").
Special precautions.
Since mycophenolate mofetil has demonstrated teratogenic effects, the capsules must not be opened or crushed. Inhalation of the powder contained in the capsules or direct contact with skin or mucous membranes must be avoided. If such contact occurs, the affected area should be thoroughly washed with soap and water, and eyes should be rinsed with water only.
Unused medication should be disposed of according to local requirements.
Interaction with other medicinal products and other forms of interaction.
Acyclovir. Plasma concentrations of acyclovir are higher when administered concomitantly with mycophenolate mofetil compared to acyclovir alone. Changes in the pharmacokinetics of the phenolic glucuronide of mycophenolic acid (increase by 8% for MPAG) were minimal and not considered clinically significant. Since plasma concentrations of MPAG as well as acyclovir increase in the presence of renal impairment, there is a potential for mycophenolate mofetil and acyclovir or its prodrugs (e.g., valacyclovir) to compete for tubular secretion, possibly leading to further increases in concentrations of both substances.
Antacids and proton pump inhibitors (PPIs). A reduction in the exposure of mycophenolic acid (MPA) has been observed when antacids such as magnesium and aluminum hydroxides, and PPIs including lansoprazole and pantoprazole, are administered concomitantly with mycophenolate mofetil. No significant differences in graft rejection rate or graft loss rate were observed between patients receiving PPIs concomitantly with mycophenolate mofetil and those not receiving PPIs. These data support extrapolation of these findings to all antacids, as the reduction in exposure with concomitant use of mycophenolate mofetil and magnesium and aluminum hydroxides is considerably less than with concomitant use of mycophenolate mofetil and PPIs.
Medicinal products affecting enterohepatic recirculation (e.g., cholestyramine, cyclosporine A, antibiotics). Caution is advised with medicinal products that interfere with enterohepatic recirculation due to their potential to reduce the efficacy of mycophenolate mofetil.
Cholestyramine. After administration of a single 1.5 g dose of mycophenolate mofetil to healthy volunteers who had previously received 4 g cholestyramine three times daily for 4 days, a 40% reduction in AUC of MPA was observed (see sections "Special precautions for use", "Pharmacokinetics"). Concomitant use of mycophenolate mofetil and cholestyramine should be approached with caution due to the potential for reduced efficacy of mycophenolate mofetil.
Cyclosporine A. The pharmacokinetics of cyclosporine A are not altered by administration of mycophenolate mofetil. Conversely, upon discontinuation of concomitant cyclosporine therapy, an approximately 30% increase in AUC of MPA can be expected. Cyclosporine A affects the enterohepatic recirculation of MPA, resulting in a 30–50% reduction in MPA exposure in kidney transplant patients receiving mycophenolate mofetil and cyclosporine A compared to patients receiving sirolimus or belatacept with similar doses of mycophenolate mofetil (see also section "Special precautions for use"). Conversely, changes in MPA exposure should be anticipated when switching patients from cyclosporine A to an immunosuppressant that does not affect the enterohepatic cycle of MPA.
Antibiotics that reduce the number of β-glucuronidase-producing bacteria in the gut (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may affect the enterohepatic recirculation of MPAG/MPA, potentially leading to reduced systemic exposure to MPA. Available information on the following antibiotics is provided.
Ciprofloxacin and amoxicillin with clavulanic acid. A reduction in the pre-dose (trough) concentration of MPA by approximately 50% has been reported during several days following oral administration of ciprofloxacin or amoxicillin with clavulanic acid in kidney transplant patients. With continued antibiotic therapy, this effect tended to diminish and disappeared after discontinuation of antibiotic treatment. Changes in trough levels may not accurately reflect changes in total MPA exposure. Therefore, dosage adjustment of mycophenolate mofetil is usually not necessary in the absence of clinical signs of graft dysfunction. However, careful clinical monitoring is recommended during and shortly after concomitant antibiotic therapy.
Norfloxacin and metronidazole. No significant interaction was observed in healthy volunteers when mycophenolate mofetil was administered concomitantly with norfloxacin or metronidazole separately. However, the combination of norfloxacin and metronidazole may reduce MPA exposure by approximately 30% after a single dose of mycophenolate mofetil.
Trimethoprim/sulfamethoxazole. No effect on MPA bioavailability was observed.
Medicinal products affecting glucuronidation (e.g., isavuconazole, telmisartan).
Concomitant use of medicinal products affecting glucuronidation of MPA may alter MPA exposure. Therefore, caution is recommended when using these medicinal products concomitantly with mycophenolate mofetil.
Isavuconazole. An increase in AUC0–∞ of MPA by 35% was observed during concomitant administration with isavuconazole.
Telmisartan. Concomitant administration of telmisartan and mycophenolate mofetil results in a reduction of MPA concentration by approximately 30%. Telmisartan affects MPA elimination by increasing the expression of gamma receptors that activate peroxisome proliferation, thereby enhancing the expression and activity of UGT1A9. When comparing graft rejection rate, graft loss rate, or adverse reaction profile among patients receiving mycophenolate mofetil with or without concomitant telmisartan, no clinical consequences of the pharmacokinetic interaction were observed.
Ganciclovir. Based on a study of single oral doses of recommended amounts of mycophenolate mofetil and intravenous administration of ganciclovir, and considering the known impact of renal impairment on the pharmacokinetics of mycophenolate mofetil and ganciclovir, concomitant use of these agents (which compete for tubular secretion) may lead to increased concentrations of MPAG and ganciclovir. No significant change in the pharmacokinetics of MPA is expected; therefore, dosage adjustment of mycophenolate mofetil is not required. In patients with renal impairment receiving concomitant mycophenolate mofetil and ganciclovir or its prodrugs (e.g., valganciclovir), the recommended dosing regimen for ganciclovir should be followed, and patients should be closely monitored.
Oral contraceptives. Concomitant administration of mycophenolate mofetil does not affect the pharmacokinetics or pharmacodynamics of oral contraceptives (see section "Pharmacokinetics").
Rifampicin. In patients not receiving cyclosporine, concomitant use of mycophenolate mofetil and rifampicin results in a reduction of MPA exposure (AUC0–12 hours) from 18% to 70%. Monitoring of MPA exposure levels and appropriate dose adjustment of mycophenolate mofetil are recommended to maintain clinical efficacy when rifampicin is co-administered.
Sevelamer. A reduction in Cmax and AUC0–12 hours of mycophenolic acid by 30% and 25%, respectively, was observed when mycophenolate mofetil was administered concomitantly with sevelamer, without any clinical consequences (i.e., no graft rejection). It is recommended to administer mycophenolate mofetil at least 1 hour before or 3 hours after sevelamer to minimize the impact on MPA absorption. Data on interaction between mycophenolate mofetil and other phosphate-binding agents other than sevelamer are lacking.
Tacrolimus. In liver transplant patients, no significant effect on AUC and Cmax of mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed with concomitant use of tacrolimus and mycophenolate mofetil. However, an increase in AUC of tacrolimus by approximately 20% has been reported in liver transplant patients after multiple doses of mycophenolate mofetil (1.5 g twice daily, morning and evening) administered to patients receiving tacrolimus. In kidney transplant patients, however, tacrolimus concentrations were not altered by mycophenolate mofetil (see section "Special precautions for use").
Live vaccines. Live vaccines must not be administered to patients with impaired immune response. Antibody response to other vaccines may be reduced (see section "Special precautions for use").
Children. Information on interactions is available only in adults.
Potential interactions. Concomitant administration of probenecid and mycophenolate mofetil in monkeys was associated with a threefold increase in AUC of MPAG in plasma. Therefore, other medicinal products undergoing tubular secretion in the kidneys may compete with MPAG, leading to increased plasma concentrations of MPAG or of the other drug undergoing tubular secretion.
Special precautions for use.
Neoplasms
Patients receiving immunosuppressive regimens consisting of combinations of medicinal products, including mycophenolate mofetil, have an increased risk of developing lymphomas and other malignancies, particularly of the skin (see section "Adverse reactions"). The risk is likely related more to the intensity and duration of immunosuppression than to the use of any specific medicinal product. A general recommendation to minimize the risk of skin cancer is to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using sun-protective agents with a high sun protection factor.
Infections
Excessive suppression of the immune system increases susceptibility to infections, including opportunistic infections (bacterial, fungal, viral, and protozoal), fatal infections, and sepsis. Such opportunistic infections include reactivation of latent viral infections, such as hepatitis B reactivation or hepatitis C reactivation, and infections caused by polyomaviruses (BK virus-associated nephropathy and progressive multifocal leukoencephalopathy associated with JC virus). Cases of hepatitis due to reactivation of hepatitis B or C viruses have been reported in carrier patients receiving immunosuppressants. These infections are often associated with high cumulative immunosuppression and may lead to serious, including fatal, outcomes. These conditions should be considered in the differential diagnosis of immunosuppressed patients with renal dysfunction or neurological symptoms. Mycophenolic acid exerts a cytostatic effect on B- and T-lymphocytes; therefore, increased severity of COVID-19 may occur, and appropriate clinical measures should be considered. Hypogammaglobulinemia with recurrent infections has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some cases, switching from mycophenolate mofetil to an alternative immunosuppressant led to normalization of plasma IgG levels. Patients with recurrent infections receiving mycophenolate mofetil should have plasma immunoglobulin levels monitored. In cases of persistent, clinically significant hypogammaglobulinemia, appropriate therapeutic interventions should be considered, taking into account the potent cytostatic effects of mycophenolic acid on T- and B-lymphocytes.
Bronchiectasis has been reported in adults and children receiving mycophenolate mofetil concomitantly with other immunosuppressants. In some cases, switching from mycophenolate mofetil therapy to another immunosuppressant resulted in improvement of respiratory symptoms. The risk of bronchiectasis may be associated with hypogammaglobulinemia or a direct effect on the lungs. Isolated cases of interstitial lung disease and pulmonary fibrosis, some of which were fatal, have also been reported (see section "Adverse reactions"). Patients with persistent pulmonary symptoms such as cough and dyspnea should be evaluated.
Blood and immune system
Patients receiving mycophenolate mofetil require monitoring for neutropenia, which may be related to treatment with MifenaX® itself, concomitant use of other medicinal products, viral infections, or a combination of these factors. Patients taking mycophenolate mofetil should undergo complete blood counts once weekly during the first month, twice monthly during the second and third months of treatment, and then once monthly during the first year. In the event of neutropenia (absolute neutrophil count <1.3×10³/µL), interruption or discontinuation of MifenaX® may be appropriate.
Cases of pure red cell aplasia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism of pure red cell aplasia with mycophenolate mofetil is unknown. Pure red cell aplasia may be reversible with dose reduction or discontinuation of mycophenolate mofetil. Changes to mycophenolate mofetil therapy should only be made under appropriate monitoring to minimize the risk of transplant rejection (see section "Adverse reactions").
Patients taking mycophenolate mofetil should immediately report any infections, sudden onset of bruising, bleeding, or any other signs of bone marrow insufficiency.
Patients should be informed that vaccinations may be less effective during treatment with this medicinal product, and live attenuated vaccines should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). However, influenza vaccination may be administered. Physicians should follow national guidelines regarding influenza vaccination.
Gastrointestinal system
The use of mycophenolate mofetil is associated with an increased frequency of adverse events involving the gastrointestinal tract, including rare cases of ulceration, bleeding, and gastrointestinal perforation. Mycophenolate mofetil should be administered with caution in patients with severe gastrointestinal disorders in the active phase.
Mycophenolate mofetil is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). Therefore, its use should be avoided in patients with rare inherited deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), such as Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome.
Interactions
Caution should be exercised when changing combined immunosuppressive regimens that affect enterohepatic recirculation of MPA, such as switching from cyclosporine to other agents lacking this effect (e.g., tacrolimus, sirolimus, belatacept), or vice versa, as this may alter MPA exposure. Medicinal products that affect enterohepatic recirculation of MPA (e.g., cholestyramine, antibiotics) should be used with caution due to their potential to reduce plasma levels of mycophenolate mofetil and thus its efficacy (see also section "Interaction with other medicinal products and other forms of interaction"). Therapeutic monitoring of MPA may be advisable when changing combination therapy (e.g., from cyclosporine to tacrolimus or vice versa) or to ensure appropriate immunosuppression in patients at high immunological risk (e.g., rejection risk, treatment with antibiotics, addition or removal of interacting drugs).
Concomitant administration of mycophenolate mofetil with azathioprine is not recommended, as their combined use has not been studied.
The risk-benefit ratio of using mycophenolate mofetil in combination with sirolimus has not been established (see section "Interaction with other medicinal products and other forms of interaction").
Special populations
Elderly patients may have an increased risk of adverse reactions such as infections (including invasive tissue cytomegalovirus disease), gastrointestinal bleeding, and pulmonary edema (see section "Adverse reactions").
Teratogenic effect
Mycophenolate mofetil is a potent teratogen. Following use of mycophenolate mofetil during pregnancy, spontaneous abortions (with a frequency of 45–49%) and congenital malformations (with a frequency of 23–27%) have been reported. Therefore, mycophenolate mofetil is contraindicated during pregnancy except when alternative treatment for transplant rejection is unavailable.
Women and men of reproductive potential must be informed of the potential risks and should follow the recommendations outlined in the section "Use during pregnancy or breastfeeding" (including using effective contraception methods and undergoing pregnancy testing) before, during, and after treatment. The physician must ensure that women and men taking mycophenolate mofetil understand the risk of fetal harm and the necessity of using effective contraception and seeking immediate medical consultation in case of possible pregnancy.
Contraception (see section "Use during pregnancy or breastfeeding")
Due to reliable clinical evidence indicating a high risk of miscarriage and congenital malformations with use of mycophenolate mofetil during pregnancy, all measures should be taken to avoid pregnancy during treatment. Therefore, women of reproductive potential should use at least one reliable method of contraception before starting treatment, during treatment, and for 6 weeks after discontinuation of therapy, or choose abstinence from sexual intercourse as a contraceptive method (see section "Interaction with other medicinal products and other forms of interaction"). Simultaneous use of two complementary contraceptive methods is preferred to minimize the risk of contraceptive failure and unintended pregnancy.
Additional warnings
Patients must not donate blood during treatment and for at least 6 weeks after its discontinuation. Men must not donate sperm during treatment and for 90 days after its discontinuation.
Excipients: This medicinal product contains less than 1 mmol (23 mg) of sodium per capsule, i.e., essentially sodium-free.
Disposal of unused medicinal product and waste material: Environmental contamination by the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or as household waste. Disposal should be carried out via a designated waste collection system, if available.
Use during pregnancy or breastfeeding.
Women of reproductive potential
Pregnancy should be avoided during treatment with mycophenolate mofetil. Therefore, women of reproductive potential must use at least one reliable method of contraception (see section "Contraindications") before starting mycophenolate mofetil therapy, during therapy, and for 6 weeks after discontinuation of therapy, unless abstinence from sexual intercourse is the chosen contraceptive method. Simultaneous use of two complementary contraceptive methods is preferred.
Pregnancy
Mycophenolate mofetil is contraindicated during pregnancy except when alternative treatment for transplant rejection is unavailable. Therapy with this medicinal product should not be initiated until a negative pregnancy test result is obtained to prevent accidental exposure.
Women of reproductive potential must be informed of the increased risk of miscarriage and congenital malformations at the start of treatment and must be warned about pregnancy prevention and planning.
Before initiating treatment, women of reproductive potential should have two negative pregnancy tests (urine or blood plasma) with a sensitivity of at least 25 mIU/mL to exclude unintended embryonic exposure to mycophenolate. The second test should be performed 8–10 days after the first. For transplants from deceased donors, if it is not possible to perform two tests 8–10 days apart before treatment initiation (due to organ availability timelines), a pregnancy test should be performed immediately before starting treatment, and the next test 8–10 days later. Pregnancy testing should be repeated as necessary (e.g., after a contraceptive interruption). The results of pregnancy tests should be discussed with the patient. Patients must be informed of the need for immediate medical consultation if pregnancy occurs.
Mycophenolate mofetil is a potent teratogen. Following use of mycophenolate mofetil during pregnancy, spontaneous abortions and congenital malformations have been reported:
– Spontaneous abortions occurred in 45–49% of pregnant women receiving mycophenolate mofetil, compared to a reported frequency of 12–33% in patients after solid organ transplantation receiving other immunosuppressants besides mycophenolate mofetil;
– According to scientific literature, congenital malformations were observed in 23–27% of live-born children whose mothers received mycophenolate mofetil during pregnancy (compared to 2–3% of live-born children in the general population and approximately 4–5% of live-born children whose mothers received other immunosuppressants besides mycophenolate mofetil after solid organ transplantation).
Congenital malformations, including reports of multiple malformations, have been observed in the post-marketing period in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. The most frequently reported congenital malformations include:
– Ear abnormalities (e.g., abnormally formed or absent external/middle ear), atresia of the external auditory canal;
– Congenital heart defects, e.g., atrial and ventricular septal defects;
– Facial malformations, e.g., cleft lip, cleft palate, micrognathia, and orbital hypertelorism;
– Eye abnormalities (e.g., coloboma);
– Congenital hand and foot defects (e.g., polydactyly, syndactyly);
– Tracheoesophageal malformations (e.g., esophageal atresia);
– Congenital nervous system defects, such as failure of vertebral arch fusion;
– Kidney abnormalities.
Additionally, isolated reports have been received of the following congenital malformations:
– Microphthalmia;
– Congenital choroid plexus cyst;
– Agenesis of the septum pellucidum;
– Olfactory nerve agenesis.
Animal studies have shown that mycophenolate mofetil causes reproductive toxicity.
Breastfeeding
Limited data demonstrate that mycophenolic acid passes into human breast milk. Due to the potential for serious adverse reactions in breastfed infants, this medicinal product is contraindicated during breastfeeding (see section "Contraindications").
Men
Limited clinical data do not indicate an increased risk of congenital malformations or miscarriage following paternal exposure to mycophenolate mofetil.
MPA is a potent teratogen. It is unknown whether MPA is present in semen. Calculations based on animal study data suggest that the maximum amount of MPA potentially transferred to a woman is so low that it is unlikely to have any effect. Animal studies have shown that mycophenolate is genotoxic at concentrations exceeding the narrow therapeutic range in humans by only a small margin; therefore, the risk of genotoxic effects on spermatozoa cannot be completely excluded.
Therefore, the following preventive measures are recommended: sexually active men or their female partners should use reliable contraceptive methods during treatment of the male patient and for at least 90 days after discontinuation of mycophenolate mofetil therapy. Men of reproductive potential must be informed and should discuss potential risks of fatherhood with a qualified healthcare professional.
Ability to affect reaction speed when driving or operating machinery.
Mycophenolate mofetil has a moderate influence on the ability to drive vehicles or operate machinery.
Mycophenolate mofetil may cause somnolence, confusion, dizziness, tremor, or arterial hypotension; therefore, patients are advised to exercise caution when driving vehicles or operating machinery.
Method of Administration and Dosage
Treatment with Myfenax® should be initiated and managed by qualified transplant specialists.
Dosage
Prevention of Kidney Transplant Rejection
Adults
The recommended dose for patients with kidney transplants is 1 g twice daily (total daily dose – 2 g). Treatment should be initiated within 72 hours after transplantation.
Children aged 2 to 18 years
The recommended dose is 600 mg/m² body surface area orally twice daily (maximum daily dose – 2 g). The drug should only be administered 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, the drug may be administered at a dose of 750 mg twice daily (total daily dose – 1.5 g). For patients with a body surface area greater than 1.5 m², the drug may be administered at a dose of 1 g twice daily (total daily dose – 2 g). Since certain adverse reactions occur more frequently in children and adolescents than in adults, temporary dose reduction or discontinuation of treatment may be necessary. Important clinical factors, including severity of the reaction, should be considered.
Children under 2 years of age
There are limited data on the safety and efficacy of the drug in children under 2 years of age. Therefore, use of the drug in children under 2 years of age is not recommended.
Prevention of Heart Transplant Rejection
Adults
The recommended dose for patients with heart transplants is 1.5 g twice daily (total daily dose – 3 g). Treatment should be initiated within 5 days after transplantation.
Children
There are no data on the safety and efficacy of the drug in children following heart transplantation.
Prevention of Liver Transplant Rejection
Adults
The recommended dose for patients with liver transplants is 1.5 g twice daily (total daily dose – 3 g). Treatment should be initiated as soon as possible, provided the drug is tolerated.
Children
There are no data on the safety and efficacy of the drug in children following liver transplantation.
Special Patient Groups
Elderly Patients
For elderly patients (≥65 years) after kidney transplantation, the recommended dose is 1 g twice daily; after heart or liver transplantation, the recommended dose is 1.5 g twice daily.
Renal Impairment
In patients with kidney transplants and severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73 m²), except in the immediate post-transplant period, doses exceeding 1 g twice daily should be avoided. These patients require close monitoring. Dose adjustment is not required in patients experiencing postoperative delayed graft function (see section "Pharmacokinetics"). Data in patients with severe chronic renal impairment who have undergone heart or liver transplantation are lacking.
Severe Hepatic Impairment
Dose adjustment is not required in patients with severe parenchymal liver disease who have undergone kidney transplantation. Data in patients with severe parenchymal liver disease who have undergone heart transplantation are lacking.
Treatment during Episodes of Rejection
Mycophenolic acid is the active metabolite of mycophenolate mofetil. Kidney transplant rejection does not alter the pharmacokinetics of mycophenolic acid. In such cases, discontinuation or dose reduction of the drug is not required. There are no data on the pharmacokinetics of mycophenolic acid during liver transplant rejection. There are no data on dose adjustment during heart transplant rejection.
Children
There are no data on treatment of the first episode or refractory rejection after transplantation in children.
Method of Administration
Oral administration.
Precautions to be taken before administration of this medicinal product
Since mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Myfenax® capsules should not be opened or crushed to avoid inhalation of the powder contained in the capsules and direct contact with skin or mucous membranes. If such contact occurs, the affected skin area should be thoroughly washed with soap and water, and eyes should be rinsed with running water only.
Children
There are no data on the safety and efficacy of the drug in children following liver or heart transplantation. There are limited data on the safety and efficacy of the drug in children under 2 years of age following kidney transplantation. There are no data on treatment of the first episode or refractory rejection after transplantation in children.
Overdose.
Data on mycophenolate mofetil overdose were obtained from clinical trials and post-marketing experience. In many of these cases, adverse reactions were not reported. Adverse reactions observed in cases of overdose were consistent with the known safety profile of the drug.
Overdose with mycophenolate mofetil is expected to result in excessive immunosuppression, increased susceptibility to infections, and bone marrow suppression (see section "Special Warnings and Precautions for Use"). If neutropenia develops, the drug should be discontinued or the dose reduced (see section "Special Warnings and Precautions for Use").
Clinically significant elimination of MPA or MPAG by hemodialysis is not expected. Bile acid-binding agents such as cholestyramine may eliminate MPA by reducing enterohepatic recirculation of the drug (see section "Pharmacokinetics").
Adverse Reactions
Summary of Safety Profile
Approximately 1557 patients received mycophenolate mofetil in five clinical studies evaluating prevention of acute transplant rejection. Of these, 991 were enrolled in three kidney transplantation studies, 277 in one liver transplantation study, and 289 in one heart transplantation study. Azathioprine was used as the comparator in the liver and heart transplantation studies, as well as in two of the kidney transplantation studies. The other kidney transplantation study was placebo-controlled. In all study groups, patients also received cyclosporine and corticosteroids. The types of adverse reactions reported during post-marketing use of mycophenolate mofetil are similar to those observed in controlled kidney, heart, and liver transplantation studies.
The most common and/or serious adverse reactions associated with the use of mycophenolate mofetil in combination with cyclosporine and corticosteroids were diarrhea, leukopenia, sepsis, and vomiting. There are also data indicating an increased incidence of certain types of infections (see section "Special Warnings and Precautions for Use").
The table below lists adverse reactions observed in clinical studies and during post-marketing use, classified by system organ class according to MedDRA and frequency. The appropriate frequency category for each adverse drug reaction is based on the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). Due to significant differences observed in the frequency of certain adverse reactions among different transplantation indications, frequencies are listed separately for kidney, liver, and heart transplant patients.
Summary of adverse reactions occurring in patients receiving mycophenolate mofetil in clinical studies and during the post-marketing period
Adverse Reactions(MedDRA) System Organ Class |
Kidney Transplantation n=991 |
Liver Transplantation n=277 |
Heart Transplantation n=289 |
| Frequency |
Frequency |
Frequency |
|
| Infections and infestations |
|||
| Bacterial infections |
Very common |
Very common |
Very common |
| Fungal infections |
Common |
Very common |
Very common |
| Protozoal infections |
Uncommon |
Uncommon |
Uncommon |
| Viral infections |
Very common |
Very common |
Very common |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) |
|||
| Benign skin neoplasm |
Common |
Common |
Common |
| Lymphoma |
Uncommon |
Uncommon |
Uncommon |
| Lymphoproliferative disorder |
Uncommon |
Uncommon |
Uncommon |
| Neoplasm |
Common |
Common |
Common |
| Skin cancer |
Common |
Uncommon |
Common |
| Blood and lymphatic system disorders |
|||
| Anemia |
Very common |
Very common |
Very common |
| True red cell aplasia |
Uncommon |
Uncommon |
Uncommon |
| Bone marrow failure |
Uncommon |
Uncommon |
Uncommon |
| Ecchymoses |
Common |
Common |
Very common |
| Leukocytosis |
Common |
Very common |
Very common |
| Leukopenia |
Very common |
Very common |
Very common |
| Pancytopenia |
Common |
Common |
Uncommon |
| Pseudolymphoma |
Uncommon |
Uncommon |
Common |
| Thrombocytopenia |
Common |
Very common |
Very common |
| Metabolism and nutrition disorders |
|||
| Acidosis |
Common |
Common |
Very common |
| Hypercholesterolemia |
Very common |
Common |
Very common |
| Hyperglycemia |
Common |
Very common |
Very common |
| Hyperkalemia |
Common |
Very common |
Very common |
| Hyperlipidemia |
Common |
Common |
Very common |
| Hypocalcemia |
Common |
Very common |
Common |
| Hypokalemia |
Common |
Very common |
Very common |
| Hypomagnesemia |
Common |
Very common |
Very common |
| Hypophosphatemia |
Very common |
Very common |
Common |
| Hyperuricemia |
Common |
Common |
Very common |
| Gout |
Common |
Common |
Very common |
| Weight decreased |
Common |
Common |
Common |
| Psychiatric disorders |
|||
| Confusion |
Common |
Very common |
Very common |
| Depression |
Common |
Very common |
Very common |
| Insomnia |
Common |
Very common |
Very common |
| Agitation |
Uncommon |
Common |
Very common |
| Anxiety |
Common |
Very common |
Very common |
| Thinking abnormal |
Uncommon |
Common |
Common |
| Nervous system disorders |
|||
| Dizziness |
Common |
Very common |
Very common |
| Headache |
Very common |
Very common |
Very common |
| Hypertonia |
Common |
Common |
Very common |
| Paresthesia |
Common |
Very common |
Very common |
| Somnolence |
Common |
Common |
Very common |
| Tremor |
Common |
Very common |
Very common |
| Seizures |
Common |
Common |
Common |
| Taste disorder |
Uncommon |
Uncommon |
Common |
| Cardiac disorders |
|||
| Tachycardia |
Common |
Very common |
Very common |
| Vascular disorders |
|||
| Arterial hypertension |
Very common |
Very common |
Very common |
| Arterial hypotension |
Common |
Very common |
Very common |
| Lymphocele |
Uncommon |
Uncommon |
Uncommon |
| Venous thrombosis |
Common |
Common |
Common |
| Vasodilatation |
Common |
Common |
Very common |
| Respiratory, thoracic and mediastinal disorders |
|||
| Bronchiectasis |
Uncommon |
Uncommon |
Uncommon |
| Cough |
Very common |
Very common |
Very common |
| Dyspnea |
Very common |
Very common |
Very common |
| Interstitial lung disease |
Uncommon |
Very rare |
Very rare |
| Pleural effusion |
Common |
Very common |
Very common |
| Lung fibrosis |
Very rare |
Uncommon |
Uncommon |
| Gastrointestinal disorders |
|||
| Abdominal distension |
Common |
Very common |
Common |
| Abdominal pain |
Very common |
Very common |
Very common |
| Colitis |
Common |
Common |
Common |
| Constipation |
Very common |
Very common |
Very common |
| Decreased appetite |
Common |
Very common |
Very common |
| Diarrhea |
Very common |
Very common |
Very common |
| Dyspepsia |
Very common |
Very common |
Very common |
| Esophagitis |
Common |
Common |
Common |
| Eructation |
Uncommon |
Uncommon |
Common |
| Flatulence |
Common |
Very common |
Very common |
| Gastritis |
Common |
Common |
Common |
| Gastrointestinal hemorrhage |
Common |
Common |
Common |
| Gastrointestinal ulcer |
Common |
Common |
Common |
| Gingival hyperplasia |
Common |
Common |
Common |
| Intestinal obstruction |
Common |
Common |
Common |
| Mouth ulcers |
Common |
Common |
Common |
| Nausea |
Very common |
Very common |
Very common |
| Pancreatitis |
Uncommon |
Common |
Uncommon |
| Stomatitis |
Common |
Common |
Common |
| Vomiting |
Very common |
Very common |
Very common |
| Immune system disorders |
|||
| Hypersensitivity |
Uncommon |
Common |
Common |
| Hypogammaglobulinemia |
Uncommon |
Very rare |
Very rare |
| Hepatobiliary disorders |
|||
| Increased blood alkaline phosphatase |
Common |
Common |
Common |
| Increased blood lactate dehydrogenase |
Common |
Uncommon |
Very common |
| Increased liver enzymes |
Common |
Very common |
Very common |
| Hepatitis |
Common |
Very common |
Uncommon |
| Hyperbilirubinemia |
Common |
Very common |
Very common |
| Jaundice |
Uncommon |
Common |
Common |
| Skin and subcutaneous tissue disorders |
|||
| Acne |
Common |
Common |
Very common |
| Alopecia |
Common |
Common |
Common |
| Rash |
Common |
Very common |
Very common |
| Skin hypertrophy |
Common |
Common |
Very common |
| Musculoskeletal and connective tissue disorders |
|||
| Arthralgia |
Common |
Common |
Very common |
| Muscle weakness |
Common |
Common |
Very common |
| Renal and urinary disorders |
|||
| Increased blood creatinine |
Common |
Very common |
Very common |
| Increased blood urea |
Uncommon |
Very common |
Very common |
| Hematuria |
Very common |
Common |
Common |
| Renal dysfunction |
Common |
Very common |
Very common |
| General disorders and administration site conditions |
|||
| Asthenia |
Very common |
Very common |
Very common |
| Chills |
Common |
Very common |
Very common |
| Edema |
Very common |
Very common |
Very common |
| Hernia |
Common |
Very common |
Very common |
| Malaise |
Common |
Common |
Common |
| Pain |
Common |
Very common |
Very common |
| Pyrexia |
Very common |
Very common |
Very common |
| Acute inflammatory syndrome associated with de novo purine synthesis inhibitors |
Uncommon |
Uncommon |
Uncommon |
Note: 991 (mycophenolate mofetil 2 g/3 g daily), 289 (mycophenolate mofetil 3 g daily orally), and 277 (mycophenolate mofetil 2 g daily intravenously/3 g daily orally) patients received treatment in Phase III studies for prevention of kidney, heart, and liver transplant rejection, respectively.
Description of selected adverse reactions
Malignant neoplasms
Patients receiving immunosuppressive regimens, including combination therapies containing Myfenax®, have an increased risk of developing lymphomas and other malignancies, particularly of the skin (see section "Dosage and Administration"). Three-year safety data in kidney and heart transplant patients show no unexpected changes in the incidence of malignancies compared to one-year data. Liver transplant patients were followed for at least 1 year but less than 3 years.
Infections
All patients receiving immunosuppressive agents, including Myfenax®, are at increased risk of bacterial, viral, and fungal infections (some of which may be fatal), including those caused by opportunistic pathogens, as well as reactivation of latent viral infections. This risk increases with greater overall immunosuppressive burden (see section "Dosage and Administration"). The most serious infections reported included sepsis, peritonitis, meningitis, endocarditis, tuberculosis, and atypical mycobacterial infection. The most common opportunistic infections in kidney, heart, and liver transplant patients receiving mycophenolate mofetil (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials and followed for at least 1 year were cutaneous and mucosal candidiasis, CMV viremia/syndrome, and herpes simplex. The incidence of CMV viremia/syndrome was 13.5%. Cases of BK virus-associated nephropathy and JC virus-associated progressive multifocal leukoencephalopathy have been reported in patients receiving immunosuppressive therapy, including mycophenolate mofetil.
Blood and lymphatic system disorders
Cytopenias, including leukopenia, anemia, thrombocytopenia, and pancytopenia, are known risks associated with mycophenolate mofetil use and may lead to or contribute to infections and bleeding (see section "Dosage and Administration"). Cases of agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients receiving mycophenolate mofetil is recommended (see section "Dosage and Administration"). Cases of anemia and bone marrow failure have been reported in patients receiving mycophenolate mofetil, some of which were fatal.
Cases of pure red cell aplasia have been reported in patients receiving mycophenolate mofetil (see section "Dosage and Administration").
Isolated cases of neutrophil morphology abnormalities, including Pelger-Huët anomaly, have been reported in patients receiving mycophenolate mofetil. These changes are not associated with impaired neutrophil function and may reflect a left shift in neutrophil maturation on blood examination, which may be misinterpreted as a sign of infection in immunosuppressed patients, including those receiving mycophenolate mofetil.
Gastrointestinal disorders
The most serious gastrointestinal events were ulceration and bleeding, which are known risks associated with mycophenolate mofetil use. In pivotal clinical trials, ulcers of the oral mucosa, esophagus, stomach, duodenum, and intestine were commonly reported, often complicated by bleeding, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis. However, the most common gastrointestinal disorders were diarrhea, nausea, and vomiting. Endoscopic evaluation of patients with mycophenolate mofetil-associated diarrhea revealed isolated cases of intestinal villous atrophy (see section "Dosage and Administration").
Hypersensitivity
Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been reported.
Pregnancy, postpartum, and perinatal conditions
Spontaneous abortions have been observed in female patients receiving mycophenolate mofetil, primarily during the first trimester (see section "Pregnancy and Lactation").
Congenital disorders
Congenital malformations have been observed post-marketing in children whose mothers received mycophenolate mofetil in combination with other immunosuppressants during pregnancy (see section "Pregnancy and Lactation").
Respiratory, thoracic, and mediastinal disorders
Isolated cases of interstitial lung disease and pulmonary fibrosis, some fatal, have been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants. Bronchiectasis has also been reported in both children and adults.
Immune system disorders
Hypogammaglobulinemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants.
General disorders and administration site conditions
In pivotal studies, edema, including peripheral, facial, and scrotal edema, was very commonly reported. Musculoskeletal pain, such as myalgia, as well as neck and back pain, was also very commonly reported.
An acute inflammatory syndrome associated with de novo purine synthesis inhibitors has been described in post-marketing experience as a paradoxical proinflammatory reaction related to mycophenolate mofetil and mycophenolic acid, characterized by fever, arthralgia, arthritis, myalgia, and elevated inflammatory markers. Reports of such cases indicate rapid improvement after discontinuation of the drug.
Special patient groups
Children
The type and frequency of adverse reactions in children aged 2 to 18 years receiving mycophenolate mofetil at a dose of 600 mg/m² orally twice daily are generally similar to those observed in adults receiving mycophenolate mofetil 1 g twice daily. However, in children, particularly those under 6 years of age, treatment-related adverse events such as diarrhea, sepsis, leukopenia, anemia, and infections occur more frequently.
Elderly patients
Elderly patients (≥65 years) may generally have an increased risk of adverse reactions due to immunosuppression. In elderly patients receiving mycophenolate mofetil as part of combination therapy, the risk of certain infections (including tissue-invasive forms of cytomegalovirus infection), gastrointestinal bleeding, and pulmonary edema is generally higher than in younger patients.
Shelf life. 3 years.
Storage conditions.
The medicinal product does not require special storage conditions. Keep out of reach of children.
Packaging.
10 capsules in a blister, 3 or 10 blisters in a carton.
Prescription category. Prescription only.
Manufacturer.
Teva Pharmaceutical Works Private Limited Company.
Manufacturer's address and location of operations.
Site 1; H-4042 Debrecen, Pallagi str. 13, Hungary.