Mikop

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MYCOPE (MYCOPE)

Composition:

Active substance: mycophenolate mofetil;

1 capsule contains 250 mg of mycophenolate mofetil;

Excipients: pregelatinized starch, sodium croscarmellose, povidone, magnesium stearate;

Capsule shell: gelatin, titanium dioxide (E 171), indigo carmine (E 132), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size "1" with brown body and blue cap, marked with "H" on the cap and "M1" on the body, filled with white to almost white powder.

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).
The 2-morpholinoethyl ester of mycophenolic acid is a potent, selective, non-competitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), thereby suppressing de novo synthesis of guanosine nucleotides without incorporation into DNA. The 2-morpholinoethyl ester of mycophenolic acid 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 extensive presystemic metabolism to form the active metabolite mycophenolic acid (MPA). Immunosuppressive activity of the drug correlates with mycophenolic acid concentration, as demonstrated by suppression of acute allograft rejection in kidney transplantation. The mean bioavailability of mycophenolate mofetil after oral administration, based on AUC_MPA (area under the concentration-time curve), is 94% relative to intravenous administration. Food intake does not affect the extent of mycophenolate mofetil absorption (AUC_MPA) when administered at a dose of 1.5 g twice daily in kidney transplant recipients. However, the maximum concentration of mycophenolic acid is reduced by 40% when the drug is taken with food. After oral administration, plasma concentrations of mycophenolate mofetil are not detectable.

Distribution

Due to enterohepatic recirculation of the drug, a secondary increase in plasma mycophenolic acid concentration is typically observed approximately 6–12 hours after administration. Concomitant administration with cholestyramine (4 g three times daily) reduces AUC_MPA by approximately 40%, indicating significant enterohepatic recirculation.

Mycophenolic acid is 97% bound to plasma albumin at clinically relevant concentrations.

Metabolism

Mycophenolic acid is primarily metabolized by glucuronosyltransferase (isoform UGT1A9) to form the inactive phenolic glucuronide of mycophenolic acid. In vivo, the phenolic glucuronide of mycophenolic acid is converted back to free mycophenolic acid via enterohepatic recirculation. A minor acyl glucuronide (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 mycophenolic acid. After oral administration of radiolabeled mycophenolate mofetil, 93% of the administered dose is recovered in urine and 6% in feces. A substantial portion (approximately 87%) of the administered dose is excreted in urine as the phenolic glucuronide of mycophenolic acid.

Mycophenolic acid and the phenolic glucuronide of mycophenolic acid are not significantly removed by hemodialysis at clinically relevant concentrations. However, at higher concentrations of the phenolic glucuronide of mycophenolic acid (> 100 µg/mL), a small amount may be removed.

Bile acid sequestrants such as cholestyramine reduce AUC_MPA by interrupting enterohepatic recirculation of the drug (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 (up to 40 days after kidney, heart, or liver transplantation), mean AUC_MPA values were approximately 30% lower, and maximum concentrations 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 AUC_MPA 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 less severe renal impairment. However, after a single dose, mean AUC of the phenolic glucuronide of mycophenolic acid was 3–6 times higher in patients with severe renal impairment than in those with mild renal impairment and healthy volunteers, consistent with known data on 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. Data are lacking for patients with severe chronic renal impairment after heart or liver transplantation.

Delayed graft function

In patients with delayed renal allograft function after transplantation, mean AUC_0–12 for mycophenolic acid was comparable to that in patients whose grafts functioned immediately after transplantation. Mean AUC_0–12 for the phenolic glucuronide of mycophenolic acid in plasma was 2–3 times higher than in patients with immediate graft function. A transient increase in free fraction and plasma concentration of mycophenolic acid may occur in patients with delayed graft function. Dose adjustment of mycophenolate mofetil 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 the glucuronidation of mycophenolic acid. The impact of liver disease on this process depends on the specific condition. However, in liver diseases predominantly affecting biliary pathways (e.g., primary biliary cirrhosis), the effect may differ.

Children

Pharmacokinetic parameters were studied in children after kidney transplantation (aged 2 to 18 years) who received mycophenolate mofetil at a dose of 600 mg/m² orally twice daily. At this dose, AUC_MPA was similar to that observed in adult kidney transplant recipients receiving mycophenolate mofetil 1 g twice daily during both early and late post-transplant periods. AUC_MPA values across different age groups were comparable in both early and late post-transplant periods.

Elderly patients

No changes in the pharmacokinetics of mycophenolate mofetil or its metabolites were 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 women after transplantation who were not receiving other immunosuppressants, concomitant administration of mycophenolate mofetil (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 a clinically significant impact on the ovulation-suppressing effect of oral contraceptives. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were not significantly altered.

Clinical characteristics.

Indications.

Prevention of acute organ rejection in patients following allogeneic kidney, heart, or liver transplantation as part of a combined therapy with cyclosporine and corticosteroids.

Contraindications.

Mycop drug should not be administered to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid, or to any other component of the drug. Cases of hypersensitivity reactions have been observed during use of mycophenolate mofetil (see section "Adverse reactions").

Mycop should not be administered to women of childbearing potential who are not using highly effective contraception (see section "Use during pregnancy or breastfeeding").

Treatment with Mycop should not be initiated in women of childbearing potential without first obtaining a pregnancy test to exclude inadvertent use during pregnancy (see section "Use during pregnancy or breastfeeding").

Mycop should not be administered to pregnant women, except when no suitable alternative treatment is available to prevent transplant rejection (see section "Use during pregnancy or breastfeeding").

Mycop should not be administered to breastfeeding women (see section "Use during pregnancy or breastfeeding").

Special safety measures.

Since mycophenolate mofetil has demonstrated teratogenic effects in animal studies, Mycop capsules should not be opened or crushed. Inhalation of the powder contained in Mycop capsules or direct contact with skin or mucous membranes should 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.

Interaction with other medicinal products and other forms of interaction.

Acyclovir.

Higher plasma concentrations of acyclovir were observed when mycophenolate mofetil was administered concomitantly with acyclovir compared to acyclovir alone. Changes in the pharmacokinetics of the phenolic glucuronide of mycophenolic acid (an 8% increase for the phenolic glucuronide of mycophenolic acid) were minimal and not considered clinically significant. Since plasma concentrations of the phenolic glucuronide of mycophenolic acid, as well as acyclovir, increase in renal impairment, there is a possibility that mycophenolate mofetil and acyclovir or its prodrugs, such as valacyclovir, compete for tubular secretion, further increasing plasma concentrations of both drugs.

Antacids and proton pump inhibitors.

Reduced exposure to mycophenolic acid was observed when mycophenolate mofetil was co-administered with antacids (aluminum and magnesium hydroxide) and proton pump inhibitors, including lansoprazole and pantoprazole. No significant difference in transplant rejection rates was observed between patients receiving mycophenolate mofetil with proton pump inhibitors and those receiving mycophenolate mofetil without proton pump inhibitors. This result allows extrapolation of these data to all antacids, as the reduction in exposure with concomitant use of mycophenolate mofetil and aluminum and magnesium hydroxides was considerably less than with concomitant use of mycophenolate mofetil and proton pump inhibitors.

Drugs affecting enterohepatic circulation (e.g., cholestyramine, cyclosporine A, antibiotics).

Caution is required when administering mycophenolate mofetil concomitantly with drugs affecting enterohepatic circulation, as they may reduce the efficacy of Mycop.

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 mycophenolic acid (MPA) was observed (see sections "Special instructions for use", "Pharmacokinetics"). Caution is advised when co-administering mycophenolate mofetil and cholestyramine due to the potential for reduced efficacy of Mycop.

Cyclosporine A

Mycophenolate mofetil does not affect the pharmacokinetics of cyclosporine A. However, if concomitant use of cyclosporine is discontinued, an approximately 30% increase in the area under the concentration-time curve (AUC) may be expected. Cyclosporine A affects enterohepatic recirculation, resulting in a 30–50% reduction in exposure to mycophenolic acid in kidney transplant patients receiving mycophenolate mofetil and cyclosporine A, compared to patients receiving sirolimus or belatacept with similar doses of mycophenolate mofetil (see sections "Special instructions for use"). Conversely, changes in exposure to mycophenolic acid should be expected when switching patients from cyclosporine A to an immunosuppressant that does not affect enterohepatic circulation.

Antibiotics that reduce the number of β-glucuronidase-producing bacteria in the gut (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may affect the enterohepatic circulation of MPA glucuronide (MPAG)/MPA, potentially leading to reduced systemic exposure to MPA. Available information on the following antibiotics:

Ciprofloxacin or amoxicillin with clavulanic acid

For several days immediately following oral administration of ciprofloxacin or amoxicillin with clavulanic acid in kidney transplant patients, a decrease of approximately 50% in the pre-dose (trough) concentration of mycophenolic acid was observed. This effect tended to diminish with continued antibiotic therapy and disappeared after discontinuation of antibiotics. Changes in pre-dose levels of mycophenolic acid may not accurately reflect changes in total exposure to mycophenolic acid. Therefore, dose adjustment of Mycop is usually not necessary due to the lack of clinical data on transplant dysfunction. However, careful clinical monitoring is required during combination therapy and immediately after completion of antibiotic treatment.

Norfloxacin and metronidazole

No significant interaction was observed in healthy volunteers when mycophenolate mofetil was administered concomitantly with either of these antibacterial agents. However, concomitant administration of mycophenolate mofetil with norfloxacin and metronidazole reduced exposure to mycophenolic acid by approximately 30% after a single dose.

Trimethoprim/sulfamethoxazole

No effect on the bioavailability of mycophenolic acid was observed.

Drugs affecting glucuronidation (e.g., isavuconazole, telmisartan)

Concomitant administration of drugs that inhibit glucuronidation of MPA may increase exposure to MPA. Therefore, caution is recommended when using these drugs simultaneously with Mycop.

Isavuconazole

A 35% increase in AUC_0-∞ of MPA was observed during concomitant administration with isavuconazole.

Telmisartan

Concomitant administration of telmisartan and mycophenolate mofetil resulted in a decrease in mycophenolic acid concentration by approximately 30%. Telmisartan alters the elimination of mycophenolic acid by enhancing the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which in turn increases the expression and activity of uridine diphosphate-glucuronosyltransferase isoform 1A9 (UGT1A9). No clinical consequences of the pharmacokinetic interaction between these drugs were observed when comparing rates of transplant rejection or adverse reaction profiles in patients receiving mycophenolate mofetil with or without concomitant telmisartan.

Ganciclovir

Based on results from a study with single oral doses of recommended doses of mycophenolate mofetil and intravenous administration of ganciclovir, and considering the known effect of renal impairment on the pharmacokinetics of mycophenolate mofetil (see section "Dosage and administration") and ganciclovir, it can be assumed that concomitant use of these drugs (which compete for tubular secretion mechanisms) will increase plasma concentrations of the phenolic glucuronide of mycophenolic acid and ganciclovir. No significant change in the pharmacokinetics of mycophenolic acid is expected; therefore, dose adjustment of Mycop is not required. However, if Mycop and ganciclovir or its prodrugs (e.g., valganciclovir) are administered concomitantly to patients with renal impairment, the recommended dosing regimen for ganciclovir should be followed, and patients should be closely monitored.

Oral contraceptives

Mycop does not affect the pharmacokinetics or pharmacodynamics of oral contraceptives when administered concomitantly (see section "Pharmacokinetics").

Rifampicin

In patients not receiving cyclosporine, concomitant administration of mycophenolate mofetil and rifampicin was associated with a reduction in exposure to mycophenolic acid ranging from 18% to 70% (AUC_{0-12 hours}). Monitoring of mycophenolic acid exposure and dose adjustment of Mycop are recommended to maintain clinical efficacy when used concomitantly.

Sevelamer

A 30% reduction in C_max and a 25% reduction in AUC_{(0-12 hours)} of mycophenolic acid were observed when mycophenolate mofetil was administered concomitantly with sevelamer, without any clinical consequences (i.e., no transplant rejection). However, to minimize the impact of sevelamer on mycophenolic acid absorption, Mycop should be taken at least 1 hour before or 3 hours after sevelamer. No data are available on the use of mycophenolate mofetil with other phosphate binders besides sevelamer.

Tacrolimus

No significant effect on AUC and C_max of mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed when tacrolimus and mycophenolate mofetil were administered concomitantly in liver transplant patients. In patients with liver transplants, AUC of tacrolimus increased by approximately 20% after multiple doses of mycophenolate mofetil at 1.5 g twice daily. However, in kidney transplant patients, administration of mycophenolate mofetil did not affect tacrolimus concentrations (see section "Special instructions for use").

Live vaccines

Live vaccines should not be administered to patients with impaired immune response. Antibody formation in response to other vaccines may be reduced (see section "Special instructions for use").

Children.

Interaction studies have been conducted only in adults.

Potential interactions.

Concomitant administration of probenecid and mycophenolate mofetil in monkeys was associated with a threefold increase in plasma AUC of the phenolic glucuronide of mycophenolic acid. Thus, other drugs undergoing tubular secretion in the kidneys may compete with the phenolic glucuronide of mycophenolic acid, leading to increased plasma concentrations of either the phenolic glucuronide of mycophenolic acid or the other drug undergoing tubular secretion.

Special precautions for use.

Neoplasms

In patients receiving immunosuppressive therapy, including combination regimens containing mycophenolate mofetil, there is an increased risk of developing lymphomas and other malignancies, particularly of the skin (see section "Adverse reactions"). This risk appears to be related not to the use of any specific drug per se, but rather to the intensity and duration of immunosuppression. To minimize the risk of skin cancer, exposure to sunlight and ultraviolet radiation should be limited by wearing protective clothing and using sunscreens with a high protective factor.

Infections

Patients receiving immunosuppressive therapy, including mycophenolate mofetil, are at increased risk of opportunistic infections (bacterial, fungal, viral, and protozoal), fatal infections, and sepsis (see section "Adverse reactions"). Such 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, progressive multifocal leukoencephalopathy associated with JC virus). Cases of hepatitis B or hepatitis C reactivation have been reported in carrier patients who received immunosuppressive therapy. These infections are often associated with high overall immunosuppressive burden and may lead to serious or fatal outcomes, which physicians should consider when performing differential diagnosis in immunosuppressed patients with impaired renal function or neurological symptoms.

Mycophenolic acid has a cytostatic effect on B- and T-lymphocytes; therefore, worsening severity of COVID-19 may occur, and appropriate clinical measures should be considered.

Cases of hypogammaglobulinemia associated with recurrent infections have been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching patients from mycophenolate mofetil treatment to an alternative immunosuppressive therapy was accompanied by normalization of serum IgG levels. Serum immunoglobulin levels should be determined in patients receiving mycophenolate mofetil therapy who develop recurrent infections. In cases of persistent clinically significant hypogammaglobulinemia, appropriate clinical measures should be considered, taking into account the potential cytostatic effects of mycophenolic acid on T- and B-lymphocytes.

Cases of bronchiectasis have been reported in adults and children receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching patients from mycophenolate mofetil 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. There are also isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see section "Adverse reactions"). Patients who develop persistent pulmonary symptoms such as cough or dyspnea should be evaluated.

Blood and lymphatic system

Patients receiving Mypco should be monitored for neutropenia, which may be related to Mypco therapy itself, concomitant use of other medicinal products, viral infections, or a combination of these factors. Complete blood counts should be performed weekly during the first month of Mypco treatment, twice monthly during the second and third months, and monthly thereafter during the first year. If neutropenia develops (absolute neutrophil count < 1300/µL), treatment with Mypco should be interrupted or discontinued.

Cases of pure red cell aplasia have been reported in patients receiving 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 upon dose reduction or discontinuation of mycophenolate mofetil. Changes in Mypco therapy should be made only under appropriate patient monitoring after transplantation to minimize the risk of transplant rejection (see section "Adverse reactions").

Patients taking Mypco should be informed to immediately report any signs of infection, bleeding (bruising), hemorrhage, or other signs of bone marrow suppression.

Patients should be informed that vaccination may be less effective during Mypco treatment and that live attenuated vaccines should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). Physicians should follow national recommendations for influenza vaccination.

Gastrointestinal tract

Because mycophenolate mofetil has been associated with an increased risk of gastrointestinal adverse reactions, including rare cases of gastrointestinal ulceration, gastrointestinal bleeding, and gastrointestinal perforation, Mypco should be used with caution in patients with active serious gastrointestinal disorders.

Mycophenolate mofetil is an inosine monophosphate dehydrogenase inhibitor. Therefore, Mypco should not be administered to patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase, such as Lesch–Nyhan and Kelley–Seegmiller syndromes.

Interactions

Caution is required when switching patients from combination therapy containing immunosuppressants that affect the enterohepatic recirculation of mycophenolic acid (e.g., cyclosporine) to those that do not (e.g., tacrolimus, sirolimus, belatacept), or vice versa, as this may lead to changes in mycophenolic acid exposure. Medicinal products that affect the enterohepatic circulation of mycophenolic acid (e.g., cholestyramine, antibiotics) should be used with caution due to their potential to reduce plasma levels and efficacy of Mypco (see section "Interaction with other medicinal products and other forms of interaction"). Therapeutic monitoring of mycophenolic acid may be appropriate when changing combination therapy (e.g., from cyclosporine to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g., rejection risk, antibiotic treatment, addition or removal of interacting drugs).

Concomitant administration of Mypco with azathioprine is not recommended, as their combined use has not been studied.

The risk-benefit ratio of using mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see section "Interaction with other medicinal products and other forms of interaction").

Special patient groups

In elderly patients, an increased risk of adverse events may occur, including certain infections (including invasive tissue cytomegalovirus infection), and possibly gastrointestinal bleeding and pulmonary edema, compared to younger patients (see section "Adverse effects").

Teratogenic effects

Mycophenolate is a potent human teratogen. Spontaneous abortion (occurring at a frequency of 45–49%) and congenital malformations (estimated at 23–27%) have been reported following exposure to mycophenolate mofetil during pregnancy. Therefore, Mypco is contraindicated during pregnancy except when no suitable alternative therapy is available to prevent transplant rejection. Women and men of reproductive potential should be informed about the risks and the necessity to follow the recommendations outlined in the section "Use during pregnancy or breastfeeding" (e.g., contraceptive methods, pregnancy testing) before, during, and after Mypco therapy. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the fetus, the need for effective contraception, and the necessity of immediate consultation with a physician if pregnancy is suspected.

Contraception (see section "Use during pregnancy or breastfeeding")

Clear clinical evidence indicates a high risk of miscarriage and congenital malformations with mycophenolate mofetil use during pregnancy; therefore, all measures should be taken to avoid pregnancy during Mypco treatment. Women of reproductive potential should use at least one reliable method of contraception or two reliable methods of contraception before initiating Mypco therapy, during treatment, and for 6 weeks after discontinuation of treatment, unless abstinence is the chosen method of contraception. To minimize the likelihood of contraceptive failure and unintended pregnancy, simultaneous use of two complementary contraceptive methods is preferred.

Additional precautions

Patients should not donate blood during therapy and for at least 6 weeks after discontinuation of mycophenolate. Men should not donate sperm during therapy and for 90 days after discontinuation of mycophenolate.

Disposal of unused and expired medication: Environmental contamination should be minimized. The medicinal product should not be disposed of via wastewater or household waste. Disposal should be carried out via a "waste collection system" if available.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Pregnancy should be avoided during mycophenolate mofetil use. Therefore, women of reproductive age should use at least one reliable method of contraception before starting Mypco therapy, during treatment, and for 6 weeks after discontinuation of treatment, unless abstinence is the chosen method of contraception. Simultaneous use of two complementary contraceptive methods is preferred.

Pregnancy

Mypco is contraindicated during pregnancy, except when no suitable alternative therapy is available to prevent transplant rejection.

Treatment should not be initiated in women of reproductive age without negative pregnancy test results to exclude inadvertent use during pregnancy.

Women and men of reproductive potential should be informed at the start of treatment about the increased risk of fetal loss and congenital malformations and should be counseled on pregnancy prevention and planning.

Before initiating Mypco therapy, women of reproductive age should have two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL to exclude unintended embryonic exposure to mycophenolate mofetil. Two serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL are recommended; the second test should be performed 8–10 days after the first and immediately before starting mycophenolate mofetil. In deceased donor transplants, if it is not possible to perform two tests 8–10 days apart before treatment initiation (due to uncertainty about the timing of organ availability), a pregnancy test should be performed immediately before starting treatment, and the next test 8–10 days later.

Pregnancy tests should be repeated when clinically indicated (e.g., after a report of contraceptive failure). All pregnancy test results should be discussed with the patient. Patients should be instructed to consult their physician immediately if pregnancy occurs.

Mycophenolate is a potent human teratogen and is associated with an increased risk of spontaneous abortions and congenital malformations upon exposure during pregnancy:

• Spontaneous abortions were observed in 45–49% of pregnant women receiving mycophenolate mofetil, compared to a reported frequency of 12–33% in transplant patients receiving other immunosuppressants;
• According to scientific literature, congenital malformations occurred 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 after solid organ transplantation).

Congenital malformations, including reports of multiple malformations, have been observed in the post-marketing period in children of patients who received mycophenolate mofetil in combination with other immunosuppressants during pregnancy. The most frequently reported malformations include:

• Ear abnormalities (e.g., abnormally formed or absent external/middle ear), external auditory canal atresia;
• 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);
• Hand and foot malformations (e.g., polydactyly, syndactyly);
• Tracheoesophageal malformations (e.g., esophageal atresia);
• Nervous system malformations, such as failure of spinal 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 demonstrated reproductive toxicity.

Breastfeeding

Limited data show that mycophenolic acid is excreted in breast milk. Due to the potential for serious adverse reactions from mycophenolic acid in breastfed infants, Mypco is contraindicated during breastfeeding (see section "Contraindications").

Men

Limited clinical data do not indicate an increased risk of congenital malformations or miscarriage if the father was exposed to mycophenolate mofetil.

MMF is a potent teratogen. It is unknown whether MMF is present in semen. Calculations based on animal study data suggest that the maximum amount of MMF potentially transferred to a woman is so small that an effect is unlikely. Animal studies have shown that mycophenolate mofetil is genotoxic at concentrations slightly exceeding human therapeutic exposures; therefore, a genotoxic effect on sperm cells cannot be completely ruled out.

Therefore, the following precautions are recommended: sexually active male patients or their partners should use a reliable method of contraception during treatment of the male patient and for at least 90 days after discontinuation of mycophenolate mofetil. A qualified healthcare professional should inform and discuss with male patients of reproductive potential the possible risks associated with conceiving a child.

Ability to affect reaction rate when driving or operating machinery.

Mycophenolate mofetil has a moderate influence on the ability to drive vehicles and operate machinery. Mycophenolate mofetil may cause somnolence, confusion, dizziness, tremor, or arterial hypotension; therefore, patients are advised to be cautious when driving vehicles or operating machinery.

Method of Administration and Dosage

Treatment with the drug Mycop should be prescribed and monitored by a transplantation specialist with appropriate qualifications.

Dosage

Prevention of Kidney Rejection

Adults

Administration of the drug should begin within 72 hours after transplantation. For patients with kidney transplants, the recommended dose is 1 g twice daily (total daily dose 2 g).

Children aged 2 to 18 years

The recommended dose of mycophenolate mofetil is 600 mg/m² orally twice daily (up to a maximum daily dose of 2 g). Mycop should only be prescribed to patients with a body surface area of at least 1.25 m². For patients with a body surface area between 1.25 and 1.5 m², Mycop capsules 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, Mycop capsules may be administered at a dose of 1 g twice daily (total daily dose – 2 g). Since some adverse reactions occur more frequently in children and adolescents than in adults (see section "Adverse Reactions"), temporary dose reduction or discontinuation of Mycop treatment may be necessary. Important clinical factors, including severity of the reaction, should be considered in such cases.

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, available data are insufficient to provide dosage recommendations, and the use of Mycop in children under 2 years of age is not recommended.

Prevention of Heart Rejection

Adults

Oral administration of the drug should begin within 5 days after heart transplantation. Patients with heart transplants are recommended to take 1.5 g twice daily (total daily dose – 3 g).

Children

There are no data on the safety and efficacy of mycophenolate mofetil in children after heart transplantation.

Prevention of Liver Rejection

Adults

Mycop should be administered orally as soon as possible, depending on the patient's ability to tolerate the drug. The recommended dosage regimen is 1.5 g twice daily (total daily dose – 3 g).

Children

There are no data on the safety and efficacy of mycophenolate mofet,il in children after 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.

Patients with Renal Impairment

In patients with severe chronic renal impairment (glomerular filtration rate less than 25 ml/min/1.73 m²) who are outside the immediate post-transplantation period, doses exceeding 1 g twice daily should be avoided. These patients require close monitoring. Dose adjustment is not required in patients experiencing delayed graft function after kidney transplantation (see section "Pharmacokinetics"). There are no data available for patients with severe renal impairment who have undergone heart or liver transplantation.

Patients with Hepatic Impairment

Dose adjustment is not required in patients after kidney transplantation who have severe hepatic parenchymal damage. There are no data available for patients with severe hepatic parenchymal damage who have undergone heart transplantation.

Treatment during Episodes of Rejection

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Kidney transplant rejection does not alter the pharmacokinetics of mycophenolic acid. Therefore, discontinuation or dose reduction of Mycop is not required in such cases. There is no justification for dose adjustment during heart transplant rejection. There are no data on the pharmacokinetics of mycophenolic acid during liver transplant rejection.

Children

There are no data on treatment of first episodes 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, Mycop capsules should not be opened or crushed to avoid inhalation of the powder contained in the capsules or 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 mycophenolate mofetil in children after liver or heart transplantation. There are limited data on the safety and efficacy of mycophenolate mofetil in children under 2 years of age after kidney transplantation.

There are no data on treatment of first episodes or refractory rejection after transplantation in children.

Overdose

Data on mycophenolate mofetil overdose were obtained from clinical trials and post-marketing use. 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 and increased susceptibility to infections, as well as bone marrow suppression (see section "Special Warnings and Precautions for Use"). If neutropenia develops, Mycop should be discontinued or the dose reduced (see section "Special Warnings and Precautions for Use").

Hemodialysis is not expected to remove a clinically significant amount of mycophenolic acid or its 2-morpholinoethyl glucuronide metabolite from the body. Bile acid-binding agents such as cholestyramine may enhance elimination of mycophenolic acid from the body by interrupting its enterohepatic recirculation (see section "Pharmacokinetics").

Adverse reactions.

The main adverse reactions associated with the use of mycophenolate mofetil in combination with cyclosporine and corticosteroids are diarrhea, leukopenia, sepsis, and vomiting; there is also evidence of an increased frequency of certain types of infections (see section "Special precautions").

Adverse reactions reported from clinical trials and post-marketing experience are listed in Table 1 by MedDRA System Organ Class (SOC) and frequency. The following frequency categories are used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), and very rare (<1/10000). Due to significant differences observed in the frequency of certain adverse reactions across different transplant indications, frequencies are presented separately for kidney, liver, and heart transplant patients.

Summary of adverse drug reactions

observed in patients receiving Mycophenolate mofetil, capsules,

reported from clinical trials and post-marketing experience

Table 1.

Adverse reaction (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
Benign, malignant and unspecified neoplasms (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
Anaemia	Very common	Very common	Very common
True red cell aplasia	Uncommon	Uncommon	Uncommon
Bone marrow failure	Uncommon	Uncommon	Uncommon
Ecchymosis	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
Hypercholesterolaemia	Very common	Common	Very common
Hyperglycaemia	Common	Very common	Very common
Hypokalaemia	Common	Very common	Very common
Hyperlipidaemia	Common	Common	Very common
Hypocalcaemia	Common	Very common	Common
Hypokalaemia	Common	Very common	Very common
Hypomagnesaemia	Common	Very common	Very common
Hypophosphataemia	Very common	Very common	Common
Hyperuricaemia	Common	Common	Very common
Gout	Common	Common	Very common
Weight decreased	Common	Common	Common
Psychiatric disorders
Confusional state	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
Paraesthesia	Common	Very common	Very common
Somnolence	Common	Common	Very common
Tremor	Common	Very common	Very common
Convulsions	Common	Common	Common
Dysgeusia	Uncommon	Uncommon	Common
Cardiac disorders
Tachycardia	Common	Very common	Very common
Vascular disorders
Hypertension	Very common	Very common	Very common
Hypotension	Common	Very common	Very common
Cystic lymphangioma	Uncommon	Uncommon	Uncommon
Venous thrombosis	Common	Common	Common
Vasodilation	Common	Common	Very common
Respiratory, thoracic and mediastinal disorders
Bronchiectasis	Uncommon	Uncommon	Uncommon
Cough	Very common	Very common	Very common
Dyspnoea	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
Appetite decreased	Common	Very common	Very common
Diarrhoea	Very common	Very common	Very common
Dyspepsia	Very common	Very common	Very common
Oesophagitis	Common	Common	Common
Eructation	Uncommon	Uncommon	Common
Flatulence	Common	Very common	Very common
Gastritis	Common	Common	Common
Gastrointestinal haemorrhage	Common	Common	Common
Gastrointestinal ulcer	Common	Common	Common
Gingival hyperplasia	Common	Common	Common
Intestinal obstruction	Common	Common	Common
Oral ulceration	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
Hypogammaglobulinaemia	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
Hyperbilirubinaemia	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
Haematuria	Very common	Common	Common
Renal function impairment	Common	Very common	Very common
General disorders
Asthenia	Very common	Very common	Very common
Cold-like symptoms	Common	Very common	Very common
Oedema	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

Note: 991 (2 g/3 g daily dose regimen), 289 (3 g daily dose regimen) and 277 (2 g IV/3 g oral daily dose regimen) patients were treated in Phase III studies for prevention of rejection in kidney, heart and liver transplantation, respectively.

Description of selected adverse reactions

Malignancies

Patients receiving immunosuppressive regimens, including combinations of drugs such as mycophenolate mofetil capsules, have an increased risk of developing lymphomas and other malignancies, particularly of the skin (see section "Special warnings and precautions for use"). Three-year safety data in kidney and heart transplant patients revealed no unexpected changes in malignancy incidence compared to year 1 data. Liver transplant patients were followed for at least 1 year but less than 3 years.

Infections

All patients receiving immunosuppressants are at increased risk of bacterial, viral, and fungal infections (some of which may be fatal), including those caused by opportunistic pathogens and latent viral reactivation. The risk increases with overall immunosuppressive burden (see section "Special warnings and precautions for use"). The most serious infections included sepsis, peritonitis, meningitis, endocarditis, tuberculosis, and atypical mycobacterial infection. The most common opportunistic infections in patients receiving mycophenolate mofetil capsules (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of kidney, heart, and liver transplant recipients followed for at least 1 year were mucocutaneous candidiasis, CMV viremia/syndrome, and herpes simplex. The incidence of CMV viremia/syndrome was 13.5%. Cases of BK virus-associated nephropathy and progressive multifocal leukoencephalopathy (PML) associated with JC virus have been reported in patients receiving immunosuppressive therapies, including mycophenolate mofetil capsules.

Blood and lymphatic system disorders

Cytopenias, including leukopenia, anemia, thrombocytopenia, and pancytopenia, are known risks associated with mycophenolate mofetil and may lead to or contribute to infections and hemorrhages (see section "Special warnings and precautions for use"). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients receiving mycophenolate mofetil capsules is recommended (see section "Special warnings and precautions for use"). Aplastic anemia and bone marrow failure have been reported in patients receiving mycophenolate mofetil capsules, some of which were fatal.

Cases of pure red cell aplasia (PRCA) have been reported in patients receiving mycophenolate mofetil capsules (see section "Special warnings and precautions for use").

Isolated cases of abnormal neutrophil morphology, including acquired Pelger-Huët anomaly, have been observed in patients receiving mycophenolate mofetil capsules. These changes are not associated with impaired neutrophil function. These morphological changes may indicate a "left shift" in neutrophil maturation on hematological examination, which may be misinterpreted as a sign of infection in immunocompromised patients, such as those receiving mycophenolate mofetil capsules.

Gastrointestinal disorders

The most serious gastrointestinal disorders were ulceration and bleeding, which are known risks associated with mycophenolate mofetil. Ulcers of the mouth, esophagus, stomach, duodenum, and intestine are often complicated by hemorrhage. Hematemesis, melena, and hemorrhagic forms of gastritis and colitis were also reported during key clinical trials. However, the most common gastrointestinal disorders were diarrhea, nausea, and vomiting. Endoscopic examination of patients with mycophenolate mofetil capsule-related diarrhea revealed isolated cases of intestinal villous atrophy (see section "Special warnings and precautions for use").

Hypersensitivity

Hypersensitivity reactions, including angioedema and anaphylactic reaction, have been reported.

Pregnancy, puerperium and perinatal conditions

Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil, primarily during the first trimester (see section "Use in pregnancy or lactation").

Congenital disorders

Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants (see section "Use in pregnancy or lactation").

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients receiving mycophenolate mofetil in combination with other immunosuppressants, some of which were fatal. 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

Edema, including peripheral, facial, and scrotal edema, was reported very commonly during main clinical studies. Musculoskeletal pain, such as myalgia, neck pain, and back pain, was also reported very commonly.

Special patient populations

Paediatric population

The type and frequency of adverse reactions in a clinical study involving 92 paediatric patients aged 2 to 18 years receiving 600 mg/m² mycophenolate mofetil orally twice daily were generally similar to those observed in adult patients receiving 1 g mycophenolate mofetil twice daily. However, treatment-related adverse events occurred more frequently in the paediatric population, especially in children under 6 years of age, compared to adults: diarrhea, sepsis, leukopenia, anemia, and infection.

Elderly patients

Elderly patients (≥ 65 years of age) generally have an increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination immunosuppressive regimen may have an increased risk of certain infections (including invasive cytomegalovirus tissue disease), and possibly gastrointestinal bleeding and pulmonary edema, compared to younger individuals.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 capsules in a blister pack, 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.