Myfortic^® (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Productions GmbH (Germany)

Or

Novartis Neva, LLC (Russia)

Packaging and Quality Control Release

NOVARTIS PHARMA PRODUCTIONS, GmbH (Germany)

Or

LEK PHARMACEUTICALS, d.d. (Slovenia)

Or

NOVARTIS NEVA, LLC (Russia)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

L04AA06 (Mycophenolic acid)

Active Substance

Mycophenolic acid (Rec.INN registered by WHO)

Dosage Forms

	Myfortic®	Gastro-resistant film-coated tablets, 180 mg: 50, 60, 100, 120 or 250 pcs.
		Gastro-resistant film-coated tablets, 360 mg: 50, 60, 100, 120 or 250 pcs.

Dosage Form, Packaging, and Composition

Gastro-resistant film-coated tablets light green in color, round, with beveled edges, printed with “C” on one side.

Excipients: anhydrous lactose – 45 mg, crospovidone (type A), povidone (K-30), corn starch, colloidal silicon dioxide, magnesium stearate; coating: hypromellose phthalate (HP50), titanium dioxide (E171), yellow iron oxide (E172), indigo carmine (E132).

10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
10 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (25) – cardboard packs.

Gastro-resistant film-coated tablets grayish-pink in color, oval in shape, printed with “CT” on one side.

Excipients: anhydrous lactose – 90 mg, crospovidone (type A), povidone (K-30), corn starch, colloidal silicon dioxide, magnesium stearate; coating: hypromellose phthalate (HP50), titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
10 pcs. – blisters (12) – cardboard packs.
10 pcs. – blisters (25) – cardboard packs.

The presence of primary opening control on the cardboard pack is allowed.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Mechanism of action

Mycophenolic acid (MPA) inhibits the synthesis of guanosine nucleotides by selectively suppressing the key enzyme of purine synthesis, inosine monophosphate dehydrogenase. Due to this mechanism, MPA effectively suppresses the proliferation of T- and B-lymphocytes, and to a much greater extent than other cells, since lymphocyte proliferation depends mainly on de novo purine synthesis.

The suppression of T- and B-lymphocyte proliferation by MPA complements the action of calcineurin inhibitors, which disrupt cytokine production and affect T-lymphocytes in the resting phase of the cell cycle.

Clinical efficacy and safety

Two multicenter randomized double-blind pivotal studies were used to approve the use of Myfortic^® (MPA) in adults. Both studies were clinical studies using the marketed drug CellCept^® (mycophenolate mofetil – MMF) as a comparator. Both studies demonstrated comparable efficacy and safety relative to MMF. The first study included 423 adult patients who underwent de novo kidney transplantation (ERLB301) and demonstrated that MPA is equivalent to MMF in efficacy, with a comparable safety profile. The second study was conducted in 322 renal transplant recipients on maintenance therapy (ERLB302) and demonstrated that renal transplant recipients receiving MMF in maintenance immunosuppressive therapy can be safely switched to MPA without loss of efficacy.

Adult de novo renal transplant recipients (study ERLB301)

A double-blind, randomized, double-dummy de novo clinical study (ERLB301) involving 423 renal transplant patients (MPA=213, MMF=210) aged 18-75 years was designed to prospectively evaluate the therapeutic equivalence of MPA and MMF by determining the failure rate (i.e., biopsy-proven acute rejection (BPAR), graft loss, death, or study discontinuation) during the first 6 months of treatment (primary endpoint) and the rate of death, graft loss, and study discontinuation at 12 months (combined primary endpoint).

Patients received either 1.44 g/day MPA or 2 g/day MMF within the first 48 hours after transplantation for 12 months in combination with cyclosporine and corticosteroids. In the MPA and MMF groups, 39.4% and 42.9%, respectively, received antibody therapy as induction therapy.

Therapeutic equivalence was demonstrated based on the failure rate over 6 months (MPA 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]). At 12 months, the rate of BPAR, graft loss, or death was 26.3% and 28.1% and BPAR alone was 22.5% and 24.3% for MPA and MMF, respectively. Among patients with BPAR, the rate of severe acute rejection was 2.1% with MPA and 9.8% with MMF (p=ns).

Table 1. Analysis of the primary efficacy endpoint and its components over 6 and 12 months (study ERLB301)

* Study discontinuations include patients who discontinued the study without biopsy-proven acute rejection, graft loss, or death. Criteria for therapeutic equivalence were met: 95% CI for differences in the rate of the primary variable (BRAP, graft loss, death or study discontinuation within 6 months) fully included the interval (-12%, 12%).

The overall safety profile and hematological profiles were similar between the two treatment groups. Adverse events potentially related to the drug were 51.1% and 60.5% in the MPA and MMF groups, respectively. There were no differences in the overall rate of infection. The overall rate of serious infections was 22.1% in the MPA group and 27.1% in the MMF group. The incidence of severe pneumonia was lower in the MPA group (0.5% vs. 4.3%, p=0.01). There were no differences in the overall rate of gastrointestinal adverse reactions (80.8% vs. 80%, p=ns, MPA vs. MMF, respectively).

Adult renal transplant patients on maintenance therapy (study ERLB302)

A maintenance therapy study was conducted with 322 renal transplant patients (MPA=159, MMF=163) aged 18-75 years who had received 2 g/day MMF in combination with cyclosporine with or without corticosteroids for at least 4 weeks prior to study start within the last 6 months post-transplantation. Patients were randomized 1:1 to groups receiving 1.44 g/day MPA or 2 g/day MMF for 12 months. The efficacy endpoint was the failure rate (i.e., BPAR, graft loss, or death) at 6 and 12 months.

Over 12 months, similar rates of failure (MPA 2.5%; MMF 6.1%; p=ns), biopsy-proven acute rejection (MPA 1.3%; MMF 3.1%; p=ns) and biopsy-proven chronic rejection (MPA 3.8%; MMF 4.9%; p=ns) were found in both groups.

Table 2. Secondary efficacy endpoints (study ERLB302)

* Study discontinuations include patients who discontinued the study without biopsy-proven acute rejection, graft loss, or death.

The maintenance therapy study also demonstrated an overall similar safety profile except for cases of serious infections (8.8 vs. 16%; p<0.05, MPA vs. MMF). The overall rate of infections was 59% in each group. The MPA group had a lower incidence of pneumonia (1.9%) compared to the MMF group (4.9%), which was not statistically significant. A similar frequency of overall gastrointestinal adverse events was noted (69.2% vs. 61.8%, MPA vs. MMF), although the number of any gastrointestinal adverse reactions was higher in the group of patients taking MPA over 12 months (29.6 vs. 24.5% at the end of the period equal to 12 months), and the increase in severity of gastrointestinal adverse reactions was lower in patients with MPA.

Preclinical safety data

Carcinogenicity, mutagenicity, impairment of fertility

In a carcinogenicity study with oral administration of mycophenolate sodium to rats daily at a dose of 9 mg/kg body weight for 104 weeks, no tumor occurrence was detected. The highest tested dose resulted in approximately 0.6-1.2-fold systemic exposure compared to exposure in renal transplant patients at the recommended dose of 1.44 g/day. Similar results were observed in a parallel study in rats administered mycophenolate mofetil. In a 26-week carcinogenicity study in the P53± (heterozygous) transgenic mouse model, administered mycophenolate sodium orally daily at doses up to 200 mg/kg body weight, no tumor occurrence was noted. The highest tested dose was 200 mg/kg body weight, resulting in approximately 5-fold systemic exposure compared to exposure in renal transplant patients (at a dose of 1.44 g/day).

The genotoxic potential of mycophenolate sodium was determined in five studies. MPA was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in Chinese hamster V79 cells, and the in vivo mouse micronucleus assay. Mycophenolate sodium did not show genotoxicity in the bacterial mutation assay or the chromosomal aberration assay in human lymphocytes. The lowest dose showing genotoxic properties in the mouse bone marrow micronucleus assay was approximately 3 times the systemic exposure (AUC or C_max) in renal transplant patients at the tested clinical dose of Myfortic^® of 1.44 g/day. The observed mutagenic activity was likely associated with a change in the relative excess of nucleotides in the cellular pool used in DNA synthesis.

Mycophenolate sodium had no effect on fertility in male rats when administered orally at doses up to 40 mg/kg/day. Systemic exposure at this dose is approximately 9 times the clinical exposure when using Myfortic^® at a clinical dose of 1.44 g/day. No effects on female fertility were noted at a dose of 20 mg/kg, at which maternal toxicity and embryotoxicity were already observed.

Pharmacology and repeated dose toxicity studies in animals

The hematopoietic and lymphoid systems were the primary organs affected in toxicological studies with mycophenolate sodium administration in rats and mice. Aplastic, regenerative anemia was identified as the dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a significant decrease in the number of erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent increase in spleen size with enhanced extramedullary hematopoiesis. These effects were observed at systemic exposures that were equal to or lower than the clinical exposure at the recommended dose of Myfortic^® 1.44 g/day in renal transplant patients.

The toxicity profile of mycophenolate sodium, established in preclinical studies, is consistent with adverse events in humans exposed to MPA, which now provide safety data more relevant to the patient population (see section “Adverse Reactions”).

Single administration of MPA was moderately well tolerated in rats (LD50 is from 350 to 700 mg/kg), well tolerated in mice and monkeys (LD50 greater than 1000 mg/kg), and very well tolerated in rabbits (LD50 greater than 6000 mg/kg).

Reproductive toxicity

In a teratogenicity study conducted with mycophenolate sodium in rats at a dose of less than 1 mg/kg, malformations were observed in the offspring, including anophthalmia, exencephaly, and umbilical hernia. Systemic exposure at this dosage represents 0.05-fold the clinical exposure at a dose of 1.44 g/day of Myfortic^® (see section “Pregnancy and Lactation”). In pre- and postnatal development studies in rats, MPA (as the sodium salt) caused developmental delays (abnormal pupillary reflex in females and separation of the prepuce in males) at the highest dose of 3 mg/kg.

Pharmacokinetics

Absorption

After oral administration, mycophenolate sodium is intensively absorbed. Due to the presence of an enteric film coating, the C_max of MPA is reached in approximately 1.5-2 hours. In vitro studies have shown that the specific composition of the enteric film-coated preparation Myfortic^® prevents the release of MPA in an acidic environment similar to the acidic environment of the stomach.

In patients with a stably functioning renal transplant receiving basic immunosuppressive therapy with cyclosporine in microemulsion form, the extent of MPA absorption from the gastrointestinal tract is 93%, and the absolute bioavailability is 72%. In the dose range from 180 mg to 2160 mg, the pharmacokinetics of Myfortic^® are linear and dose-dependent. The AUC value when taking Myfortic^® on an empty stomach did not differ from that when taking the drug with a high-fat meal (55 g fat, 1000 calories). However, the C_max of MPA decreases by 33%.

Distribution

The V_d of MPA at steady state is 50 L. Both MPA and MPAG (MPA glucuronide) are highly bound to plasma proteins – 97% and 82%, respectively. With a decrease in the number of protein binding sites (in uremia, hepatic insufficiency, hypoalbuminemia, simultaneous use of drugs with high plasma protein binding), an increase in the concentration of free MPA in plasma is possible.

Metabolism

MPA is predominantly metabolized with the participation of glucuronyltransferase to form the main pharmacologically inactive metabolite, phenolic glucuronide of MPA (MPAG). In patients with a stably functioning renal transplant receiving basic immunosuppressive therapy with cyclosporine in microemulsion form, about 28% of the oral dose of MPA is metabolized to MPAG during the “first pass” through the liver.

Elimination

The T_1/2 of MPA is 11.7 hours, clearance is 8.6 L/h. MPA is excreted mainly in the urine as MPAG, and a small amount (<1%) is excreted unchanged. The T_1/2 of MPAG is 15.7 hours, clearance is 0.45 L/h. MPAG is also secreted with bile into the intestine, where it is broken down (by deconjugation) by the intestinal flora. The MPA resulting from this breakdown can then be reabsorbed. A second peak in MPA concentration is observed 6-8 hours after taking Myfortic^®, which corresponds to the reabsorption of deconjugated MPA.

Pharmacokinetics in patients who have undergone kidney transplantation and are receiving basic immunosuppressive therapy with cyclosporine in microemulsion form

Table 3 presents the mean values of the pharmacokinetic parameters of MPA after taking Myfortic^®. The values of the pharmacokinetic parameters of MPA after a single dose can predict the possible values of these parameters with repeated and long-term use. The mean AUC and C_max values of MPA, measured in the early post-transplant period, were approximately 50% of the values determined 6 months after transplantation.

Table 3. Mean (SD) pharmacokinetic parameters of MPA after oral administration of Myfortic^® in patients who have undergone kidney transplantation and are receiving basic immunosuppressive therapy with cyclosporine in microemulsion form

Abbreviations used in the table

C_max – maximum plasma concentration;

T_max – time to reach maximum plasma concentration;

AUC – area under the concentration-time curve;

SD – standard deviation.

Pharmacokinetics in special patient groups

Patients with impaired renal function. The pharmacokinetics of MPA are independent of renal function. The AUC of MPAG in renal impairment, on the contrary, increases; for example, in anuric patients, MPAG AUC values are approximately 8 times higher. Hemodialysis does not affect the clearance of MPA and MPAG. In renal failure, the concentration of free MPA in plasma may increase significantly, which is probably due to reduced binding of MPA to proteins under conditions of high blood urea concentration.

Patients with impaired hepatic function. In patients with alcoholic liver cirrhosis, no influence of this disease on the glucuronidation reactions of MPA was noted. The presence or absence of an effect of liver disease on the pharmacokinetics of MPA may depend on the nature of the disease (predominant parenchymal damage, or biliary system damage, or other).

Gender. No clinically significant differences in pharmacokinetic parameters depending on patient gender were found.

Elderly patients. Based on preliminary study data, it is assumed that MPA concentration does not change clinically significantly with age.

Children

Experience with Myfortic^® in children is limited. Table 3 shows the mean pharmacokinetic parameters in children with stable kidney transplants receiving cyclosporine microemulsion as immunosuppressive therapy. C_max and AUC values for MPA in children were characterized by greater variability compared to adult patients. When taking the usual single dose of Myfortic^® 720 mg in children, the MPA AUC was higher than the corresponding value in adults. The mean MPA clearance was about 7.7 L/h. It is expected that at a Myfortic^® dose of 200-300 mg/m², the MPA AUC will be between 30 and 50 µg×h/ml.

Indications

Adults

• Prevention of acute transplant rejection in patients with allogeneic kidney transplants receiving basic immunosuppressive therapy with cyclosporine in microemulsion form and glucocorticosteroids.

ICD codes

Dosage Regimen

Orally, the tablets should be swallowed whole, without chewing; tablets should not be broken. Myfortic^® can be taken on an empty stomach or with food.

Treatment with Myfortic^® should be carried out by qualified transplant physicians.

Treatment with Myfortic^® in patients who have not received it before is started within the first 48 hours after transplantation. The recommended dose is 720 mg (4 enteric-coated tablets of 180 mg or 2 tablets of 360 mg) twice daily (total daily dose 1440 mg).

In patients previously receiving mycophenolate mofetil (MMF) at a daily dose of 2 g, mycophenolate mofetil can be replaced with Myfortic^® at a dose of 720 mg twice daily (total daily dose 1440 mg).

Special patient groups

Elderly patients

No dose adjustment is required in elderly patients.

Patients with impaired renal function

In patients with delayed postoperative recovery of renal transplant function, no dose adjustment of Myfortic^® is required. Close monitoring is necessary for patients with chronic severe renal impairment (GFR less than 25 ml×min^-1×1.73 m^-2).

Patients with impaired hepatic function

In patients with severe liver disease associated with predominant parenchymal damage, no dose adjustment of Myfortic^® is required.

Episodes of rejection reaction

Transplant rejection reaction does not affect the pharmacokinetics of MPA. In these cases, no changes in the dosing regimen are required.

Children

The efficacy and safety of Myfortic^® in children aged 0 to 18 years have not been studied. There are limited data on the pharmacokinetics of MPA in children who have undergone kidney transplantation (see section “Pharmacokinetics”). Currently, specific recommendations for the dosing regimen in children have not been developed.

Adverse Reactions

Summary of the safety profile

The following adverse events were observed during two safety studies of Myfortic^® and mycophenolate mofetil in 423 patients with a recently transplanted kidney, not previously receiving maintenance therapy (de novo renal transplant patients), and in 322 patients with a transplanted kidney previously receiving maintenance therapy. The frequency of adverse events was the same in both patient groups.

When using Myfortic^® in combination with cyclosporine and corticosteroids, adverse events such as leukopenia (19.2%) and diarrhea (23.5%) were observed very often (≥10%).

In elderly patients, the risk of adverse events of immunosuppression in general may be higher. In clinical trials in elderly patients receiving Myfortic^® as a component of combination immunosuppression, no higher risk of adverse reactions was identified compared to younger patients.

Description of selected adverse reactions

Malignant neoplasms

Patients receiving immunosuppressive therapy with multiple drugs, including MPA, have an increased risk of developing lymphomas and other neoplasms, particularly of the skin. During the studies, malignant neoplasms developed while taking Myfortic^® with the following frequency: lymphoproliferative disorders or lymphomas developed in two de novo renal transplant patients (0.9%) and in two patients (1.3%) with a transplanted kidney receiving maintenance therapy over a period of up to 1 year; non-melanoma skin carcinomas developed in 0.9% of de novo renal transplant patients and in 1.8% of patients with a transplanted kidney previously receiving maintenance therapy with Myfortic^® over a period of up to 1 year; other malignant neoplasms developed in 0.5% of de novo renal transplant patients and in 0.6% of patients with a transplanted kidney receiving maintenance therapy.

Infectious diseases (opportunistic infections)

In patients with a recently transplanted kidney receiving Myfortic^® as part of complex immunosuppressive therapy for 1 year, cytomegalovirus (CMV) infection, candidiasis, and herpes simplex virus infection were most frequently reported. During the studies, it was shown that CMV infection (serologically confirmed viremia or clinical data) was noted with a frequency of 21.6% in patients with a recently transplanted kidney and 1.9% in patients with a stably functioning transplant on long-term maintenance therapy.

Other adverse events

Below are the adverse events identified while taking Myfortic^® at a dose of 1440 mg/day for 12 months in combination with cyclosporine microemulsion and corticosteroids during two clinical studies in de novo renal transplant patients and in patients with a transplanted kidney previously receiving maintenance therapy. These events had a possible or probable causal relationship with taking Myfortic^®.

Adverse drug reactions are presented according to the MedDRA classification by system organ class and listed by frequency. The frequency of adverse reactions is assessed as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000, including isolated reports).

Infections and infestations: very common – viral, bacterial and fungal infections (up to 22.1%), such as urinary tract infections, herpes zoster, oral candidiasis, sinusitis, gastroenteritis, herpes simplex, nasopharyngitis; common – upper respiratory tract infections, pneumonia; uncommon – wound infections; Isolated cases of sepsis and osteomyelitis were noted.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – lymphoproliferative disorders. Isolated cases of skin papilloma, basal cell carcinoma, Kaposi’s sarcoma, squamous cell carcinoma* were noted.

Blood and lymphatic system disorders very common – leukopenia (19.2%); common – anemia, thrombocytopenia; isolated cases of lymphocele, lymphopenia, neutropenia were noted.

Metabolism and nutrition disorders very common – hypocalcemia, hypokalemia, hyperuricemia; common – hyperkalemia, hypomagnesemia; uncommon – loss of appetite, hyperlipidemia, hypophosphatemia; isolated cases of diabetes mellitus, hypercholesterolemia were noted.

Psychiatric disorders common – anxiety; isolated cases of delusional perception were noted.

Nervous system disorders: common – dizziness, headache; uncommon – tremor; isolated cases of insomnia were noted.

Eye disorders isolated cases of conjunctivitis, blurred vision were noted.

Cardiac disorders: uncommon – tachycardia; isolated cases of pulmonary edema and ventricular extrasystoles were noted.

Vascular disorders very common – increased blood pressure; common – increased severity of arterial hypertension, decreased blood pressure.

Respiratory, thoracic and mediastinal disorders: common – cough, dyspnea, exertional dyspnea; uncommon – interstitial lung disease, incl. pulmonary fibrosis with fatal outcome; isolated cases of “congested” lung, stridor were noted.

Gastrointestinal disorders: very common – diarrhea (23.5%); common – abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, loose stools, nausea, vomiting; uncommon – abdominal wall tension, pancreatitis, belching, gastrointestinal bleeding; isolated cases of halitosis (bad breath), intestinal obstruction, esophagitis, peptic ulcer, subileus, dry mouth, lip ulceration, blockage of the parotid salivary gland duct, gastroesophageal reflux disease, gingival hyperplasia, peritonitis were noted.

Hepatobiliary disorders common – abnormal liver function test results.

Skin and subcutaneous tissue disorders: uncommon – alopecia, bruising, acne; rare – skin rash.

General disorders: common – fatigue, pyrexia; sometimes – influenza-like illness, lower limb edema*, pain, tremor*, thirst*, weakness*.

Musculoskeletal and connective tissue disorders: common – arthralgia, asthenia, myalgia; uncommon – muscle cramps; isolated cases of back pain and arthritis were noted.

Renal and urinary disorders: common – increased blood creatinine level; uncommon – urethral stricture; isolated cases of hematuria, renal tubular necrosis were noted.

General disorders and administration site conditions common – increased fatigue, pyrexia; uncommon – influenza-like illness, peripheral edema, pain; isolated cases of lower limb edema, chills, weakness were noted.

Adverse effects observed with the use of MPA derivatives (“class effects”) colitis, esophagitis (including CMV colitis and CMV esophagitis), CMV gastritis, pancreatitis, intestinal wall perforation, gastrointestinal bleeding, gastric and/or duodenal ulcer, severe intestinal infection, sometimes life-threatening infectious diseases, including meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infections, polyomavirus nephropathy, especially associated with BK virus, cases of progressive multifocal leukoencephalopathy, in some cases with fatal outcome, agranulocytosis, neutropenia, pancytopenia. When using MPA derivatives in combination with other immunosuppressants, cases of partial red cell aplasia of the bone marrow have been reported.

Post-marketing data

Congenital anomalies

Congenital anomalies have been reported in children of female patients taking MMF in combination with other immunosuppressive drugs.

Pregnancy, postpartum period, perinatal period

In female patients receiving mycophenolate mofetil, cases of spontaneous abortions, mainly in the first trimester of pregnancy, have been noted.

General disorders and administration site conditions

Based on spontaneous reports and literature data in the post-marketing period of Myfortic^® use, the adverse drug reaction “acute inflammatory syndrome associated with de novo purine synthesis” has been identified. It is impossible to accurately determine its frequency, as the reports are spontaneous and the population is undefined, so in this case the frequency is classified as “unknown”.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil or to any excipients included in the drug;
• Pregnancy due to the mutagenic and teratogenic effects of the drug;
• Women with preserved reproductive potential not using highly effective methods of contraception;
• Period of breastfeeding.

Use in Pregnancy and Lactation

Women of childbearing potential (contraception in men and women)

The use of the drug during pregnancy and in women with preserved reproductive potential not using highly effective methods of contraception (where the probability of pregnancy is less than 1%) is contraindicated (see section “Contraindications”).

Women and men with preserved reproductive potential should be informed about the increased risk of miscarriage and congenital anomalies and instructed on pregnancy prevention and planning before starting the drug.

Before starting therapy with Myfortic^®, 2 negative pregnancy test results (beta-hCG in plasma or urine) with a sensitivity of at least 25 mIU/ml should be obtained. The second test should be performed 8-10 days after the first, immediately before starting therapy with Myfortic^®. Pregnancy tests should also be repeated at follow-up visits. The results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult a doctor immediately if pregnancy is suspected.

Before starting therapy with Myfortic^®, throughout the entire therapy and for 6 weeks after its completion, women with preserved reproductive potential should use 2 reliable methods of contraception, considering the mutagenic and teratogenic potential of Myfortic^®, including at least 1 highly effective method, provided that sexual abstinence is not chosen as a method of contraception.

Male patients who are sexually active are recommended to use a condom during therapy with the drug and for at least 90 days after taking the last dose. In this regard, they should be warned and have the opportunity to discuss with a qualified specialist the potential risks when conceiving a child or donating sperm. This recommendation applies both to men with preserved reproductive potential and to men after vasectomy, as men after vasectomy still have a risk of semen transmission. Female partners of men taking Myfortic^® are recommended to use a highly effective method of contraception during therapy and for at least 90 days after taking the last dose.

Pregnancy

The use of Myfortic^® during pregnancy is associated with an increased risk of spontaneous abortion and congenital anomalies. Although controlled clinical studies on the use of Myfortic^® in pregnant women have not been conducted, in the post-marketing period with the use of mycophenolate mofetil in combination with other immunosuppressants during pregnancy, an increased frequency of congenital malformations, including multiple ones, was noted. The following anomalies were most frequently observed in children when mycophenolate mofetil was used during pregnancy

• Malformations of the facial skull: cleft lip, cleft palate, micrognathia (underdevelopment of the jaw), ocular hypertelorism;
• Development of the ear (for example, unusual shape or absence of the inner/outer ear), and the eye (for example, coloboma, microphthalmia);
• Finger malformations (for example, polydactyly, syndactyly, brachydactyly);
• Cardiac anomalies, such as atrial and ventricular septal defects;
• Esophageal malformations (for example, esophageal atresia);
• CNS malformations, for example, spina bifida.

According to the literature, after the use of mycophenolate mofetil during pregnancy, the risk of these phenomena is 45-49% compared to a risk of 12-33% in patients receiving other immunosuppressive drugs for solid organ transplantation.

Since mycophenolate mofetil is converted to MPA after oral or intravenous administration, all the information presented above must be taken into account when using the drug Myfortic^®.

A teratogenic effect of MPA was observed in animal studies. Reproductive toxicity/teratogenic effects of mycophenolate mofetil were identified in studies in rats and rabbits. (see the subsection “Preclinical Safety Data”).

Breastfeeding period

The use of the drug during breastfeeding is contraindicated due to the risk of serious adverse reactions in breastfed infants (see section “Contraindications”). There are no data on the effect of the drug Myfortic^® on the breastfed child or on milk production. Studies in rats have shown that MMF passes into breast milk. It is not known whether MPA is excreted in human breast milk. Due to the potential risk of serious adverse events in the breastfed child, a decision should be made either to discontinue the use of the drug Myfortic^®, or, taking into account the importance of therapy with this drug for the mother, to discontinue breastfeeding throughout the therapy and for 6 weeks after its discontinuation.

Infertility

There are no data on the effect of the drug Myfortic^® on human fertility. Mycophenolate sodium did not affect fertility in female and male rats when administered orally at doses up to 40 mg/kg/day and 20 mg/kg/day, respectively, which, when converted, are higher than the exposure at the maximum recommended human clinical dose (1440 mg/day) by 9 and 4.5 times.

Use in Hepatic Impairment

In patients with severe liver disease associated with predominant parenchymal damage, no dose adjustment of the drug Myfortic^® is required.

Use in Renal Impairment

Close monitoring of patients with chronic severe renal impairment (GFR less than 25 ml×min^-1×1.73 m^-2) is necessary.

Pediatric Use

The efficacy and safety of the drug Myfortic^® in children aged 0 to 18 years have not been studied. Currently, specific recommendations for the dosing regimen in children have not been developed.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

MPA is an inhibitor of IMPDH (inosine monophosphate dehydrogenase). The drug Myfortic^® should not be used in patients with a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), observed in patients with rare Lesch-Nyhan and Kelley-Seegmiller syndromes.

Women of childbearing potential, pregnancy and breastfeeding

The use of the drug Myfortic^® is associated with an increased risk of pregnancy loss, including spontaneous abortion and congenital malformations. Therapy with the drug Myfortic^® should not be initiated in women of childbearing potential until a negative pregnancy test is obtained (see section “Pregnancy and Lactation”).

The drug Myfortic^® is contraindicated during pregnancy and breastfeeding (see sections “Contraindications”, “Pregnancy and Lactation”).

Malignancies

Patients receiving combined immunosuppressive therapy, including the drug Myfortic^®, especially with long-term use and high doses, have an increased risk of developing lymphomas and other malignancies, especially of the skin. There are data on the genotoxic effect of the drug Myfortic^®. This risk is most likely not associated with the use of the drug, but with the intensity and duration of immunosuppressive therapy. To reduce exposure to sunlight and ultraviolet radiation in order to reduce the risk of skin cancer, it is recommended to protect the skin with clothing and use sunscreens with a high protection factor.

Infections

Excessive immunosuppression increases the likelihood of developing infections, including opportunistic ones, as well as sepsis and fatal infections.

In patients receiving immunosuppressive therapy with MPA derivatives, including the drug Myfortic^® and mycophenolate mofetil, reactivation of hepatitis B and C virus infection has been observed. In infected patients, clinical symptoms and laboratory parameters of the infectious process activity should be monitored.

In patients treated with MPA derivatives, including the drug Myfortic^® and mycophenolate mofetil, cases of progressive multifocal leukoencephalopathy (PML) associated with the JC virus, in some cases with a fatal outcome, have been reported. Cases of PML during treatment with MPA derivatives (mycophenolate mofetil and mycophenolate sodium) were noted mainly in patients with risk factors for PML, including therapy with immunosuppressive drugs and immune disorders. Physicians should consider the possibility of PML during therapy with the drug in immunocompromised patients and, if necessary, refer patients with neurological disorders for consultation with a neurologist.

The development of polyomavirus-associated nephropathy, especially associated with the BK virus, should be taken into account in the differential diagnosis of the causes of renal function impairment in patients receiving immunosuppressive therapy. If PML or polyomavirus-associated nephropathy develops, the physician should consider the possibility of reducing the intensity of immunosuppressive therapy. However, in transplant patients, reducing immunosuppression may increase the risk of transplant rejection.

In patients receiving therapy with the drug Myfortic^®, the development of neutropenia cannot be ruled out, due to both the effect of MPA itself and concomitant drugs, viral infections, or a combination of these factors.

Changes in blood tests

In patients receiving the drug Myfortic^®, a complete blood count should be performed regularly (to detect neutropenia or anemia): during the first month of therapy – weekly, during the second and third months – twice a month, then, during the first year – once a month. If neutropenia develops (absolute neutrophil count <1.5×10³/mm³) or anemia, it is advisable to interrupt or discontinue therapy with the drug Myfortic^®.

When using MPA derivatives (mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants, cases of partial bone marrow aplasia have been reported. The mechanism of development of partial red cell aplasia of the bone marrow during therapy with MPA derivatives, as well as the role of other immunosuppressants and their combinations, is currently unknown. However, it should be taken into account that MPA derivatives can cause neutropenia and anemia. In a number of cases, when the dose was reduced or therapy with MPA derivatives was discontinued, normalization of the patients’ condition was noted. Changing the dosing regimen of the drug Myfortic^® should be carried out only under proper monitoring of the patient’s condition to reduce the risk of transplant rejection. Patients should be informed of the need to immediately inform the doctor of all signs of infection, bruising and bleeding for no apparent reason, or any other signs of bone marrow suppression.

Vaccination

Patients should be warned that during therapy with MPA derivatives, vaccination may be less effective and that the use of live attenuated vaccines should be avoided. Influenza vaccination should be carried out in accordance with the recommendations of local health authorities regarding influenza vaccination.

Gastrointestinal disorders

Since taking the drug Myfortic^® may be accompanied by adverse reactions from the gastrointestinal tract (ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, gastrointestinal perforations), caution should be exercised when using it in patients with severe diseases of the digestive tract in the acute phase.

Combination with other drugs

The drug Myfortic^® has been used in combination with the following drugs: antithymocyte globulin, basiliximab, cyclosporine (in microemulsion form) and glucocorticoids. The efficacy and safety of the drug Myfortic^® when used with other immunosuppressive drugs have not been studied.

Excipients

The drug Myfortic^® contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take the drug Myfortic^®.

Effect on the ability to drive vehicles and mechanisms

The effect of taking the drug Myfortic^® on the ability to drive a car and work with mechanisms has not been established. The mechanism of action of the drug Myfortic^®, its pharmacodynamic effects and registered adverse events indicate a low likelihood of such an effect. Nevertheless, patients should be warned about possible adverse events of the drug and the need for caution when performing work requiring concentration.

Overdose

Reports have been received of intentional and unintentional overdose of the drug Myfortic^®; in these cases, expected adverse events were not observed in all patients.

Symptoms

With an overdose of the drug Myfortic^®, signs of hyperimmunosuppression and increased susceptibility to various infections, including opportunistic ones, leading to death and sepsis, may occur. The need to interrupt therapy should be considered if blood dyscrasia develops (for example, neutropenia with an absolute neutrophil count <1.5×10³/µl or anemia).

Treatment

Although the inactive metabolite MPAG is removed by hemodialysis, this method is not expected to effectively remove clinically significant amounts of active MPA. This is largely due to the high degree (97%) of MPA binding to plasma proteins. Cholestyramine and other bile acid sequestrants interfere with the absorption of MPA from the intestine and, therefore, can lead to a decrease in its blood concentration.

Drug Interactions

Azathioprine

Since no specific studies of the interaction of the drug Myfortic^® and azathioprine have been conducted, these drugs should not be prescribed simultaneously.

Live vaccines

Live vaccines should not be used in patients with an impaired immune response. When using other vaccines, antibody production may be reduced.

Acyclovir

In patients with impaired renal function, the blood concentrations of both MPAG and acyclovir may increase. Possibly, both drugs compete during elimination from the body (similar elimination pathway – tubular secretion). Such patients require careful monitoring.

Antiulcer drugs (including antacids and proton pump inhibitors)

Antacids containing magnesium and aluminum hydroxide. When used concomitantly with antacids, the absorption of mycophenolate sodium is reduced, resulting in a 37% decrease in MPA AUC and a 25% decrease in C_max. Caution should be exercised when using the drug Myfortic^® concomitantly with antacids containing magnesium and aluminum hydroxide.

Proton pump inhibitors. In healthy volunteers, with the combined use of mycophenolate mofetil at a dose of 1000 mg and pantoprazole at a dose of 40 mg twice/day, a decrease in MPA AUC and C_max by 27% and 57%, respectively, was noted. However, when using the drug Myfortic^® together with pantoprazole in these patients, no change in the pharmacokinetic parameters of MPA was observed.

Cholestyramine and drugs affecting enterohepatic circulation

Due to its ability to bind bile acids in the intestine, cholestyramine may reduce MPA blood concentration and AUC. Due to the possible decrease in the effectiveness of the drug Myfortic^®, caution should be exercised when using it concomitantly with cholestyramine and drugs affecting enterohepatic circulation.

Ganciclovir

The addition of ganciclovir does not affect the pharmacokinetics of MPA and MPAG. When therapeutic concentration of MPA is achieved, the clearance of ganciclovir does not change.

However, with the simultaneous use of the drug Myfortic^® and ganciclovir, patients with impaired renal function may require adjustment of the ganciclovir dosing regimen. Patients receiving simultaneous therapy with MPA drugs and ganciclovir should be carefully monitored.

Tacrolimus

In patients with a stable kidney transplant, a crossover study investigated the steady-state pharmacokinetics of the drug Myfortic^® when used concomitantly with cyclosporine and tacrolimus. The mean MPA AUC values when taking the drug Myfortic^® concomitantly with tacrolimus were 19% higher than when taking the drug Myfortic^® concomitantly with cyclosporine, and the MPA C_max values were 20% lower. For MPAG, the AUC and C_max values were 30% lower when taking the drug Myfortic^® with tacrolimus than when taking the drug Myfortic^® with cyclosporine.

Oral contraceptives

Oral contraceptives are metabolized through oxidation reactions, while the drug Myfortic^® is metabolized through glucuronidation. The effect of oral contraceptives on the pharmacokinetics of the drug Myfortic^® is unlikely, and therefore, no clinically significant interactions are to be expected. On the other hand, taking into account the fact that the effect of long-term therapy with the drug Myfortic^® on the pharmacokinetics of oral contraceptives has not yet been studied, the possibility of reduced contraceptive effectiveness cannot be ruled out.

Cyclosporine

Studies in patients with stable renal transplants have shown that the pharmacokinetics of cyclosporine did not change against the background of steady-state concentrations of the drug Myfortic^®.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 36 months. The drug should not be used after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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