Myfortic

Each gastro-resistant tablet contains 360 mg mycophenolic acid (MPA) equivalent to 384.8 mg mycophenolate sodium.
Excipients/Inactive Ingredients: Maize starch; povidone (K-30); crospovidone; lactose; colloidal silicon dioxide; magnesium stearate.
The gastro-resistant tablet coating consists of hypromellose phthalate/hydroxypropylmethylcellulose phthalate; titanium dioxide; yellow iron oxide; red iron oxide.

Pharmacotherapeutic group: immunosuppressant. (ATC code: L04 A A06).
Pharmacology: Mechanism of Action: MPA inhibits the proliferation of T- and B lymphocytes more potently than other cells because in contrast to other cell types that can utilize purine salvage pathways the lymphocyte proliferation is critically dependent on de novo synthesis. Thus the mode of action is complementary to calcineurin inhibitors which interfere with cytokine transcription and resting T-lymphocytes.
Clinical Studies: Two multi-center randomized, double-blind pivotal trials were used for mycophenolic acid (MPA) approval in adults. Both studies were reference therapy-controlled clinical studies using commercially marketed MMF (Cellcept) as the comparator. Both studies demonstrated comparable efficacy and safety to MMF. The first study included 423 adult de novo renal transplants (ERLB301) and demonstrated that MPA was equivalent to MMF in efficacy and had a comparable safety profile. The second study was conducted in 322 maintenance kidney transplant recipients (ERLB302) and demonstrated that renal transplant patients receiving MMF maintenance immunosuppressive therapy could be safely converted to MPA without compromising efficacy.
De novo adult renal transplant patients (study ERL B301): The double-blind, double-dummy randomized de novo study (ERLB301) was conducted in 423 renal transplant patients (MPA=213, MMF=210), aged 18-75 years, and was designed prospectively to test therapeutic equivalence of MPA to MMF as measured by the incidence of efficacy failure (i.e., biopsy proven acute rejection (BPAR), graft loss, death or loss to follow up) within the first 6 months of treatment (primary endpoint) and by the incidence of death, graft loss or loss to follow-up at 12 months (co-primary endpoint).
Patients were administered either MPA 1.44 g/day or MMF 2 g/day within 48 hours post-transplant 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 an induction treatment.
Based on the incidence of efficacy failure at 6 months (MPA 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) therapeutic equivalence was demonstrated. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and incidence of BPAR alone was 22.5% and 24.3% for MPA and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with MPA and 9.8% with MMF (p=ns). (See Table 1.)

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The overall safety and hematologic profiles were similar between the two treatment groups. Drug-suspected AEs were 51.1% and 60.5% in the MPA vs. MMF groups, respectively. No difference in overall incidence of infection was observed. The overall incidence of serious infections was 22.1% in the MPA group and 27.1% in the MMF group. The incidence of serious pneumonia was lower in the MPA group (0.5% vs 4.3%, p=0.01). No difference in the overall incidence of GI AEs was observed (80.8% vs. 80%, p=ns, MPA vs. MMF, respectively).
Maintenance adult renal transplant patients (study ERL B302): The maintenance study was conducted in 322 renal transplant patients (MPA=159, MMF=163), aged 18 to 75 years, who were at least 6 months post-transplant receiving 2 g/day MMF in combination with cyclosporine, with or without corticosteroids for at least four weeks prior to entry in the study. Patients were randomized 1:1 to MPA 1.44 g/day or MMF 2 g/day for 12 months. The efficacy endpoint was the incidence of efficacy failure (i.e., BPAR, graft loss, or death) at 6 and 12 months.
At 12 months, similar rates of efficacy 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 observed in both groups. (See Table 2.)

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The maintenance study also demonstrated an overall similar safety profile, with the exception of the incidence of serious infections (8.8 vs 16%, p<0.05, MPA vs. MMF). The incidence of overall infections was 59% in each group. Less pneumonia was observed in the MPA group (1.9%) than the MMF group (4.9%), but it was not statistically significant. A similar incidence of overall GI AEs was observed (69.2 vs 61.8%, MPA vs. MMF), although "any GI AE" was numerically higher in the MPA-treated patients up to 12 months (29.6% vs. 24.5% at month 12), and the increase in GI severity tended to be lower in MPA patients.
Pharmacokinetics: Absorption: Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal MPA concentration was approximately 1.5 to 2 hours. In vitro studies demonstrated that the enteric coated mycophenolic acid (Myfortic) formulation -prevents the release of MPA under acidic conditions as in the stomach.
In stable renal transplant patients on ciclosporin for microemulsion based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Mycophenolic acid pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2,160 mg. Compared to the fasting state, administration of 720 mg mycophenolic acid (Myfortic) with a high fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC) which is the most relevant PKparameter linked to efficacy. However there was a 33% decrease in the maximal concentration of MPA (C_max).
Distribution: The volume of distribution of MPA at steady state is 50 liters. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound, 97% and 82%, respectively. The free MPA concentration may increase under conditions of decreased protein binding sites (uremia, hepatic failure, hypoalbuminemia, concomitant use of drugs with high protein binding). This may put patients at increased risk of MPA-related adverse effects.
Biotransformation/ Metabolism: The half-life of MPA is 11.7 hours and the clearance is 8.6 L/hr. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG) MPAG is the predominant metabolite of MPA and does not manifest biologic activity. In stable renal transplant patients on ciclosporin for microemulsion based immunosuppression, approximately 28% of the oral mycophenolic acid (Myfortic) dose is converted to MPAG by presystemic metabolism. The half-life of MPAG is longer than that of MPA, approximately 15.7 hours and its clearance is 0.45 L/hr.
Elimination: Although negligible amounts of MPA are present in the urine (<1.0%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6 to 8 hours after mycophenolic acid (Myfortic) dosing a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA.
Pharmacokinetics in renal transplant patients on ciclosporin for microemulsion based immunosuppression: Table 3 as follows shows mean pharmacokinetic parameters for MPA following mycophenolic acid (Myfortic) administration. Single dose pharmacokinetics predicts multiple dose and chronic dosing pharmacokinetics. In the early post-transplant period, mean MPA AUC and mean MPA C_max was approximately one-half of that measured six months post-transplant. (See Table 3.)

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Special Populations: Renal impairment: MPA pharmacokinetic appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by hemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased MPA plasma protein binding in the presence of high blood urea concentration.
Hepatic impairment: In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Pediatric population (below 18 years): Safety and efficacy in children have not been established. Limited pharmacokinetics data are available on the use of mycophenolic acid (Myfortic) in children. In the table previously mentioned, mean (SD) MPA pharmacokinetics are shown for stable pediatric renal transplant patients on ciclosporin microemulsion based immunosuppression. Increased variability of MPA C_max and AUC were noted in these pediatric patients compared to adult renal transplant patients. Mean MPA AUC at this dose was higher than typically measured in adults receiving 720 mg. The mean apparent MPA clearance was approximately 7.7 L/hr. A dose of 200 to 300 mg/m² would be expected to result in a MPA AUC of 30 to 50 micrograms hr/mL.
Gender: There are no clinically significant gender differences in mycophenolic acid (Myfortic) pharmacokinetics.
Geriatric population (65 years of age or above): Based on preliminary data MPA exposure does not appear to vary to a clinically significant degree by age.
Race/ethnicity: Following a single dose administration of 720 mg mycophenolic acid (Myfortic) to 18 healthy Japanese and Caucasian subjects, the exposure (AUC_inf) for MPA and MPAG were 15 and 22% lower in Japanese subjects compared to Caucasians. The peak MPAG concentrations (C_max) were similar between the two populations, however, Japanese subjects had 9.6% higher C_max for MPA. These results do not suggest any clinically relevant differences.
Toxicology: Non-Clinical Safety Data: Carcinogenicity and mutagenicity: In a 104-week oral carcinogenicity study in rats, mycophenolate sodium at daily doses up to 9 mg/kg was not tumorigenic. The highest dose tested resulted in approximately 0.6 to 1.2 times the systemic exposure observed in renal transplant patients at the recommended dose of 1440 mg/day. Similar results were observed in a parallel study in rats performed with mycophenolate mofetil. In a 26-week oral carcinogenicity assay in a P53± (heterozygous) transgenic mouse model, mycophenolate sodium at daily doses up to 200 mg/kg was not tumorigenic. The highest dose tested was 200 mg/kg, resulting in approximately 5 times the systemic exposure observed in renal transplant patients (1440 mg/day).
The genotoxic potential of mycophenolate sodium was determined in five assays. MPA was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay or the chromosomal aberration assay in human lymphocytes. The lowest dose showing genotoxic effects in a mouse bone marrow micronucleus resulted in approximately 3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the tested clinical dose of 1440 mg of mycophenolic acid per day. It is probable that the mutagenic activity observed was due to a shift in the relative abundance of the nucleotides in the cellular pool used for DNA synthesis.
Fertility: Mycophenolate sodium had no effect on male rats fertility at oral doses up to 40 mg/kg/day. The systemic exposure at this dose represents approximately 9 times the clinical exposure at the tested clinical MRHD of 1440 mg mycophenolic acid (Myfortic) per day. No effects on female fertility were seen up to a dose of 20 mg/kg/day, a dose at which maternal toxicity and embryotoxicity were already observed.
Safety pharmacology and repeat dose toxicity: The hematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate sodium in rats and mice. Aplastic, regenerative anemia was identified as the dose-limiting toxicity in MPA-exposed rodents. Evaluation of myelograms showed a marked decrease in erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent spleen enlargement and increase in extramedullary hematopoiesis. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1440 mg/day mycophenolic acid in renal transplant patients.
The non-clinical toxicity profile of mycophenolate sodium appears to be consistent with adverse events observed in MPA-exposed humans, which now provide safety data of more relevance to the patient population (see ADVERSE REACTIONS).
Single oral doses of MPA are moderately well tolerated in rats (LD50 of 350 to 700 mg/kg), well tolerated in mice or monkeys (LD50 of more than 1,000 mg/kg), and extremely well tolerated in rabbits (LD50 of more than 6,000 mg/kg).
Reproductive toxicity: For information on reproductive toxicity, see USE IN PREGNANCY & LACTATION.

Prophylaxis of acute transplant rejection in patients receiving allogeneic renal transplants in combination with ciclosporin for microemulsion and corticosteroids.

Dosage regimen: The recommended dose is 720 mg twice daily (1,440 mg daily dose). In patients receiving 2 g mycophenolate mofetil (MMF), treatment can be replaced by 720 mg twice daily (1,440 mg daily dose).
General target population: Treatment should be initiated and maintained by appropriately qualified transplant specialists.
Mycophenolic acid (Myfortic) should be initiated in de-novo patients within 48 hours following transplantation.
Can be taken with or without food.
Special populations: Renal impairment: No dose adjustments are needed in patients experiencing delayed post-operative renal graft function (see PHARMACOLOGY: PHARMACOKINETICS under ACTIONS). Patients with severe chronic renal impairment <25 mL • min^-1 • 1.73 m^-2 should be carefully monitored.
Hepatic impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.
Pediatric patients (below 18 years): Safety and efficacy in pediatric patients have not been established. Limited pharmacokinetic data are available for pediatric renal transplant patients (see PHARMACOLOGY under ACTIONS).
Geriatric patients (65 years of age or above): No dose adjustment is required in this patient population.
Treatment during rejection episodes: Renal transplant rejection does not affect mycophenolic acid pharmacokinetics; dosage reduction or interruption of mycophenolic acid (Myfortic) is not required.
Method of administration: Mycophenolic acid (Myfortic) tablets should not be crushed in order to maintain the integrity of the enteric coating (see PHARMACOLOGY under ACTIONS and INSTRUCTIONS FOR USE AND HANDLING under CAUTIONS FOR USAGE).

There have been anecdotal reports of deliberate or accidental overdoses with mycophenolic acid (Myfortic), whereas not all patients experienced related adverse events.
In overdose cases in which adverse events were reported, the events fall within the known safety profile of the class. Accordingly an overdose could possibly result in oversuppression of the immune system and may increase the susceptibility to infection including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count <1.5 x 10³/micro L or anemia) it may be appropriate to interrupt or discontinue mycophenolic acid (Myfortic) (see PRECAUTIONS and ADVERSE REACTIONS).
Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.

Patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see DESCRIPTION).

Patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT): Mycophenolic acid (Myfortic) is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, it should therefore be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Malignancies: Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolic acid (Myfortic), are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
As general advice to minimize the risk of skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a high protection factor sunscreen.
Infections: Patients receiving mycophenolic acid (Myfortic) should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Oversuppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see ADVERSE REACTIONS).
Reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives Myfortic and MMF. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with MPA derivatives which include mycophenolate mofetil and mycophenolate sodium (see ADVERSE REACTIONS). The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune functions. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, should be included in the differential diagnosis in immunosuppressed patients with deteriorating renal function (see ADVERSE REACTIONS). Consideration should be given to reducing the total immunosuppression in patients who develop PML or PVAN. In transplant patients, however, reduced immunosuppression may place the graft at risk.
Blood dyscrasias: Patients receiving mycophenolic acid (Myfortic) should be monitored for blood dyscrasias (e.g. neutropenia or anemia - see ADVERSE REACTIONS), which may be related to MPA itself, comedication, viral infections, or some combination of these causes. Patients should have complete blood cell counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly throughout the first year. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count <1.5 x 103 / micro L or anemia) it may be appropriate to interrupt or discontinue mycophenolic acid.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressants (see ADVERSE REACTIONS). The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. However, MPA derivatives may cause blood dyscrasias (see previous text). In some cases PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to mycophenolic acid (Myfortic) therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.
Vaccinations: Patients should be advised that vaccinations may be less effective during treatment with MPA and the use of the live attenuated vaccines should be avoided (see INTERACTIONS). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastrointestinal disorders: As MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage and perforation, Mycophenolic acid should be administered with caution in patients with active serious digestive system disease.
Combination with other agents: Mycophenolic acid (Myfortic) has been administered in combination with the following agents in clinical trials: antithymocyte globulin, basiliximab, ciclosporin for microemulsion and corticosteroids. The efficacy and safety of the use of mycophenolic acid (Myfortic) with other immunosuppressants have not been studied.
Use in Pregnancy & Lactation: Use of mycophenolic acid during pregnancy is associated with an increased risk of pregnancy loss including spontaneous abortion and/or congenital malformations. Mycophenolic acid (Myfortic) therapy should not be initiated in females of reproductive potential until a negative pregnancy test has been obtained. For information on use in pregnancy and contraceptive requirements (see USE IN PREGNANCY & LACTATION).
Mycophenolic acid should not be used during breast-feeding (see USE IN PREGNANCY & LACTATION).

Use of mycophenolic acid during pregnancy is associated with an increased risk of pregnancy loss including spontaneous abortion and/or congenital malformations. Mycophenolic acid (Myfortic) therapy should not be initiated in females of reproductive potential until a negative pregnancy test has been obtained. For information on use in pregnancy and contraceptive requirements (see PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL as follows). Mycophenolic acid should not be used during breast-feeding (see PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL as follows).
Pregnancy: Risk summary: Use of mycophenolic acid during pregnancy is associated with an increased risk of spontaneous abortion and congenital malformations. Although there are no adequate and well controlled studies in pregnant women conducted with mycophenolic acid, based on data from the US National Transplant Pregnancy Registry (NTPR), use of mycophenolate mofetil in combination with other immunosuppressants during pregnancy was associated with an increased rate of 22% (four cases in 18 liveborn with exposure) of congenital malformations, compared to the rate of 4 to 5% for malformations seen among transplant patients in the NTPR. Congenital malformations that have been reported with mycophenolate mofetil include outer ear and other facial abnormalities including cleft lip and palate, congenital diaphragmatic hernia, anomalies of the distal limbs, heart, esophagus and kidney. Use of mycophenolate mofetil during pregnancy was also reported to be associated with increased risk of spontaneous abortion. Since MMF is converted to MPA following oral or IV administration, the previously mentioned risks must be taken into account for mycophenolic acid as well. The teratogenic potential of MPA was observed in animal studies (see ANIMAL DATA as follows).
Mycophenolic acid should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. Patients should be instructed to consult their physician immediately should pregnancy occur.
Animal data: In a teratology study in rats, administration of mycophenolic acid (Myfortic) during organogenesis resulted in malformations including anophthalmia, exencephaly and umbilical hernia, at an oral dose as low as 1 mg/kg/day. The systemic exposure at this dose represents 0.05 times the clinical exposure at the MRHD (maximum recommended human dose) of 1440 mg/day mycophenolic acid (Myfortic). In a pre- and postnatal development study in rats oral administration of mycophenolic acid (as sodium salt) during gestation and lactation caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg, which is below MRHD based on body surface area.
Lactation: Risk summary: It is not known whether MPA is transferred into human milk. There are no data on the effects of mycophenolic acid (Myfortic) on the breastfed child or on milk production.
As many drugs are transferred into human milk, and due to the potential for serious adverse reactions in breast-fed newborns/infants, a decision should be made whether to abstain from breast-feeding during treatment and for 6 weeks after stopping the therapy or to abstain from using the medicinal product, taking into account the importance of the drug to the mother (see PRECAUTIONS).
Females and males of reproductive potential: Pregnancy testing: Mycophenolic acid (Myfortic) therapy should not be initiated until a negative pregnancy test has been obtained.
Contraception:Females: Females of reproductive potential must use effective contraception (methods that result in less than 1 % pregnancy rates) before beginning mycophenolic acid (Myfortic) therapy, during therapy and for six weeks after their last mycophenolic acid (Myfortic) dose (see INTERACTIONS).
Males: Male patients are recommended to use condoms during treatment, and for a total of 13 weeks after their last mycophenolic acid (Myfortic) dose. Accordingly, male patients of reproductive potential should be made aware of and discuss with a qualified health-care professional the potential risks of fathering a child or donating semen. In addition, female partners of the male patients are recommended to use effective contraception (methods that result in less than 1 % pregnancy rates) during treatment and for a total of 13 weeks after the last mycophenolic acid (Myfortic) dose.
Infertility: There is no data on the effect of mycophenolic acid (Myfortic) on human fertility. Mycophenolate sodium had no effect on male and female rat's fertility at oral doses up to 40 mg/kg/day and 20 mg/kg/day respectively, equivalent to 9 and 4.5 (calculated) times the clinical exposure at the MRHD of 1440 mg mycophenolic acid (Myfortic) per day (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).

Summary of the safety profile: The following undesirable effects cover adverse drug reactions from two controlled clinical trials. The trials evaluated the safety of mycophenolic acid and mycophenolate mofetil in 423 de novo and in 322 maintenance renal transplant patients (randomized 1:1); the incidence of adverse events was similar between treatments in each population.
The very common (≥10%) adverse drug reactions associated with mycophenolic acid in combination with ciclosporin for microemulsion and corticosteroids include leucopenia and diarrhea.
Malignancies: Patient receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see Precautions). Overall rates of malignancies observed in mycophenolic acid clinical trials are as follows: lymphoproliferative disease or lymphoma developed in 2 de novo patients (0.9%) and in 2 maintenance patients (1.3%) receiving mycophenolic acid for up to 1 year; non-melanoma skin carcinomas occurred in 0.9% de novo and 1.8% maintenance patients receiving mycophenolic acid for up to 1 year; other types of malignancy occurred in 0.5% de novo and 0.6% of maintenance patients.
Opportunistic Infections: All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see PRECAUTIONS). The most common opportunistic infections in de novo renal transplant patients receiving mycophenolic acid with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were CMV (cytomegalovirus), candidiasis and herpes simplex. The overall rate of CMV infections (serology, viremia or disease) observed in mycophenolic acid clinical trials were reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions (see Table 4) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 4 as follows contains adverse drug reactions possibly or probably related to mycophenolic acid reported in the two phase III randomized, double blind, controlled, multi-center trials: 1 in de novo kidney transplant patients and 1 in maintenance kidney transplant patients, in which mycophenolic acid was administered at a dose of 1,440 mg/day for 12 months together with ciclosporin microemulsion and corticosteroids. It is compiled according to MedDRA system organ class. (See Table 4.)

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Listing of adverse drug reactions from post-marketing experience: The following adverse drug reactions have been derived from post-marketing experience with mycophenolic acid via spontaneous case reports and literature cases. As these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to MedDRA system organ class. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Skin and subcutaneous tissue disorders: Rash has been identified as an adverse drug reaction from post-approval clinical trials, post marketing surveillance and spontaneous reports.
General disorders and administration site conditions: de novo purine synthesis inhibitors-associated acute inflammatory syndrome: The following adverse reactions are attributed to MPA derivatives as a class effect: Infections and Infestations: Serious, sometimes life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported (see PRECAUTIONS).
Blood and lymphatic system disorders: Agranulocytosis, neutropenia, pancytopenia. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressants (see PRECAUTIONS).
Gastrointestinal disorders: Colitis, esophagitis (including CMV-colitis and -esophagitis), CMV gastritis, pancreatitis, intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers, ileus.
Geriatric population (65 years of age or older): Geriatric patients may generally be at increased risk of adverse drug reactions due to immunosuppression. Geriatric patients receiving mycophenolic acid as part of a combination immunosuppressive regimen did not show an increased risk of adverse reactions, compared to younger individuals in the mycophenolic acid clinical trials.

Observed interactions resulting in a concomitant use not recommended: Azathioprine: It is recommended that mycophenolic acid should not be co-administered with azathioprine because such co-administration has not been studied (see PRECAUTIONS).
Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see PRECAUTIONS).
Observed interactions to be considered: Aciclovir: Higher plasma concentrations of both MPAG (mycophenolic acid glucuronide) and aciclovir may occur in the presence of renal impairment. Therefore, the potential exists for these two drugs to compete for tubular secretion, resulting in a further increase in the concentration of both MPAG and aciclovir. In this situation patients should be carefully monitored.
Gastroprotective agents: Antacids with magnesium and aluminum hydroxides: The absorption of mycophenolate sodium was decreased when administered with antacids. Co-administration of mycophenolic acid and antacids containing magnesium and aluminum hydroxide results in a 37% decrease in MPA systemic exposure and a 25% decrease in MPA maximal concentration. Caution should be used when co-administering antacids (containing magnesium and aluminum hydroxide) with mycophenolic acid.
Proton pump inhibitors: In healthy volunteers, co-administration of 1000 mg MMF and 40 mg pantoprazole twice daily led to a 27% decrease in MPA AUC and to a 57% decrease in MPA C_max. However, in the same study, no changes in the pharmacokinetics of MPA were observed following co-administration of mycophenolic acid and pantoprazole.
Ganciclovir: MPA and MPAG pharmacokinetics are unaffected by the addition of ganciclovir. The clearance of ganciclovir is unchanged in the setting of therapeutic MPA exposure. However, in patients with renal impairment in which mycophenolic acid and ganciclovir are coadministered the dose recommendations for ganciclovir should be observed and patients monitored carefully.
Tacrolimus: In a calcineurin cross-over study in stable renal transplant patients, steady state mycophenolic acid pharmacokinetics were measured during both Neoral and tacrolimus treatments. Mean MPA AUC was 19% higher and C_max about 20% lower. Conversely mean MPAG AUC and C_max were about 30% lower on tacrolimus treatment compared to Neoral treatment.
Ciclosporin A: When studied in stable renal transplant patients, ciclosporin A pharmacokinetics were unaffected by steady state dosing of mycophenolic acid.
Anticipated interactions to be considered: Cholestyramine and drugs that interfere with enterohepatic circulation: Due to its capacity to block the enteric circulation of drugs, cholestyramine may decrease the systemic exposure of MPA. Caution should be used when co-administering cholestyramine or drugs that interfere with enterohepatic circulation due to the potential to reduce the efficacy of mycophenolic acid.
Oral contraceptives: Oral contraceptives undergo oxidative metabolism while mycophenolic acid is metabolized by glucuronidation. A clinically significant effect of oral contraceptives on mycophenolic acid pharmacokinetics is not anticipated. However, as the long term effect of mycophenolic acid dosing on the pharmacokinetics of oral contraceptives is not known, it is possible that the efficacy of oral contraceptives may be adversely affected (see USE IN PREGNANCY & LACTATION).

Instructions for Use and Handling: Tablets should not be crushed in order to remain the integrity of the enteric coating (see DOSAGE & ADMINISTRATION and PHARMACOLOGY under ACTIONS).
Mycophenolate sodium has demonstrated teratogenic effects (see USE IN PREGNANCY & LACTATION). If for any reasons the tablet is crushed, avoid inhalation or direct contact with skin or mucous membrane of the powder.
Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.

Immunosuppressants

L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.

Rx