Mofecon-C 250/Mofecon 500

Mycophenolate mofetil.

Mofecon-C 250: Each hard gelatin capsule contains Mycophenolate mofetil 250 mg, excipients q.s.
Mofecon-C 500: Each film-coated tablet contains Mycophenolate mofetil 500 mg, excipients q.s.
Excipients/Inactive ingredients: Colours: Mofecon-C 250: Approved colours used in capsule shells.
Mofecon-C 500: Iron oxide black, Iron oxide red, Indigo carmine aluminum lake, Titanium dioxide.

Pharmacologic Category: Immunosuppressant Agent.
Pharmacology: Pharmacodynamics: Mechanism of action: Mycophenolic acid (MPA) exhibits a cytostatic effect on T and B lymphocytes. It is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits de novo guanosine nucleotide synthesis. T and B lymphocytes are dependent on this pathway for proliferation.
Pharmacokinetics: Onset of action: Peak effect: Correlation of toxicity or efficacy is still being developed. However, one study indicated that 12-hour Area under the curve (AUCs) > 40 mcg/mL/hour were correlated with efficacy and decreased episodes of rejection.
Absorption: Rapid and extensive: early post-transplant period mycophenolic acid (MPA) AUC values are lower (~45% to 53%) than later post-transplant period (> 3 months) MPA AUC values in both pediatric patients and adults.
Distribution: MPA: Oral: 4 L/kg.
Protein binding: MPA: > 97%, MPAG (inactive metabolite) 82%.
Metabolism: Hepatic and via GI tract; mycophenolate mofetil is completely hydrolyzed in the liver to mycophenolic acid (MPA: active metabolite): enterohepatic recirculation of MPA may occur. MPA is glucuronidated to MPAG (inactive metabolite).
Bioavailability: Oral: 80.7% to 94%: enterohepatic recirculation contributes to MPA concentration.
Half-life elimination: MPA: Oral: 18 hours.
Time to peak, plasma: Oral: MPA: 1 to 1.5 hours.
Excretion: MPA: Urine (<1%), feces (6%); MPAG: Urine (87%).
Special populations: Renal function impairment: mycophenolic acid AUC increased 75%, and mycophenolic acid glucuronide AUC increased 3- to 6-fold in patients with severe renal impairment (glomerular filtration rate [GFR] less than 25 mL/minute/1.73 m²). Hemodialysis usually does not remove mycophenolic acid or mycophenolic acid glucuronide.

Organ transplantation: Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients receiving allogeneic renal, cardiac or hepatic transplants.
Mofecon-C 250/Mofecon 500 is indicated for the treatment of first or refractory organ rejection in patients receiving allogeneic renal transplants.
Mofecon-C 250/Mofecon 500 is indicated for the prophylaxis of acute organ rejection in patients receiving allogeneic cardiac transplant. (In the treated population, MMF improved survival in the first year after transplantation.)
Mofecon-C 250/Mofecon 500 is indicated for the prophylaxis of acute organ rejection in patients receiving allogeneic hepatic transplants.
Mofecon-C 250/Mofecon 500 is indicated for induction and maintenance therapy of patients with Class III-IV lupus nephritis (diagnosed according to International Society of Nephrology/Renal Pathology Society classification).

Recommended dose: Transplant patients: Standard dosage for prophylaxis of renal rejection: A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of Mofecon-C 250/Mofecon 500 demonstrated an overall better safety profile compared to patients receiving 3 g/day of Mofecon-C 250/Mofecon 500.
Standard dosage for prophylaxis of cardiac rejection: A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is recommended for use in cardiac transplant patients.
Standard dosage for prophylaxis of hepatic rejection: A dose of 1 g administered twice a day (daily dose of 2 g) or 1.5 g orally twice a day (daily dose of 3 g) is recommended for use in hepatic transplant patients.
Standard dosage for treatment of first or refractory renal rejection: A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is recommended for management of first or refractory rejection.
Oral administration: The initial dose of Mofecon-C 250/Mofecon 500 should be given as soon as possible following renal, cardiac or hepatic transplantation.
Lupus nephritis patients: Standard Dosage for Induction Therapy: A dose of 750mg - 1.5g administered orally twice a day (daily dose of up to 3g) is recommended.
Standard Dosage for Maintenance Therapy: A dose of 500mg - 1g administered orally twice a day is recommended.
Mofecon-C 250/Mofecon 500 should be used in combination with corticosteroids. Doses should be introduced gradually and adjusted according to clinical response. Therapeutic drug monitoring could help prevent sub-therapeutic exposure (C_min ≥ 3.0 mg/L or inter-dose AUC ≥ 35 h*mg/L).
Geriatric use: For transplant patients, no oral dosage adjustment is recommended.
For lupus nephritis patients, no recommendation is available.
Renal function impairment: Renal transplant: In patients with severe chronic renal impairment (glomerular filtration rate less than 25 mL/minute/1.73 m²) outside the immediate posttransplant period or after treatment of acute or refractory rejection. Doses greater than 1 g administered twice daily should be avoided: patients should also be carefully observed; no dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively.
For post-transplant patients with delayed renal graft function, no dose adjustment is recommended but patients should be carefully monitored.
For cardiac or hepatic transplant patients with severe renal impairment, no data are available.
For lupus nephritis patients with GFR<30mL/min, therapeutic drug monitoring is advised.
Hemodialysis: Not removed: supplemental dose is not necessary.
Peritoneal dialysis: Supplemental dose is not necessary.
Hepatic Impairment: No dosage adjustment is recommended for renal transplant patients with severe hepatic parenchymal disease: however, it is not currently known whether dosage adjustments are necessary for hepatic disease with other etiologies.
For cardiac transplant and lupus nephritis patients with severe hepatic parenchymal disease, no data are available.
Dosage adjustment: Neutropenia: If neutropenia develops (absolute neutrophil counts [ANCs] less than 1.3 x 10³/mcL), interrupt dosing or reduce the dosage of mycophenolate, perform appropriate diagnostic test, and manage the patient appropriately.
Mode of administration: Oral: Oral dosage formulations should be administered on an empty stomach (1 hour before or 2 hours after meals).
If a dose is missed administer as soon as it is remembered. If it is close to the next scheduled dose, skip the missed dose and resume at next regularly scheduled time; do not double a dose to make up for a missed dose.

Overdose and treatment: It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase in susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with Mofecon-C 250/Mofecon 500 should be interrupted or dose should be reduced. MPA cannot be removed by hemodialysis. However, at high MPAG plasma concentrations (>100 μg/mL), small amount of MPAG are removed. Bile acid sequestrants, such as cholestyramine, can remove MPA by increasing excretion of the drug.

Hypersensitivity to mycophenolate mofetil, mycophenolic acid, mycophenolate sodium, or any component of the formulation.
Breastfeeding.
Use in Pregnancy: women of childbearing potential and not using highly effective contraceptive methods; women of childbearing potential not providing a pregnancy test result.

Blood and immune system: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of therapy. In transplant patients however reduced immunosuppression may place the graft at risk.
Patients receiving Mofecon-C 250/Mofecon 500 should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Patients on Mofecon-C 250/Mofecon 500 should have complete blood counts weekly during the first month of treatment, twice monthly for the second and third months, then monthly through the first year. In particular, patients receiving Mofecon-C 250/Mofecon 500 should be monitored for neutropenia. The development of neutropenia may be related to Mofecon-C 250/Mofecon 500, concomitant medications, viral infection or some combination of these causes. If neutropenia develops (absolute neutrophil count <1.3 x 10³/mcL), dosing with Mofecon-C 250/Mofecon 500 should be interrupted or the dose should be reduced and the patient carefully observed.
Vaccination: Patients should be advised that during treatment with Mofecon-C 250/Mofecon 500 vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see Interactions). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastro-intestinal: Mofecon-C 250/Mofecon 500 has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation. Mofecon-C 250/Mofecon 500 should be administered with caution in patients with active digestive system disease.
Mofecon-C 250/Mofecon 500 is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Infection: Risk for bacterial, viral, fungal, and protozoal infections including opportunistic infections is increased with immunosuppressant therapy; infections may be serious and potentially fatal. Polyomavirus associated nephropathy (PVAN), JC virus-associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV), have been reported with use.
Neoplasms: Risk of development of lymphoma and skin malignancy is increased.
Interaction: Caution should be exercised when swathing combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal of an interacting medication).
Drug which interfere with MPA's enterohepatic cycle (e.g. cholestyramine, sevelamer, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of Mofecon-C 250/Mofecon 500. Sevelamer and other calcium free phosphate binders should be taken 2 hours after Mofecon-C 250/Mofecon 500 intake to minimize the impact on the absorption of MPA.
It is recommended that Mofecon-C 250/Mofecon 500 should not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied.
Renal function impairment: Avoid doses of more than 1 g of mycophenolate twice daily in renal transplant patients and carefully observe these patients.
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Mycophenolate may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.
Use in Pregnancy & Lactation: Mycophenolate is associated with an increased risk of congenital malformations and first trimester pregnancy loss when used by pregnant women. Females of reproductive potential must be counseled about pregnancy prevention and planning. Acceptable forms of contraception should be used during treatment and for 6 weeks after therapy is discontinued.
It is not known if mycophenolate is excreted in human milk. Breastfeeding is not recommended during therapy or for 6 weeks after treatment is complete.
Mofecon-C 250/Mofecon 500 is contraindicated in pregnancy and during breastfeeding.
Use in Children: Safety and efficacy in pediatric patients receiving allogeneic cardiac or hepatic transplants, or in renal transplant patients younger than 3 months have not been established.
Use in the Elderly: Use caution in dosage selection for an elderly patient, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse reactions compared with younger individuals.

Pregnancy: Pregnancy category D.
Mycophenolate is contraindicated during pregnancy.
Mycophenolate is associated with an increased risk of congenital malformation and first trimester pregnancy loss when used by pregnant women. Females of reproductive potential must be counseled about pregnancy prevention and planning. Advise patients to use acceptable forms of contraception during treatment and for 6 weeks after therapy is discontinued.
Lactation: It is not known if mycophenolate is excreted in human milk. Breastfeeding is not recommended during therapy or for 6 weeks after treatment is complete.

(See table.)

Click on icon to see table/diagram/image

Lymphomas/Malignancies: Patients receiving mycophenolate alone or as part of an Immunosuppressants regimen are at increased risk of developing Lymphomas and other malignancies.
Neutropenia: Severe neutropenia (ANC less than 0.5 x 10³/mcL) developed in up to 2% of renal transplant patients, up to 2.8% of cardiac transplant patients, and up to 3.6% of hepatic transplant patients receiving Mycophenolate 3 g daily.
Infections: All transplant patients are at increased risk of opportunistic infections.
Children: The type and frequency of adverse reactions in a clinical study of 100 pediatric patients 3 months to 18 years of age were generally similar to those observed in adult patients with the exception of abdominal pain, anemia, diarrhea, fever, hypertension, infection, leukopenia, pain, pharyngitis, respiratory tract infection, sepsis, and vomiting, which were observed in a higher proportion in pediatric patients.
Elderly: Elderly patients (65 years or older), may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly GI hemorrhage and pulmonary edema compared with younger individuals.
Post marketing: GI: Colitis, isolate cases of intestinal villous atrophy, pancreatitis.
Hematologic/Lymphatic: Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia.
Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.
Miscellaneous: Serious life-threatening infections, such as meningitis and infectious endocarditis. Congenital malformations, including ear, facial, cardiac, and nervous system malformations, and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate during pregnancy.

Mycophenolate may cause potentially significant drug-drug interactions requiring dose or frequency adjustment.
Avoid concomitant Use: Avoid concomitant use of mycophenolate with any of the following: BCG (intravesical); bile acid sequestrants: cholestyramine resin; natalizumab; pimecrolimus; rifamycin derivatives; tacrolimus (topical); vaccines (live).
Increased Effect/Toxicity: Mycophenolate may increase the levels/effects of acyclovir - valacyclovir, fingolimod, ganciclovir - valganciclovir, leflunomide, natalizumab, tofacitinib; vaccines (live).
The levels/effects of mycophenolate may be increased by: acyclovir-valacyclovir, denosumab, ganciclovir-valganciclovir, isavuconazonium sulfate, ocrelizumab, pimecrolimus, probenecid, roflumilast, tacrolimus (topical), teriflunomide, trastuzumab.
Decreased Effect: Mycophenolate may decrease the levels/effects of: BCG (intravesical); Coccidioides immitis skin test; estrogen derivatives (contraceptive), nivolumab; pidotimod; progestins (contraceptive); sipuleucel-T; tertomotide; vaccines (inactivated); vaccines (live).
The levels/effects of mycophenolate may be decreased by: antacids; bile acid sequestrants; cholestyramine resin: cyclosporine (systemic); echinacea; magnesium salts; metronidazole (systemic); penicillins; proton pump inhibitors; quinolones; rifamycin derivatives; sevelamer.
Food Interactions: Food decreases C_max of MPA by 40% following mycophenolate mofetil administration; the extent of absorption is not changed. Management: Take Mofecon-C 250/Mofecon 500 on an empty stomach to decrease variability; however, Mofecon-C 250/Mofecon 500 may be taken with food if necessary in stable renal transplant patients.

Store below 30°C, store in the original package in order to protect from moisture.

Immunosuppressants

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

S