Mycophenolate Mofetil is an immunosuppressive agent. It is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Therefore, it inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. Mycophenolic acid has cytostatic effects on lymphocytes. It has been shown to prevent the occurrence of acute rejection of kidney and heart allotransplantation. It also decreases antibody production.

Pharmacology

Mechanism of Action: Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis. The mechanism by which MPA inhibits the enzymatic activity of IMPDH appears to be related to the ability of MPA to structurally mimic both nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This prevents the oxidation of IMP to xanthose-5’-monophosphate which is the committed step in de novo guanosine nucleotide biosynthesis. MPA has more potent cytostatic effects on lymphocytes than on other cells because T- and B lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilize salvage pathways.

Pharmacodynamics: Mycophenolic acid, the active metabolite of mycophenolate mofetil, is a non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH blocks the de novo synthesis of guanosine nucleotides which are necessary substrates for DNA and RNA synthesis. Unlike other cell types which can use the salvage pathway, B and T lymphocytes are dependent upon the de novo pathway for the generation of guanosine. Data from in vitro studies indicate that mycophenolic acid and/or mycophenolate mofetil inhibit mixed lymphocyte responses and human peripheral blood lymphocyte proliferation induced by a variety of mitogens and antigens. Mycophenolic acid decreases intracellular pools of guanosine triphosphate (GTP) and deoxyguanosine triphosphate (dGTP) in mitogen-stimulated human peripheral blood monocytes or T lymphocytic cell lines but has no effect on GTP concentrations in human neutrophils.

Mycophenolate Mofetil in combination with corticosteroids and either ciclosporin or tacrolimus is indicated for-

• Prophylaxis of acute organ rejection and treatment of first or refractory organ rejection in patients receiving allogeneic renal transplants.
• Prophylaxis of acute organ rejection in patients receiving allogeneic cardiac transplants.
• Prophylaxis of acute organ rejection in patients receiving allogeneic hepatic transplants.
• Mycophenolate Mofetil is indicated for induction and maintenance therapy of patients with Class III-V lupus nephritis (diagnosed according to International Society of Nephrology/Renal Pathology Society classification.

Transplant patients:

Standard dosage for prophylaxis of renal rejection

• Adults: A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients.
• Children (aged 3 months to 18 years): Patients with a body surface area of 1.25 to 1.5 m² may be prescribed Mycophenolate Mofetil Tablets at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m² may be prescribed Mycophenolate Mofetil tablets at a dose of 1 gm twice daily (2 g daily dose).

Standard dosage for prophylaxis of cardiac rejection-

• Adults: A dose of 1.5 g administered orally (over not less than 2 hour) twice a day (daily dose of 3 g) is recommended for use in cardiac transplant patients.
• Children: no data are available for pediatric cardiac transplant patients.

Standard dosage for prophylaxis of hepatic rejection-

• Adults: A dose of 1.5 g orally twice a day (daily dose of 3 g) is recommended for use in hepatic transplant patients
• Children: no data are available for pediatric hepatic transplant patients.

Standard dosage for treatment of first or refractory renal rejection-

• Adults: 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.
• Children: no data are available for the treatment of first or refractory renal rejection in pediatric renal transplant patients.

Lupus nephritis patients:

Standard Dosage for Induction Therapy-

• Adults: A dose of 750 mg-1.5 g administered orally twice a day (daily dose of up to 3 g) is recommended
• Children: A dose of 600 mg/m² administered orally twice a day (up to a maximum of 2 g daily) is recommended

Standard Dosage for Maintenance Therapy-

• Adults: A dose of 500 mg-1 g administered orally twice a day is recommended
• Children: A dose of 300 mg/m² administered orally twice a day is recommended

Mycophenolate Mofetil 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 (Cmin≥3.0 mg/L or inter-dose AUC ≥35 h*mg/L).

Mycophenolic acid is contraindicated in patients with a hypersensitivity to mycophenolic acid, or to any of its excipients. Mycophenolic acid is contraindicated during pregnancy due to its mutagenic and teratogenic potential. Mycophenolic acid is contraindicated in women who are breastfeeding.

The principal adverse reactions associated with the administration of Mycophenolate Mofetil includes diarrhea, leukopenia, sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, vomiting and there is evidence of a higher frequency of certain types of infections eg. opportunistic infections.

Overdose Effects

In many of these cases no adverse events were reported. It is expected that an overdose of mycophenolate mofetil could possibly result in over suppression of the immune system and increase susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with Mycophenolate Mofetil should be interrupted or the dose reduced.

Mycophenolic acid tablets are used with caution because it-

• Can increase new or reactive viral infections. Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation, or infections caused by polyomaviruses.
• Can cause blood dyscrasias including pure red cell aplasia (PRCA).
• Can cause serious GI tract complications (gastrointestinal bleeding, perforations and ulcers).
• May increase the risk of developing lymphomas and other malignancies, particularly of the skin.
• Use of live vaccines should be avoided during treatment with Mycophenolic acid.
• Patients should not donate blood during therapy.

Pregnancy & Lactation

Mycophenolate Mofetil is contraindicated in pregnancy and during breastfeeding. The safe use of Mycophenolate Mofetil during labor and delivery has not been established.