Mycophenolate Mofetil is the morpholinoethyl ester of mycophenolic acid (MPA) with potent immunosuppressive properties. Mycophenolate stops T-cell and B-cell proliferation through selective inhibition of the de novo pathway of purine biosynthesis. In vivo, the active metabolite, MPA, reversibly inhibits inosine 5′-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. MPA displays high lymphocyte specificity and cytotoxicity due to the higher dependence of activated lymphocytes on both salvage and de novo synthesis of guanine nucleotides relative to other cell types.
Mycophenolate mofetil is an antimetabolite and potent immunosuppressive agent used as adjunctive therapy in the prevention of allograft rejection and in the treatment of serious autoimmune diseases. Mycophenolate therapy can be associated with mild serum enzyme elevations and it has been linked to rare instances of clinically apparent liver injury.
Mechanism of action of Mycophenolate mofetil
Mycophenolate mofetil is hydrolyzed to form a mycophenolic acid (MPA), which is the active metabolite. 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 without incorporation into DNA. Purines can either be synthesized de novo using Ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is potent, reversible, non-competitive inhibitor of Inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to thede novo synthesis of guanosine-5′-monophosphate(GMP) from inosine-5′-monophosphate(IMP). IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis. 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, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.
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As a potent, selective, noncompetitive, and reversible, an inhibitor of inosine monophosphate dehydrogenase (IMPDH), mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil inhibits the de novo synthesis pathway of guanosine nucleotides without being incorporated into DNA. Because T and B lymphocytes are critically dependent for their proliferation on the de novo synthesis of purines, while other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibit the proliferative responses of T and B lymphocytes to both mitogenic and allospecific stimulation. The addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B lymphocytes. MPA prevents the glycosylation of lymphocytes and monocyte glycoproteins that are involved in intercellular adhesion of these cells to endothelial cells, and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil dose not inhibits the early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 and interleukin-2, but does block the coupling of these events to DNA synthesis and proliferation.
Indications of Mycophenolate mofetil
- Autoimmune hepatitis
- Cogan’s syndrome
- Crohn’s disease
- Dermatomyositis
- Evan’s syndrome
- Graft-versus-host disease
- High cholesterol
- Inflammatory bowel disease
- Linear IgA disease
- Multiple sclerosis
- Myasthenia gravis
- Nephrotic syndrome
- Organ transplant, rejection prophylaxis
- Pemphigoid
- Pemphigus
- Psoriatic arthritis
- Pulmonary fibrosis
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Ulcerative colitis
- Uveitis
- Heart transplant rejection
- Kidney transplant rejection
- Liver transplant rejection
Therapeutic Indications
- For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
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CellCept is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
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Myclausen is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
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Mycophenolate mofetil Teva is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
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Anti-Inflammatory Agents, Non-Steroidal, Antineoplastic Agents, Dermatologic Agents, Enzyme Inhibitors, Immunosuppressive Agents
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Mycophenolate is indicated, in combination with cyclosporine and corticosteroids, for prevention of rejection of allogeneic cardiac, hepatic and renal transplants.Mycophenolate is indicated for the treatment of lupus nephritis.
Contra-Indications of Mycophenolate mofetil
- Shingles in patients without a normal immune system
- herpes simplex infection
- disease caused by cytomegalovirus infection
- opportunistic fungal infection
- severe infection
- Malignant tumor or cancer
- Constitutional aplastic anemia
- Decreased function of bone marrow
- Decreased neutrophils a type of white blood Cell
- Stomach or intestinal ulcer
- Liver problems
- Bleeding of the stomach or intestines
- Pregnancy
- A mother who is producing milk and breastfeeding
- Malignant lymphoma
- Hypoxanthine-guanine phosphoribosyltransferase deficiency
- A rupture in the wall of the stomach or intestine
- Severely decreased levels of neutrophils in the blood
- Progressive disease in the white matter of the brain
- Skin Cancer
- BK virus reactivation causing kidney problems
- chronic kidney disease stage 4 (severe)
- chronic kidney disease stage 5 (failure)
Dosages of Mycophenolate mofetil
Strengths: 250 mg; 500 mg; 200 mg/mL
Organ Transplant
Renal Transplantation
- 1 g orally or IV 2 times a day (2 gm per day); [in clinical trials, 1.5 g orally or IV 2 times a day (3 gm per day) was used effectively, however, the safety profile for 3 gm a day was lower]
Cardiac Transplantation
- 1.5 g orally or IV 2 times a day (3 gm per day)
Hepatic Transplantation
- 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)
Geriatric Organ Transplant
Renal Transplantation
- 1 g orally or IV 2 times a day (2 gm per day)
Cardiac Transplantation
- 1.5 g orally or IV 2 times a day (3 gm per day)
Hepatic Transplantation
- 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)
Pediatric Organ Transplant
Renal Transplantation3 months to 18 years of age
Oral Suspension
- 600 mg/m2 orally 2 times a day up to a maximum of 2 grams per day
- Pediatric patients with a body surface area of 1.25 to 1.5 m2 may be dosed with the oral capsules at 750 mg orally 2 times a day (1.5 g per day)
- Pediatric patients with a body surface area greater than 1.5 m2 may be dosed with the oral capsules at 1 g orally 2 times a day (2 g per day)
Side Effects of Mycophenolate mofetil
The most common
- constipation
- diarrhea
- difficulty sleeping
- dizziness
- headache
- heartburn
- stomach pain
- nausea, vomiting
- agitation, including aggressive behaviour and/or hostility
- headache
- muscle, bone or joint pain
- irritability, restlessness, feeling anxious
- depression
More common
- Sweating
- Blurred vision
- Dizziness.
- slower heart rate
- diarrhea
- dry eyes
- hair loss
- nausea
- weakness or tiredness
Common
- Cough producing mucus
- difficulty with breathing
- tightness in the chest
- Abdominal or stomach pain and tenderness
- blistering, peeling, or loosening of the skin
- Anxiety
- dry mouth
- irritability
- sleepiness or unusual drowsiness
- trouble sleeping
- Decreased appetite
Serious
- Swelling of the hands, arms, feet, ankles, or lower legs
- Chest pain
- Difficulty breathing
- Itching or rash
- Dizziness
- Lack of energy
- Black, tarry, or bloody stools
- Bloody vomit, or vomit that looks like coffee grounds
- Pale skin
Drug Interactions of Mycophenolate mofetil
Mycophenolate mofetil may interact with following drugs, supplements & may change the efficacy of drugs
- acyclovir – valacyclovir
- antacids containing magnesium and aluminum
- azathioprine
- calcium carbonate
- cholestyramine
- colesevelam
- clindamycin
- cyclosporine
- denosumab
- ganciclovir – valganciclovir
- metronidazole
- natalizumab
- oral contraceptives (birth control pills)
- penicillins (e.g., penicillin, amoxicillin, ampicillin)
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- quinolone antibiotics (e.g., ciprofloxacin, ofloxacin)
- rosiglitazone
- telmisartan
- tofacitinib
- trastuzumab
- vaccines
Pregnancy & Lactation of Mycophenolate mofetil
FDA Pregnancy Category C
Pregnancy
Mycophenolate mofetil has been reported to cause birth defects and pregnancy loss when taken by pregnant women. It should not be used during pregnancy unless the benefits outweigh the risks. Women who may become pregnant must have 2 negative urine or blood pregnancy tests before starting this medication. (The second test should be 8 to 10 days after the first test and immediately before starting treatment.) Use 2 methods of effective birth control before the start of treatment with mycophenolate mofetil, during treatment, and for 6 weeks after the medication has been stopped. Consult your doctor immediately if you become pregnant while taking this medication. Mycophenolate mofetil may make the birth control pill less effective, so the second form of contraception must always be used.
Lactation
It is not known if mycophenolate mofetil passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Breastfeeding is not recommended while taking this medication.
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