Mofilet-500

Mofilet-500

mycophenolic acid

Manufacturer:

Emcure Pharma

Distributor:

Macropharma Corp
Full Prescribing Info
Contents
Mycophenolate mofetil.
Description
Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an inosine monophosphate dehydrogenase (IMPDH) inhibitor. Mycophenolate mofetil is 2-morpholinoethyl(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H21NO7 and a molecular weight of 433.5.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: In the body, MMF is hydrolyzed to form MPA, which is the active metabolite. Mycophenolic acid 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. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize other salvage pathways. Mycophenolic acid has potent cytostatic effects on lymphocytes, it inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Mycophenolic acid also suppresses antibody formation by B-lymphocytes. It 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 does not inhibit early event in the activation of human peripheral blood mononuclear cells eg, the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but blocks the coupling of these events to DNA synthesis and proliferation.
Pharmacokinetics: Mycophenolate mofetil is rapidly and completely absorbed orally. Bioavailability of MPA is 94%. After administration of single dose of MMF in the fasting state, the maximum plasma concentration (Cmax) of 3.67±0.51 mcg/mL was achieved in 2.92±0.79 hrs (Tmax). The plasma elimination t½ of MMF was found to be 11.74±3.29 hrs. Mycophenolic acid, at clinically relevant concentrations is 97% bound to plasma albumin.
Mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. Mycophenolic acid is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active in vivo, MPAG is converted to MPA via enterohepatic recirculation. Negligible amount of drug is excreted as MPA in the urine. Most of the orally administered dose is excreted in the urine as MPAG.
Indications/Uses
Prophylaxis of cardiac and renal graft rejection, and rejection in hepatic transplantation. Mycophenolate should be used concomitantly with cyclosporine and corticosteroids.
Dosage/Direction for Use
Adults: Renal Transplantation: 1 g twice daily (2 g/day).
Cardiac or Hepatic Transplantation: 1.5 g twice daily (3 g/day).
Food has no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. It is recommended that mycophenolate be administered on an empty stomach. However, in stable renal transplant patients, MMF may be administered with food if necessary.
Overdosage
There has been no reported experience of the overdose of MMF in humans. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day.
In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of MMF tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients. Mycophenolic acid and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed. By increasing excretion of Mofilet-500, MPA can be removed by bile acid sequestrants eg, cholestyramine.
Contraindications
Hypersensitivity to mycophenolate mofitel, mycophenolic acid or any component of Mofilet-500.
Special Precautions
Patients receiving immunosuppressive regimens involving combinations of drugs, including MMF, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Over-suppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections and sepsis.
Lymphoproliferative disease or lymphoma developed in patients receiving MMF (2 or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac and hepatic transplant patients.
Severe neutropenia may develop in renal transplant patients receiving MMF 3 g daily. Patients receiving MMF should be monitored for neutropenia. The development of neutropenia may be related to MMF itself, concomitant medications, viral infections or combination of these causes. If neutropenia develops, dosing with MMF should be interrupted or the dose is reduced, appropriate diagnostic tests are performed and the patient is managed appropriately.
Patients receiving MMF should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Gastrointestinal bleeding (requiring hospitalization) has been observed in renal transplant patients treated with MMF.
Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) receiving single doses of MMF may show higher plasma MPA and MPAG AUCs. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of MMF >1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Mycophenolate mofetil is not tumorigenic in rat and mice studies. Mycophenolate mofetil is genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay but is not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay. Mycophenolate mofetil has no effect on fertility in rats.
Use in pregnancy: Pregnancy Category D: Mofilet-500 is not recommended during pregnancy. Women of childbearing potential must use effective contraception every 4 weeks prior to and 6 weeks after stopping therapy and have a negative serum or urine pregnancy test within 1 week prior to beginning therapy. Mofilet-500 may decrease the blood levels of the hormones in the oral contraceptive pill and theoretically reduce its effectiveness.
Use in lactation: Studies in rats treated with MMF have shown MPA to be excreted in the milk. It is not known whether Mofilet-500 is excreted in the human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from MMF, a decision should be made whether to discontinue nursing or Mofilet-500, taking into account the importance of Mofilet-500 to the mother.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category D: Mofilet-500 is not recommended during pregnancy. Women of childbearing potential must use effective contraception every 4 weeks prior to and 6 weeks after stopping therapy and have a negative serum or urine pregnancy test within 1 week prior to beginning therapy. Mofilet-500 may decrease the blood levels of the hormones in the oral contraceptive pill and theoretically reduce its effectiveness.
Use in lactation: Studies in rats treated with MMF have shown MPA to be excreted in the milk. It is not known whether Mofilet-500 is excreted in the human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from MMF, a decision should be made whether to discontinue nursing or Mofilet-500, taking into account the importance of Mofilet-500 to the mother.
Adverse Reactions
The principal adverse reactions associated with the administration of MMF include diarrhea, leukopenia, sepsis, vomiting and there is evidence of a higher frequency of certain types of infections. Serious life-threatening infections eg, meningitis and infectious endocarditis have been reported occasionally and there is evidence of a higher frequency of certain types of serious infections eg, tuberculosis and atypical mycobacterial infection.
Other adverse reactions reported in combination with cyclosporine and corticosteroids are as follows: Cardiovascular: Angina pectoris, atrial fibrillation, hypotension, palpitation, peripheral vascular disorder, postural hypotension, tachycardia, thrombosis, vasodilation, ventricular extrasystole, congestive heart failure (CHF), supraventricular tachycardia, ventricular tachycardia, atrial flutter, pulmonary hypertension, heart arrest, increased venous pressure, syncope, supraventricular extrasystoles, pallor, vasospasm.
Central Nervous System: Anxiety, depression, hypertonia, paresthesia, somnolence, emotional lability, neuropathy, convulsion, hallucinations, abnormal thinking, vertigo.
Dermatologic: Alopecia, fungal dermatitis, hirsutism, pruritus, benign skin neoplasm, skin disorder, sweating, hemorrhage, skin carcinoma.
Endocrine: Diabetes, parathyroid disorder, Cushing's syndrome and hypothyroidism.
Gastrointestinal: Anorexia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, gum hyperplasia, hepatitis, ileus, infection, mouth ulceration; rectal disorder, liver damage, dysphagia, jaundice, stomatitis, thirst.
Urogenital: Albuminuria, dysuria, hydronephrosis, impotence, pain, pyelonephritis, urinary frequency, nocturia, kidney failure, urine abnormality, hematuria, urinary incontinence, prostatic disorder, urinary retention.
Musculoskeletal: Arthralgia, joint disorder, leg cramps, myalgia, myasthenia.
Respiratory: Asthma, lung edema, pleural effusion, rhinitis, sinusitis, atelectasis, hiccups, pneumothorax, increased sputum, epistaxis, apnea, voice alteration, pain, hemoptysis, neoplasm, respiratory acidosis.
Special Senses: Amblyopia, cataract, conjunctivitis, ear pain, deafness, deafness, ear disorder, tinnitus, abnormal vision, lacrimation disorder, eye hemorrhage.
Miscellaneous: Enlarged abdomen, chills/fever, cyst, face edema, flu syndrome, hemorrhage, hernia, malaise, pelvic pain, ecchymosis, polycythemia, neck pain, cellulitis, increased prothrombin, decreased thromboplastin, petechia, phlebitis, thrombosis, weight gain/loss, abnormal healing dehydration.
Laboratory Test Abnormalities: Increased alkaline phosphatase, creatinine, γ-glutamyl transpeptidase, lactic dehydrogenase, aspartate transaminase (AST) and alanine transaminase (ALT), hypercalcemia, hyperlipidemia, hyperuricemia, hypervolemia; hypocalcemia, hypoglycemia, hypoproteinemia, acidosis, hypoxia, hypophosphatemia, alkalosis, hypochloremia.
Drug Interactions
Acyclovir: Co-administration of MMF and acyclovir resulted in no significant change in MPA AUC and Cmax, however MPAG and acyclovir plasma AUCs can increase. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for the 2 drugs to compete for tubular secretion, further increasing the concentrations of both drugs.
Antacids with Magnesium and Aluminum Hydroxides: Absorption of a single dose of mycophenolate mofetil is decreased when administered with antacids containing magnesium and aluminum hydroxides. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that MMF and the antacid not be administered simultaneously.
Cholestyramine: Mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation as AUC of MPA is decreased.
Ganciclovir: Since MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the 2 drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir are co-administered, patients should be monitored carefully.
Oral Contraceptives: Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. However, it is recommended that oral contraceptives be co-administered with MMF with caution and additional birth control methods be considered.
Live Vaccines: During treatment with MMF, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations might be less effective.
Azathioprine: It is recommended that MMF not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically.
Storage
Store at temperatures not exceeding 30°C. Keep in a dry and dark place.
MIMS Class
ATC Classification
L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
FC tab 500 mg x 10's.
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