Myotec

Myotec

mycophenolic acid

Manufacturer:

United Biotech

Distributor:

Triple Tact

Marketer:

A-Z Med Inc
Full Prescribing Info
Contents
Mycophenolate mofetil.
Description
Each film coated tablet contains: Mycophenolate Mofetil 250 mg.
Each film coated tablet contains: Mycophenolate Mofetil 500 mg.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Mycophenolate mofetil has been demonstrated in experimental models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow).
Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models.
Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form 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. 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.
Pharmacokinetics: Following oral administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 μg/mL).
Absorption: In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g.
Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food (see Dosage & Administration).
Distribution: The mean (± SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.
Metabolism: Following oral dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA 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. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations.
Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency (see Special Populations as follows).
Excretion: Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (> 100 μg/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug (see Overdosage). Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration.
Special Populations: Shown as follows are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment. (See table.)

Click on icon to see table/diagram/image
Indications/Uses
For the prevention of graft rejection, and has also been tried in diseases with an autoimmune or immune mediated inflammatory component with other immunosuppressants.
Dosage/Direction for Use
Renal Transplantation: A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients.
Cardiac Transplantation: A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
Hepatic Transplantation: A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.
Patients with Hepatic Impairment: No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic diseases with other etiologies. No data are available for cardiac transplant patients with hepatic parenchymal disease.
Geriatrics: The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see Use in Elderly under Precautions).
Overdosage
The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing.
Contraindications
Allergic reactions to mycophenolate mofetil have been observed; therefore, MYOTEC is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.
Warnings
Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, 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.
Oversuppression of the immunity system can also increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis. In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients.
Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients.
Neutropenia: Severe neutropenia [absolute neutrophil count (ANC) < 0.5 x 103/μL] developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily. If neutropenia develops (ANC < 1.3 x 103/μL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately.
Use in Pregnancy: Teratogenic Effects: Pregnancy Category D.
Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant woman.
Special Precautions
General: Gastrointestinal bleeding has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily.
During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective.
Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year.
Use in Pregnancy: Teratogenic Effects: Pregnancy Category D. See Warnings.
Use in Lactation: Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of mycophenolate mofetil is 600 mg/m2 bid (up to a maximum of 1 g bid). Safety and effectiveness in pediatric patients receiving allogeneic cardiac or hepatic transplants have not been established.
Use in Elderly: Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, 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.
Use In Pregnancy & Lactation
Use in Pregnancy: Teratogenic Effects: Pregnancy Category D.
Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant woman.
Use in Lactation: Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Infections and infestations: Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster. Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Skin cancer, benign neoplasm of skin.
Blood and lymphatic system disorders: Leucopenia, thrombocytopenia, anaemia. Pancytopenia, leucocytosis.
Metabolism and nutrition disorders: Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout, anorexia.
Psychiatric disorders: Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia.
Nervous system disorders: Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia.
Cardiac disorders: Tachycardia.
Vascular disorders: Hypotension, hypertension, vasodilatation.
Respiratory, thoracic and mediastinal disorders: Pleural effusion, dyspnoea, cough.
Gastrointestinal disorders: Vomiting, abdominal pain, diarrhoea, nausea. Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation.
Hepatobiliary disorders: Hepatitis, jaundice, hyperbilirubinaemia.
Skin and subcutaneous tissue disorders: Skin hypertrophy, rash, acne, alopecia.
Musculoskeletal and connective tissue disorders: Arthralgia.
Renal and urinary disorders: Renal impairment.
General disorders and administration site conditions: Oedema, pyrexia, chills, pain, malaise, asthenia.
Drug Interactions
Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine.
Acyclovir: Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs.
Antacids With 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 mycophenolate mofetil 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.
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 are coadministered with mycophenolate mofetil with caution and additional birth control methods be considered.
Rifampin: Mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.
Storage
Store at temperatures not exceeding 30°C.
MIMS Class
ATC Classification
L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
FC tab (light pink color capsule shaped, biconvex) 250 mg x 60's. 500 mg x 60's.
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