SOPEVA is Mycophenolate Mofetil, which is chemically 2-morpholinoethyl (E)-6-(1, 3-dihydro-4hydroxy-6-methoxy-7methyl-3-oxo-5 isobenzofuranyl)-4-methyl-4-hexenoate. Its empirical formula is C23H31NO7 and has a molecular weight of 433.50.

Mechanism of Action

Mycophenolate Mofetil is a morpholinoethyl ester prodrug of the immunosuppressant mycophenolic acid (MPA), a fermentation product of several Penicillium species. The mechanism of action of MPA is based on interference with purine synthesis. It is a reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) which is an enzyme that facilitates the conversion of inosine monophosphate (IMP) to xanthosine monophosphate, a precursor of guanine nucleotides.

This 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 pathways, B and T lymphocytes are dependent upon the de novo pathway for the generation of guanosine.

Pharmacokinetics

Mycophenolate Mofetil is rapidly absorbed after oral administration and converted to the active metabolite, MPA. MPA is then further metabolized to MPA glucuronide (MPAG), which is pharmacologically inactive. The mean relative bioavailability of MPA is 94% for oral administration. The maximum plasma concentration (Cmax) occurs approximately 2 hours after oral administration. Observed secondary peaks in plasma levels are due to the enterohepatic circulation of the drug.

Food has no affect 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 lowered by 40% in the presence of food. MPA binds to plasma albumin in a concentration dependent manner. MPA binding is not altered by the common immunosuppressive medications, including cyclosporine, prednisone, and tacrolimus, or other common medications, including warfarin, digoxin, and phenytoin. MPA is minimally bound to plasma lipoproteins in a concentration - independent manner.

MPA is converted to MPAG and three additional inactive metabolites, N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. Alcoholic cirrhosis does not appear to appreciably alter the hepatic metabolism of MPA to MPAG. MPA is eliminated primarily by the kidneys, with more than 90% of the dose excreted in the urine as MPAG. The mean apparent half life and plasma clearance of mycophenolic acid are 17.9 hours and 11.6 L/h, respectively after oral administration. In a single dose study of MPA, plasma area under the curve increased almost twofold in patients with severe renal impairment. Hemodialysis does not appear to significantly alter plasma MPA or MPAG levels.

Composition

Each film-coated tablet contains Mycophenolate Mofetil BP 500 mg

Indications

Allogeneic transplants : For the prophylaxis of organ rejection in patients receiving allogeneic renal, hepatic or cardiac transplant. Use Mycophenolate concomitantly with cyclosporine and corticosteroids.

Contraindications

Hypersensitivity to drug, mycophenolic acid, or any component of the drug product.

Precautions

Monitoring : Perform complete blood counts weekly during first month of treatment, twice monthly for second and third months, then monthly through the first year. GI hemorrhage: Since Mycophenolate has been associated with an increased incidence of GI adverse events, including infrequent cases of GI tract ulceration, hemorrhage, and perforation, administer with caution in patients with active serious GI disease. Delayed renal graft function post transplant: No dose adjustment is recommended for these patients, however they should be carefully observed.

Warnings

Pregnancy

There are no adequate and well controlled studies in pregnant women. Do not use in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity at least 50 mIU/ml with in 1 week prior to beginning therapy. Do not initiate Mycophenolate therapy until a negative pregnancy test report is obtained. Effective contraception must be used before beginning Mycophenolate therapy, during therapy, and for 6 weeks following discontinuation of therapy, even when there has been a history of infertility, unless due to hysterectomy. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy.

Lactation

Studies in rats treated with Mycophenolate have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants from Mycophenolate, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Children

Safety and efficacy have not been established.

Lymphomas / Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs, including Mycophenolate, 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 immune system can also increase susceptibility to infection

Neutropenia

Monitor patients receiving Mycophenolate for neutropenia. The development of neutropenia may be related to Mycophenolate itself, concomitant medications, viral infections or some combination of these causes

Renal function impairment

Avoid Mycophenolate doses > 1 g twice a day and carefully observe patients

Adverse effects

The principal adverse reactions associated with Mycophenolate include diarrhea, leucopenia, sepsis, and vomiting, and evidence of a higher frequency of certain types of infections. Serious life threatening infections such as meningitis and infectious endocarditis have been reported occasionally, and there is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterium infection.

Other adverse reactions occurring in 3% to < 20% of patients in combination with cyclosporine and corticosteroids are as follows: Cardiovascular: Angina pectoris; arterial fibrillation; hypotension; palpitation; peripheral vascular disorder, postural hypotension; tachycardia; thrombosis; vasodilatation; ventricular extrasystole; CHF; supraventricular tachycardia; ventricular tachycardia; arterial flutter; pulmonary hypertension; heart arrest; venous pressure increased; syncope; supraventricular extrasystoles; pallor; vasospasm.

CNS: Anxiety; depression; hypertonia; paresthesia; somnolence; emotional liability; neuropathy, convulsion, hallucinations, abnormal thinking, vertigo. Dermatologic: Alopecia, fungal dermatitis, hirsutism, pruritus, benign skin neoplasm, skin disorder, skin hypertrophy, skin ulcer, sweating, hemorrhage and skin carcinoma. Endocrine: Diabetes, parathyroid disorder, Cushing's syndrome, hypothyroidism GI: Anorexia, esophagitis, flatulence, gastritis, gastroenteritis, GI hemorrhage, gingivitis, gum hyperplasia, hepatitis, ileus, infection, mouth ulceration; rectal disorder, GI disorder, liver damage, dysphagia, jaundice, stomatitis, thirst.

GU: 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, hiccough, pneumothorax, increased sputum, epistaxis, apnea, voice alteration, pain, hemoptysis, neoplasm, respiratory acidosis. Special sense: Amblyopia, cataract, conjunctivitis, ear pain, deafness, ear disorder, tinnitus, abnormal vision, lacrimation disorder, eye hemorrhage Miscellaneous: Abdomen enlarged, 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, and dehydration. Lab test abnormalities: Increased alkaline phosphates, creatinine, gamma glutamyl transpeptidase, lactic dehydrogenase, AST and ALT, hypercalcemia, hyperlipdemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypoproteinemia, acidosis, hypoxia, hypophosphatemia, alkalosis and hypochloremia.

Drug Interactions

Drugs which are eliminated by renal tubular secretion (e.g. aciclovir, ganciclovir) have the potential to inhibit the elimination of MPAG through competition for renal tubular secretion. Agents that interfere with enterohepatic recycling (e.g. bile acid sequestrants, antibiotics) may reduce the amount of mycophenolic acid available for reabsorption. In healthy volunteers concomitant administration of single doses of Mycophenolate Mofetil and aciclovir resulted in a significantly higher AUC of MPAG than when Mycophenolate Mofetil was given alone.

Co administration of Mycophenolate Mofetil and cholestyramine resulted in a 40% decrease in the AUC of mycophenolic acid. Administration of a single dose of Mycophenolate Mofetil 2 g to patients with rheumatoid arthritis who were receiving an aluminum hydroxide / magnesium hydroxide antacid resulted in reductions on the AUC24 (33%) and Cmax (17%) of mycophenolic acid compared with administration of Mycophenolate Mofetil alone. Single and/or multiple dose studies have reported no pharmacokinetic interaction between Mycophenolate Mofetil and ganciclovir, cotrimoxazole, oral contraceptives or cyclosporine

Overdosage

Symptoms : At doses of 4 or 5g/day, there appears to be a higher rate, compared with the use of 3g/day or less, of GI intolerance (nausea, vomiting, diarrhea), and occasional hematologic abnormalities, principally neutropenia. Treatment: MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentration (> 100 mcg/ml), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine.

Dosage and administration

  • Renal transplantation : A dose of 1 g administered orally twice a day (daily dose of 2 g). Although a dose of 1.5 g twice daily (daily dose of 3g) 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 demonstrate an overall better safety profile than patients receiving 3 g/day.
  • Cardiac transplantation : A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is recommended.
  • Hepatic transplantation : A dose of 1.5 g administered orally twice a day is recommended.

Give the initial oral dose as soon as possible following transplant. Food has been shown to decrease MPA Cmax by 40%. It is recommended that Mycophenolate be administered on an empty stomach.

Storage

Store in a cool, dry place. Protect from light and moisture.

Presentation

SOPEVA is available as tablets in a blister of 10 tablets and 5 such blisters in a box