Mycophen

Mycophen

mycophenolic acid

Manufacturer:

Micro Labs

Distributor:

Zizawa Healthcare
Full Prescribing Info
Contents
Mycophenolate mofetil.
Description
Mycophenolate mofetil is 2-morpholin-4-ylethyl(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate.
Action
Immunosuppressive agent.
Pharmacology: Mechanism of Action: Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). It is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, 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 the de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatics effects on lymphocytes than on other cells.
Pharmacokinetics: Following oral administration, mycophenolate mofetil undergoes rapid and extensive and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g twice-daily to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. MPA at clinically relevant concentrations, is 97% bound to plasma albumin.
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6-12 hrs post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g three times daily), indicating that there is a significant amount of enterohepatic recirculation.
MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.
A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the administered dose recovered in the urine and 6% recovered in the feces.
Most (about 87%) of the administered dose is excreted in the urine as MPAG.
Indications/Uses
Renal, Cardiac and Hepatic Transplant: Prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate should be used concomitantly with cyclosporine and corticosteroids.
Dosage/Direction for Use
Renal Transplant: Adults: Mycophenolate should be initiated within 72 hrs following transplantation. The recommended dose is 1 g administered twice daily (2 g daily dose).
Children and Adolescents 2-18 years: 600 mg/m2 administered orally twice daily (up to a maximum of 2 g daily). Children <2 years: Not recommended.
Cardiac Transplant: Adults: Mycophenolate should be initiated within 5 days following transplantation. The recommended dose is 1.5 g administered twice daily (3 g daily dose). Children: No data are available for pediatric cardiac transplant patients.
Hepatic Transplant: Adults: Mycophenolate IV should be administered for the first 4 days following hepatic transplant with oral mycophenolate initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose). Children: No data are available for pediatric transplant patients.
Use in elderly (65 years): 1 g administered twice daily for renal transplant patients and 1.5 g twice daily for cardiac or hepatic transplant patients is appropriate for the elderly.
Renal Impairment: In renal transplant patients with severe chronic renal impairment (glomerular filtration rate <25 mL·min-1·1.73 m-2), outside the immediate post-transplant period, doses >1 g administered twice daily should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delay renal graft function post-operatively. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Severe Hepatic Impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
Treatment During Rejection Episodes: Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of mycophenolate is not required. There is no basis for mycophenolate dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.
Overdosage
Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdosage cases in which adverse events were reported, the events fall within the known safety profile of Mycophen.
It is expected that an overdosage of mycophenolate mofetil could possibly result in oversuppression of the immune system, and increased susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with mycophenolate should be interrupted or the dose reduced.
Hemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants eg, cholestyramine, can remove MPA by decreasing the enterohepatic recirculation of the drug.
Contraindications
Hypersensitivity reactions to mycophenolate have been observed. Therefore, mycophenolate is contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.
Use in lactation: Mycophenolate is contraindicated in women who are breastfeeding.
Special Precautions
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate, 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. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing clothing and using a sunscreen with a high protection factor.
Patients receiving mycophenolate should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including mycophenolate, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Patients receiving mycophenolate should be monitored for neutropenia, which may be related to mycophenolate itself, concomitant medications, viral infections or some combinations of these causes. Patients taking mycophenolate should have complete blood counts weekly during the 1st month, twice monthly for the 2nd and 3rd months of treatment, then monthly through the 1st year. If neutropenia develops (absolute neutrophil count <1.3 x 103/microliter), it may be appropriate to interrupt or discontinue mycophenolate.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate in combination with other immunosuppressants. The mechanism for mycophenolate mofetil-induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate therapy. Changes to mycophenolate therapy should only be under appropriate supervision in transplant recipients in order to minimize the risk or graft rejection.
Patients should be advised that during treatment with mycophenolate, vaccinations may be less effective and the use of live attenuated vaccines should only be undertaken appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.
Patients should be advised that during treatment with mycophenolate, vaccinations may less be effective, and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Because mycophenolate has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, mycophenolate should be administered with caution in patients with active serious digestive system disease.
Mycophenolate is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) eg, Lesch-Nyhan and Kelley-Seegmiller syndrome.
It is recommended that mycophenolate should not be administered concomitantly with azathioprine because such concomitant administration has not been studied. In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in concomitant administration of mycophenolate with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate.
The risk: Benefit of mycophenolate mofetil in combination with tacrolimus has not been established.
Use in pregnancy: The use of mycophenolate is not recommended during pregnancy.
Use In Pregnancy & Lactation
Use in pregnancy: The use of mycophenolate is not recommended during pregnancy.
Use in lactation: Mycophenolate is contraindicated in women who are breastfeeding.
Side Effects
Acne, constipation, diarrhea, difficulty in sleeping, dizziness, gas, headache, heartburn, loss of appetite, nausea and vomiting, pain, skin rash, weakness.
Drug Interactions
Interaction studies have only been performed in adults.
Aciclovir: Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs eg, valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.
Antacids with Magnesium and Aluminum Hydroxides: Absorption of mycophenolate mofetil was decreased when administered with antacids.
Cholestyramine: Following single dose administration of mycophenolate mofetil 1.5 g to normal healthy subjects pre-treated with 4 g 3 times daily of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA. Caution should be used during concomitant administration because of the potential to reduce efficacy of mycophenolate. Medicinal products that interfere with enterohepatic circulation: Caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of mycophenolate.
Ciclosporin A: Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil.
In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.
Ganciclovir: Based on the results of a single dose administration study of recommended dose of oral mycophenolate and ganciclovir IV and the known effects of renal impairment on the pharmacokinetics of mycophenolate and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanism of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate dose adjustment is not required. In patients with renal impairment in which mycophenolate and ganciclovir or its prodrugs eg, valganciclovir are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.
Oral Contraceptives: The pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by co-administration of mycophenolate.
Rifampicin: In patients not also taking ciclosporin, concomitant administration of mycophenolate and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18-70%. It is recommended to monitor MPA exposure levels and to adjust mycophenolate doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.
Sirolimus: In renal transplant patients, concomitant administration of mycophenolate and CsA resulted in reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus and similar doses of mycophenolate.
Sevelamer: Decreased MPA Cmax and AUC0-12h by 30% and 25%, respectively, were observed when mycophenolate was concomitantly administered with sevelamer without any clinical consequences (ie, graft rejection). It is recommended, however, to administer mycophenolate at least 1 hr before or 3 hrs after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on mycophenolate with phosphate binders other than sevelamer.
Trimethoprim/Sulfamethoxazole: No effect on the bioavailability of MPA was observed.
Norfloxacin and Metronidazole: In healthy volunteers, no significant interaction was observed when mycophenolate was concomitantly administered with norfloxacin and metronidazole separately. However, combined norfloxacin and metronidazole reduced the MPA exposure by approximately 30% following a single dose of mycophenolate.
Ciprofloxacin and Amoxicillin Plus Clavulanic Acid: Reductions in predose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
Tacrolimus: In hepatic transplant patients initiated on mycophenolate and tacrolimus, the AUC and Cmax of MPA, the active metabolite of mycophenolate, were not significantly affected by co-administration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of mycophenolate (1.5 g twice daily) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by mycophenolate.
Other Interactions: Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substance known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.
Live Vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
Storage
Store below 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 250 mg x 6 x 10's. 500 mg x 6 x 10's.
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