Immucept 250/Immucept 500

Mycophenolate mofetil.

Immucept 250: Each capsule contains Mycophenolate mofetil (INN: Mycophenolic acid) 250 mg. Immucept 500: Each tablet contains Mycophenolate mofetil (INN: Mycophenolic acid) 500 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways. Therefore, MPA has potent cytostatic effects on lymphocytes than on other cells.
Pharmacokinetics: Absorption: Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV.
Food 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 C_max was decreased by 40% in the presence of food.
In the early post-transplant period (<40 days post-transplant), renal, cardiac and hepatic patients have mean MPA AUCs and C_max lower compared to the late post-transplant period (3-6 months post-transplant).
Distribution: At clinically relevant concentrations, MPA is 97% bound to plasma albumin. Following oral administration of mycophenolate mofetil, the mean volume of distribution of MPA is 4 l/kg.
Metabolism: Following oral administration, mycophenolate mofetil undergoes complete presystemic metabolism to the active metabolite, MPA. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is inactive metabolite.
As a result of enterohepatic recirculation, secondary increases in the plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately a 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.
Excretion: A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil results 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. Half-life of elimination for oral is 18 hours whereas median time to peak plasma concentration is 1-1.5 hours.

Mycophenolate Mofetil is indicated in combination with cyclosporine and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants and treatment of refractory acute transplant rejection in patients receiving allogeneic renal.
Mycophenolate Mofetil is indicated for induction and maintenance therapy of patients Class III-IV Lupus nephritis (diagnosed according to the International Society of Nephrology / Renal Pathology Society classification).

Recommended Doses: Treatment with mycophenolate mofetil should be initiated and maintained by appropriately qualified transplant specialists.
Use in renal transplant: Adults: Oral mycophenolate mofetil should be initiated within 72 hours following transplantation.
The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
Children and adolescents (aged 2 to 18 years): The recommended dose of mycophenolate mofetil is 600 mg/m² administered orally twice daily (up to a maximum dose of 2 g daily). Mycophenolate mofetil should only be prescribed to patients with a body surface area of at least 1.25 m². Patients with a body surface area of 1.25 m² to 1.5 m² may be prescribed mycophenolate mofetil at a dosed of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m² may be prescribed mycophenolate mofetil at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group compared with adult, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.
Children (< 2 years): Safety and efficacy in renal transplantation children younger than 2 years of age have not been established.
Use in cardiac transplant: Adults: Oral mycophenolate mofetil should be initiated as soon as possible following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).
Children: No data available for paediatric cardiac transplant patients.
Use in hepatic transplant: Adults: Oral Mycophenolate Mofetil should be initiated as soon as possible following transplantation. The recommended dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).
Children: No data available for paediatric hepatic transplant patients.
Use in elderly (≥ 65 years): The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.
Use in renal impairment: In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 m²), outside the immediate post-transplant period, dose greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Use in severe hepatic impairment: No data 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.
Lupus nephritis patients: Standard Dosage for Induction Therapy: A Dose of 750 mg - 1.5 g administered orally twice a day (daily dose of up to 3 g) is recommended.
Standard Dosage for Maintenance Therapy: A Dose of 500 mg - 1 g administered orally twice a day (daily dose of up to 2 g) is recommended.
Mycophenolate Mofetil should be used in combination with corticosteroids. Doses should be introduced gradually and adjusted according to clinical response. Therapeutic drug monitoring could help prevent sub-therapeutic exposure (Cmin ≥ 3.0 mg/L or inter-dose AUC ≥ 35 h*mg/L).
Mode of Administration: Capsule for oral use.

Overdose: Reports of overdoses with mycophenolate mofetil have been received from clinical and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.
Treatment: It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with mycophenolate mofetil should be interrupted or the dose reduced.
Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug.

This drug is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product and in women who are breastfeeding.

Lymphomas/Malignancies: Patients receiving immunosuppressive regimens involving combinations of medical products, including mycophenolate mofetil, 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 minimize the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients receiving mycophenolate mofetil capsules 250 mg should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Infection: Patient treated with immunosuppressants, including mycophenolate mofetil, are increased risk for opportunistic infections (bacterial, fungal, viral, and protozoal), fatal infections and sepsis. The opportunistic infections are BK virus associated nephropathy (BKVAN) 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.
Neutropenia: Patients receiving mycophenolate mofetil should be monitored for neutropenia, which may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes. Patient taking mycophenolate mofetil should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count <1.3 x 10³/μl), it may be appropriated to interrupt or discontinue mycophenolate mofetil.
Pure red cell aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil 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. Change to mycophenolate mofetil therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Vaccines: Patients should be advised that during treatment with mycophenolate mofetil, vaccinations may be less 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.
GI effect: Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Mycophenolate Mofetil should be administered with caution in patients with active serious digestive system disease.
Rare hereditary deficiency: Mycophenolate Mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Pregnancy: It is recommended that mycophenolate mofetil therapy should not be initiated until a negative pregnancy test (not pregnancy) has been obtained. Effective contraception must be used before beginning mycophenolate mofetil therapy, during therapy, and for six weeks following discontinuation of therapy. Patient should be instructed to consult their physician immediately should pregnancy occur.
The use of mycophenolate mofetil is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. Mycophenolate mofetil should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of mycophenolate mofetil in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported with patients exposed to mycophenolate mofetil. Studies in animals have shown reproductive toxicity.
Lactation: Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, mycophenolate mofetil is contraindicated in nursing mothers.

The following undesirable effects cover adverse reactions from clinical trials: The principal adverse reactions associated with the administration of mycophenolate mofetil in combination with cyclosporine and corticosteroids include diarrhea, leukopenia, sepsis, and vomiting, and there is evidence of a higher frequency of certain types of infections.
Malignancies: Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Lymphoproliferative disease or lymphoma developed in 0.4-1% of patients receiving mycophenolate mofetil capsules 250 mg (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g), cardiac and hepatic transplant patients followed for at least 1 year. Non melanoma skin carcinomas occurred in 1.6-4.2% of patients; other types of malignancy occurred in 0.7-2.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data.
Opportunistic infections: All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load. The most common opportunistic infections in patients receiving mycophenolate mofetil capsules 250 mg (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%.
Children and adolescents (ages 2 to 18 years): The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patient given 1 g mycophenolate mofetil twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population when compared to adults: abdominal pain, anemia, diarrhea, fever, hypertension, infection, leukopenia, pain, pharyngitis, respiratory tract infection, sepsis, and vomiting.
Elderly patients (≥ 65 years): Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.
Other adverse reactions: Very common Adverse Reaction (>20%): Cardiovascular: Hypertension, hypotension, peripheral edema, edema, chest pain, tachycardia.
Central nervous system: Pain, headache, insomnia, fever, dizziness, anxiety.
Dermatologic: Rash.
Endocrine & metabolic: Hyperglycemia, hypercholesterolaemia, hypomagnesemia, hypokalemia, hypocalcemia, hyperkalemia.
Gastrointestinal: Abdominal pain, nausea, diarrhea, constipation, vomiting, anorexia, dyspepsia.
Genitourinary: Urinary tract infection.
Hematologic: Leucopenia, anemia, hypochromic, leukocytosis, thrombocytopenia.
Hepatic: Liver function tests abnormal, ascites.
Neuromuscular & skeletal: Back pain, weakness, tremor, paresthesia.
Renal: Creatinine increased, BUN increased, kidney function abnormal.
Respiratory: Dyspnea, respiratory tract infection, pleural effusion, cough, lung disorder, sinusitis.
Miscellaneous: Lactate dehydrogenase increased.
Common Adverse Reaction (3% to 20%): Cardiovascular: Angina, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, cardiac failure, CHF, extrasystole, facial edema, hyper/hypovolemia, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, supraventricular tachycardia, syncope, thrombosis, vasospasm, venous pressure increased, ventricular extrasystole, ventricular tachycardia.
Central nervous system: Agitation, chills with fever, confusion, delirium, depression, emotional lability, hallucination, hypoesthesia, malaise, nervousness, seizure, somnolence, thinking abnormal, vertigo.
Dermatologic: Acne, alopecia, bruising, cellulitis, fungal dermatitis, hirsutism, petechia, pruritus, skin carcinoma, skin hypertrophy, skin ulcer, vesiculobullous rash.
Endocrine & metabolic: Acidosis, alkalosis, Cushing's syndrome, dehydration, diabetes mellitus, Gout, hypercalcemia, hyper/hypophosphataemia, hyperlipemia, hyperuricemia, hypochloremia, hypoglycemia, hyponatremia, hypothyroidism, parathyroid disorder.
Gastrointestinal: Abdomen enlarged, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, ileus, melena, mouth ulceration, oral moniliasis, stomach disorder, stomach ulcer, stomatitis, xerostomia, weight gain/loss.
Genitourinary: Impotence, nocturia, pelvic pain, prostatic disorder, scrotal edema, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder.
Hematologic: Coagulation disorder, hemorrhage, neutropenia, pancytopenia, polycythemia, Prothrombin time increased, thromboplastin time increased.
Hepatic: Alkaline phosphatase increased, bilirubinemia, cholangitis, cholestatic jaundice, GGT increased, hepatitis, jaundice, liver damage, transaminases increased.
Local: Abscess.
Neuromuscular and skeletal: Arthralgia, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, neck pain, neuropathy.
Ocular: Amblyopia, cataract, conjunctivitis, eye hemorrhage, lacrimation disorder, vision abnormal.
Otic: Deafness, ear disorder, ear pain, tinnitus.
Renal: Albuminuria, creatinine increased, dysuria, hematuria, hydronephrosis, oliguria, Pyelonephritis, renal failure, renal tubular necrosis.
Respiratory: Apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, respiratory acidosis, pharyngitis, pneumonia, pneumothorax, pulmonary edema, pulmonary hypertension, respiratory moniliasis, rhinitis, sputum increased, voice alteration.
Miscellaneous: Candida (mucocutaneous), CMV viremia/syndrome, CMV tissue invasive disease, Herpes zoster, cutaneous disease, cyst, diaphoresis, flu-like syndrome, healing abnormal, hernia, ileus infection, neoplasm, peritonitis, thirst.
Post-marketing and /or case report: Atypical mycobacterial infection, BK virus- associated-nephropathy, colitis, gastrointestinal perforation, infectious endocarditis, interstitial lung disorder, villous atrophy, lymphoma, lymphoproliferative disease, malignancy, meningitis, pancreatitis, progressive multifocal leukoencephalopathy (sometime fatal), pulmonary fibrosis (fatal), pure red cell aplasia, tuberculosis.

Interaction studies have only been performed in adults.
Acyclovir, Ganciclovir and valacyclovir: Higher acyclovir plasma concentrations were observed when mycophenolate mofetil was administered with acyclovir in comparison to the administration of acyclovir alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir, ganciclovir and valaciclovir concentrations, the potential exists for these drug to compete for tubular secretion, and further increase in concentrations of these drugs may occur. Carefully monitor patients with renal impairment when these agents are coadministered.
Antacids with magnesium and aluminum hydroxides: Absorption of mycophenolate mofetil was decreased when administered with antacid.
Cholestyramine: Following coadministration of mycophenolate mofetil with cholestyramine, 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 mofetil.
Medical products that interfere with enterohepatic recirculation: Caution should be used with medical products that interfere with enterohepatic recirculation because of the potential to reduce efficacy of mycophenolate mofetil.
Cyclosporin A: Coadministration of mycophenolate mofetil with cyclosporine A may reduce enterohepatic recirculation of mycophenolate. It is recommended to monitor mycophenolic acid concentrations and response to therapy. Adjust the mycophenolate dose as needed.
Rifampin: Concomitant use of rifampin with mycophenolate mofetil is resulted in a decrease in MPA exposure. It is recommended to monitor MPA exposure levels and to adjust mycophenolate mofetil doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly. Concomitant use of mycophenolate mofetil and rifampin is not recommended unless benefit outweighs risk.
Sevelamer: Decrease in MPA plasma concentrations were observed when mycophenolate mofetil was concomitantly administered with sevelamer. It is recommended to administer sevelamer 2 hours after intake mycophenolate mofetil.
Tacrolimus, Sirolimus: MPA trough plasma concentrations may be elevated, increasing the risk of adverse reactions. It is recommended to monitor plasma mycophenolate levels and adjust dose as needed.
Norfloxacin and metronidazole: Concomitant use of mycophenolate mofetil and the anti-infective combination of norfloxacin and metronidazole not recommended due to potential pharmacokinetic interaction (decreased systemic exposure of mycophenolic acid); however, no substantial effect on systemic exposure of mycophenolic acid was observed when mycophenolate mofetil was administered with norfloxacin or metronidazole.
Ciprofloxacin and amoxicillin plus clavulanic: Reductions in pre-dose (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 pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil 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.
Oral contraceptives: Potential pharmacokinetic interaction with concomitant use of levonogestrel with mycophenolate mofetil (decreased plasma concentrations of levonogestrel). Pharmacokinetic interaction unlikely with concomitant use of mycophenolate mofetil with ethinyl estradiol, desogestrel, or gestodene. Oral contraceptives should be administered with caution in patients receiving mycophenolate and additional methods of birth control methods should be used.
Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
Other interactions: Co-administration of probenecid with mycophenolate mofetil in animals raises plasma AUC of MPAG by 3-fold and MPA by 2-fold.

Do not store above 30°C.

Immunosuppressants

L04AA06 - mycophenolic acid ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.

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