WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES AND SERIOUS INFECTIONS
Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning.
Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should prescribe CellCept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. |
CLINICAL PHARMACOLOGY
Mechanism of Action
Mycophenolate mofetil has been demonstrated in experimental animal 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.
INDICATIONS AND USAGE
Renal, Cardiac, and Hepatic Transplant
CellCept is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. CellCept should be used concomitantly with cyclosporine and corticosteroids.
CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral suspension. CellCept Intravenous should be administered within 24 hours following transplantation. CellCept Intravenous can be administered for up to 14 days; patients should be switched to oral CellCept as soon as they can tolerate oral medication.
CONTRAINDICATIONS
Allergic reactions to CellCept have been observed; therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product. CellCept Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).
PRECAUTIONS, Drug Interactions - see package insert
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DOSAGE AND ADMINISTRATION
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Renal Transplantation
Adults
A dose of 1 g administered orally or intravenously (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) 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 of CellCept demonstrated an overall better safety profile than did patients receiving 3 g/day of CellCept.
Pediatrics (3 months to 18 years of age)
The recommended dose of CellCept oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with CellCept capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with CellCept capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
Cardiac Transplantation
Adults
A dose of 1.5 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
Hepatic Transplantation
Adults
A dose of 1 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 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 disease with other etiologies (see package insert- CLINICAL PHARMACOLOGY: Pharmacokinetics).
No data are available for cardiac transplant patients with severe 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 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see package insert - PRECAUTIONS: Geriatric Use).
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CellCept Intravenous
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Adults
CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral suspension recommended for patients unable to take oral CellCept. CellCept Intravenous should be administered within 24 hours following transplantation. CellCept Intravenous can be administered for up to 14 days; patients should be switched to oral CellCept as soon as they can tolerate oral medication.
CellCept Intravenous must be reconstituted and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP. CellCept Intravenous is incompatible with other intravenous infusion solutions. Following reconstitution, CellCept Intravenous must be administered by slow intravenous infusion over a period of NO LESS THAN 2 HOURS by either peripheral or central vein.
CAUTION: CELLCEPT INTRAVENOUS SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION (see WARNINGS).
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Preparation of Infusion Solution (6 mg/mL)
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Caution should be exercised in the handling and preparation of solutions of CellCept Intravenous. Avoid direct contact of the prepared solution of CellCept Intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water (see package insert for WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and HANDLING AND DISPOSAL).
CellCept Intravenous does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions. Additionally, this product is sealed under vacuum and should retain a vacuum throughout its shelf life. If a lack of vacuum in the vial is noted while adding diluent, the vial should not be used.
CellCept Intravenous infusion solution must be prepared in two steps: the first step is a reconstitution step with 5% Dextrose Injection USP, and the second step is a dilution step with 5% Dextrose Injection USP. A detailed description of the preparation is given below:
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Step 1
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a) Two (2) vials of CellCept Intravenous are used for preparing each 1 g dose, whereas three (3) vials are needed for each 1.5 g dose. Reconstitute the contents of each vial by injecting 14 mL of 5% Dextrose Injection USP.
b) Gently shake the vial to dissolve the drug.
c) Inspect the resulting slightly yellow solution for particulate matter and discoloration prior to further dilution. Discard the vials if particulate matter or discoloration is observed.
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Step 2
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a) To prepare a 1 g dose, further dilute the contents of the two reconstituted vials (approx. 2 x 15 mL) into 140 mL of 5% Dextrose Injection USP. To prepare a 1.5 g dose, further dilute the contents of the three reconstituted vials (approx. 3 x 15 mL) into 210 mL of 5% Dextrose Injection USP. The final concentration of both solutions is 6 mg mycophenolate mofetil per mL.
b) Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.
If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 4 hours from reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
CellCept Intravenous should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.
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Dosage Adjustments
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In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of CellCept greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see package insert - CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. CellCept may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.
If neutropenia develops (ANC <1.3 x 103/µL), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see package insert - WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests).
HANDLING AND DISPOSAL
Mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits (see package insert - Pregnancy and WARNINGS: Embryofetal Toxicity). CellCept tablets should not be crushed and CellCept capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in CellCept capsules and CellCept Oral Suspension (before or after constitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe up using paper towels wetted with water to remove spilled powder or suspension. Caution should be exercised in the handling and preparation of solutions of CellCept Intravenous. Avoid direct contact of the prepared solution of CellCept Intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
HOW SUPPLIED
CellCept Intravenous (mycophenolate mofetil hydrochloride for injection)
Supplied in a 20 mL, sterile vial containing the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt in cartons of 4 vials:
NDC Number
NDC 0004-0298-09
Storage
Store powder and reconstituted/infusion solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
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Reference:
Package Insert: Accessed May 2013.
CellCept® Intravenous (mycophenolate mofetil hydrochloride for injection)
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
MG Revised: June 2012 |
