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What is the most important information I should know about Cellsafe?
Allergic reactions to Cellsafe mofetil have been observed; therefore, Cellsafe mofetil capsules and Cellsafe mofetil tablets are contraindicated in patients with a hypersensitivity to Cellsafe mofetil, Cellsafe or any component of the drug product.
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What are the possible side effects of Cellsafe?
The following adverse reactions are discussed in greater detail in other sections of the label.
Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below derive from two randomized, comparative, active-controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients.
In the de novo trial, patients were administered either Cellsafe delayed-release tablets 1.44 grams per day (n = 213) or MMF 2 grams per day (n = 210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least 2 weeks prior to entry in the trial were randomized to Cellsafe delayed-release tablets 1.44 grams per day (n = 159) or MMF 2 grams per day (n = 163) for 12 months.
The average age of patients in both studies was 47 years and 48 years (de novo study and conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients were male; 82% were white, 12% were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries.
In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the Cellsafe delayed-release tablets and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the Cellsafe delayed-release tablets arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0 to 12 month study period was 59% and 60% in the Cellsafe delayed-release tablets and MMF arms, respectively. The most frequent reasons for dose reduction in the Cellsafe delayed-release tablets arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%).
The most common adverse reactions (≥ 20%) associated with the administration of Cellsafe delayed-release tablets were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia and postoperative pain.
The adverse reactions reported in ≥ 10% of patients in the de novo trial are presented in Table 2 below.
The trial was not designed to support comparative claims for Cellsafe delayed-release tablets for the adverse reactions reported in this table.
Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.
Lymphoma developed in two de novo patients (1%), (one diagnosed 9 days after treatment initiation) and in two conversion patients (1%) receiving Cellsafe delayed-release tablets with other immunosuppressive agents in the 12-month controlled clinical trials.
Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients.
The adverse reactions reported in < 10% of de novo or conversion patients treated with Cellsafe delayed-release tablets in combination with cyclosporine and corticosteroids are listed in Table 4.
The following additional adverse reactions have been associated with the exposure to Cellsafe (MPA) when administered as a sodium salt or as mofetil ester:
Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers, colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.
Infections: Serious life threatening infections such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection.
Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Cellsafe delayed-release tablets or other MPA derivatives. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during post approval use of Cellsafe delayed-release tablets: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi’s sarcoma.
Oral
Prophylaxis of acute renal graft rejection
Adult: As Cellsafe mofetil: 1 g bid starting within 72 hr of transplantation. Max: 2 g/day. As Cellsafe: 720 mg bid.
Child: As Cellsafe mofetil: 2-18 yr: 600 mg/m2 bid. Max: 1 g bid. BSA 1.25-1.5 m2: 750 mg bid; >1.5 m2: 1 g bid. As Cellsafe: 5-16 yr: 400 mg/m2 bid (max: 720 mg bid). BSA 1.19-1.58 m2: 540 mg bid (max: 1,080 mg); >1.58 m2: 720 mg bid (max: 1,440 mg).
Elderly: As Cellsafe: Max: 720 mg bid.
Renal impairment: Severe chronic renal impairment (GFR <25 ml/min/1.73 m2): Avoid >1 g bid of Cellsafe mofetil.
Reconstitution:
Oral suspension: Add 47 ml of water to bottle and shake well for about 1 min. Add another 47 ml of water and shake for another min. Final concentration: 200 mg/ml Cellsafe mofetil.
OralProphylaxis of cardiac graft rejection
Adult: As Cellsafe mofetil: 1.5 g bid starting within 5 days after transplantation.
Reconstitution:
Oral suspension: Add 47 ml of water to bottle and shake well for about 1 min. Add another 47 ml of water and shake for another min. Final concentration: 200 mg/ml Cellsafe mofetil.
IntravenousProphylaxis of acute renal graft rejection
Adult: As Cellsafe mofetil: 1 g bid by IV infusion over 2 hr starting within 24 hr after transplantation for up to 14 days, convert to oral therapy as soon as possible.
Renal impairment: Severe chronic renal impairment (GFR <25 ml/min/1.73 m2): Avoid >1 g bid of Cellsafe mofetil.
Reconstitution: Reconstitute in glucose 5% to a final concentration of 6 mg/ml Cellsafe mofetil.
IntravenousProphylaxis of hepatic transplant rejection
Adult: As Cellsafe mofetil: 1 g bid by IV infusion over 2 hr for the first 4 days (up to a max of 14 days) following transplantation. To be started within 24 hr of transplantation. Subsequently, convert to oral admin at 1.5 g bid as soon as possible.
Reconstitution: Reconstitute in glucose 5% to a final concentration of 6 mg/ml Cellsafe mofetil.
IntravenousProphylaxis of cardiac graft rejection
Adult: As Cellsafe mofetil: 1.5 g bid starting within 5 days after transplantation, convert to oral admin as soon as possible.
Reconstitution: Reconstitute in glucose 5% to a final concentration of 6 mg/ml Cellsafe mofetil.
Cellsafe injection belongs to a group of medicines known as immunosuppressive agents. It is used with other medicines to lower the body's natural immunity in patients who receive organ transplants (eg, kidney, heart, or liver).
When a patient receives an organ transplant, the body's white blood cells will try to get rid of (reject) the transplanted organ. Cellsafe injection prevents the white blood cells from rejecting the transplanted organ.
Cellsafe is to be given only by or under the direct supervision of your doctor.
Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, Cellsafe is used in certain patients with the following medical condition:
Cellsafe is an an immunosuppresant drug and potent anti-proliferative, and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of triple therapy including a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone. It is also useful in research for the selection of animal cells that express the E. coli gene coding for XGPRT (xanthine guanine phosphoribosyltransferase).
Use Cellsafe delayed-release tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Cellsafe delayed-release tablets.
A dose of 1 g administered orally 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 Cellsafe mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of Cellsafe mofetil.
Pediatrics (3 Months to 18 Years of Age)
The recommended dose of Cellsafe mofetil 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 Cellsafe mofetil 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 Cellsafe mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
Cardiac TransplantationAdults
A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
Hepatic TransplantationAdults
A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.
Cellsafe Mofetil Capsules and Tablets
The initial oral dose of Cellsafe mofetil capsules or Cellsafe mofetil tablets should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that Cellsafe mofetil capsules and Cellsafe mofetil tablets be administered on an empty stomach. However, in stable renal transplant patients, Cellsafe mofetil capsules and Cellsafe mofetil tablets may be administered with food if necessary.
Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take Cellsafe mofetil at the usual times.
Note:
If required, Cellsafe mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).
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.
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 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients.
Dosage Adjustments
In renal transplant patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of Cellsafe mofetil capsules or Cellsafe mofetil tablets 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.
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Cellsafe mofetil capsules and Cellsafe mofetil tablets 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 Cellsafe mofetil capsules and Cellsafe mofetil tablets should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately.
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What other drugs will affect Cellsafe?
Drugs which are eliminated by renal tubular secretion (eg, acyclovir, ganciclovir) have the potential to inhibit the elimination of MPAG through competition for renal tubular secretion.
Agents that interfere with enterohepatic recycling (eg, bile acid sequestrants, antibiotics) may reduce the amount of Cellsafe available for reabsorption.
In healthy volunteers concomitant administration of single doses of Cellsafe mofetil and acyclovir resulted in a significantly higher AUC of MPAG than when Cellsafe mofetil was given alone. Co-administration of Cellsafe mofetil and cholestyramine resulted in a 40% decrease in the AUC of Cellsafe. Administration of a single dose of Cellsafe 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 Cellsafe compared with administration of Cellsafe mofetil alone. Single and/or multiple dose studies have reported no pharmacokinetic interaction between Cellsafe mofetil and ganciclovir, cotrimoxazole, oral contraceptives or cyclosporine.
