Cellcept

Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see Warnings and Precautions, Immune).

Following single dose administration of 1.5 g mycophenolate mofetil to normal healthy subjects pretreated with 4 g three times daily of cholestyramine for 4 days, there was a mean 40% reduction in the AUC of MPA. This decrease is consistent with interruption of enterohepatic recirculation by irreversible binding, in the intestine, of recirculating MPAG with cholestyramine. Some degree of enterohepatic recirculation is also anticipated following IV administration of CellCept. Therefore, CellCept is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Reductions in pre-dose (trough) MPA concentrations of 54% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. Effects tended to diminish with continued antibiotic use and cease after discontinuation. The change in pre-dose level may not accurately represent changes in overall MPA exposure therefore clinical relevance of these observations is unclear.

Following single dose administration to healthy women, no pharmacokinetic interaction was observed between mycophenolate mofetil (1 g) and two tablets of Ortho-Novum 7/7/7 (1 mg norethindrone [NET] and 35 µg ethinyl estradiol [EE]).

Similarly, a study of coadministration of CellCept (1 g twice daily) and combined oral contraceptives containing ethinylestradiol (0.02 mg-0.04 mg) and levonorgestrel (0.05 mg-0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg-0.10 mg), showed that the pharmacokinetics of oral contraceptives were unaffected by coadministration of CellCept. This study was conducted in 18 women with psoriasis over 3 menstrual cycles and showed no clinically relevant influence of CellCept on serum levels of progesterone, LH and FSH, thus indicating no influence of CellCept on the ovulation-suppressing action of the oral contraceptives.

Although these studies demonstrate the lack of a gross pharmacokinetic interaction, one cannot exclude the possibility of changes in the pharmacokinetics of the oral contraceptive under long term dosing conditions with CellCept which might adversely affect the efficacy of the oral contraceptive.

Following single-dose administration to twelve stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and IV ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and C_max (n=10) were 54.3 (±19.0) µg·h/mL and 11.5 (±1.8) µg/mL, respectively after coadministration of the two drugs, compared to 51.0 (±17.0) µg·h/mL and 10.6 (±2.0) µg/mL, respectively after administration of IV ganciclovir alone. The mean (±SD) AUC and C_max of MPA (n=12) after coadministration were 80.9 (±21.6) µg·h/mL and 27.8 (±13.9) µg/mL, respectively compared to values of 80.3 (±16.4) µg·h/mL and 30.9 (±11.2) µg/mL, respectively after administration of mycophenolate mofetil alone. Therefore, no substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate mofetil dose adjustment is not required. However, because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the potential exists for the two drugs to compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrug e.g., valganciclovir are coadministrated, the dose recommendations for ganciclovir, or its prodrug e.g., valganciclovir should be observed and patients monitored carefully.

CellCept has been investigated with Sandimmune but not with the Neoral formulation. Cyclosporine (Sandimmune) pharmacokinetics (at doses of 275 mg/day to 415 mg/day) were unaffected by single and multiple doses of 1.5 g twice daily of mycophenolate mofetil in ten stable renal transplant patients. The mean (±SD) AUC_0-12 and C_max of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng·h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng·h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil. The effect of cyclosporine on mycophenolate mofetil pharmacokinetics could not be evaluated in this study; however, plasma concentrations of MPA were similar to that for healthy volunteers. In renal transplant patients concomitant administration of CellCept and cyclosporine resulted in reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus and similar doses of CellCept.

Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to rheumatoid arthritis patients also taking Maalox TC (10 mL four times daily). The C_max and AUC values for MPA were 38% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. CellCept may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that CellCept and the antacid not be administered simultaneously.

The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.

Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption.

Concomitant administration of sevelamer and CellCept in adults and pediatric patients decreased the MPA C_max and AUC_0-12 by 30% and 25 %, respectively. This data suggests that sevelamer or other calcium free phosphate binders should not be administered simultaneously with CellCept to minimize the impact on the absorption of MPA.

Exposure to tacrolimus concomitantly administered with CellCept had no effect on the AUC or C_max of MPA in hepatic transplant recipients. A similar finding was observed in a recent study in kidney transplant recipients.

In renal transplant patients it was shown that the tacrolimus concentration did not appear to be altered by CellCept.

However, in hepatic transplant patients, there was a 20% increase in tacrolimus AUC when multiple doses of CellCept (1.5 g twice daily) were administered to patients on tacrolimus.

It is recommended that CellCept (mycophenolate mofetil) should not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically.

In view of the significant reduction in the AUC of mycophenolic acid (MPA) by cholestyramine, caution should be used in the concomitant administration of CellCept with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of CellCept.

Patients should be advised that during treatment with CellCept vaccinations may be less effective and the use of live attenuated vaccines should be avoided. Prescribers should refer to the Canadian Immunization Guideline for further guidance.

Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine A, ganciclovir, tacrolimus, oral contraceptives, and trimethoprim/sulfamethoxazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. CellCept has not been administered concomitantly with azathioprine.

After correction for dose a 70% decrease in MPA exposure (AUC_0-12h) has been observed with concomitant rifampicin administration in a single heart-lung transplant patient. It is therefore recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.

Following single dose administration of mycophenolate mofetil (1.5 g) to twelve healthy male volunteers on day 8 of a 10 day course of Bactrim DS (trimethoprim 160 mg/sulfamethoxazole 800 mg) administered twice daily, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and C_max of MPA after concomitant administration were 75.2 (±19.8) µg·h/mL and 34.0 (±6.6) µg/mL, respectively compared to 79.2 (±27.9) µg·h/mL and 34.2 (±10.7) µg/mL, respectively after administration of mycophenolate mofetil alone.

No effect on the systemic exposure of MPA was observed when CellCept was concomitantly administered with any antibiotic separately. In contrast, the systemic exposure (AUC) of MPA was reduced by 10%, 19%, and 33% when CellCept was concomitantly administered with norfloxacin, metronidazole, and norfloxacin plus metronidazole, respectively, following a single dose of CellCept (statistically significant only for the differences seen in norfloxacin plus metronidazole when compared to baseline (P=.01)).

Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to twelve healthy volunteers resulted in no significant change in MPA AUC and C_max. However, the phenolic glucuronide of MPA (MPAG) and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug e.g., valacyclovir to compete for tubular secretion, further increasing the concentrations of both drugs.

No dose adjustment is recommended for these patients, however, they should be carefully observed (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

To prepare a 1 g dose, further dilute the contents of the two reconstituted vials (approx. 2×15 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. 3×15 mL) into 210 mL of 5% Dextrose Injection USP. The final concentration of both solutions is 6 mg mycophenolate mofetil per mL.

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 15 to 30°C.

CellCept i.v. should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.

Two (2) vials of CellCept i.v. 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.

CellCept (tablets, capsules) should be administered orally, and should be taken on an empty stomach (see Actions and Clinical Pharmacology, Absorption).

It is recommended that CellCept Powder for Oral Suspension be reconstituted by the pharmacist prior to dispensing to the patient (see Dosage and Administration, Reconstitution, Preparation of Oral Suspension).

CellCept i.v. must be reconstituted and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP (see Dosage and Administration, Reconstitution, Preparation of Infusion Solution (6 mg/mL)). CellCept i.v. is incompatible with other intravenous infusion solutions. Following reconstitution, CellCept i.v. must be administered by slow intravenous infusion over a period of no less than 2 hours by either peripheral or central vein.

A dose of 1 g twice daily administered intravenously (over no less than 2 hours or 1.5 g twice daily oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.

CellCept (mycophenolate mofetil) should be used concomitantly with standard cyclosporine and corticosteroid therapy.

CellCept Capsules, Tablets and Powder for Oral Suspension:

• The initial oral dose of CellCept 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 C_max by 40%. It is recommended that CellCept be administered on an empty stomach.

  
  

Note: If required CellCept Oral Suspension can be administered via a nasogastric tube with a minimum size of 8 French.

CellCept i.v.:

• CellCept i.v. is an alternative dosage form to CellCept capsules and tablets recommended for patients unable to take CellCept capsules or tablets. CellCept i.v. should be administered within 24 hours following transplantation. CellCept i.v. can be administered for up to 14 days; patients should be switched to oral CellCept as soon as they can tolerate oral medication.

  
  

Caution: CellCept i.v. solution should never be administered by rapid or bolus intravenous injection.

A dose of 1 g administered orally or intravenously (over 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 per day of CellCept in these trials demonstrated an overall better safety profile than did patients receiving 3 g per day of CellCept.

Tap the closed bottle several times to loosen the powder.

Dispense with patient information leaflet and oral dispensers. Oral dispensers are for use with CellCept oral suspension only. It is recommended to write the date of expiration of the reconstituted suspension on the bottle label in the space provided. (The shelf life of the reconstituted suspension is 60 days.)

Net contents after reconstitution of the oral suspension is 175 mL, containing 200 mg/mL mycophenolate mofetil. Store reconstituted suspension at 15 to 30°C. Do not freeze. Discard any unused portion 60 days after reconstitution.

CellCept i.v. does not contain an antibacterial preservative; therefore reconstitution and dilution of the product must be performed under aseptic conditions.

CellCept i.v. 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:

In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m²) outside the immediate post-transplant period, doses of CellCept greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. CellCept should 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 <1.3×10³/µL), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see Warnings and Precautions, Immune, Monitoring and Laboratory Tests and Adverse Reactions).

A dose of 1.5 g twice daily administered intravenously (over no less than 2 hours) or 1.5 g twice daily oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.

The recommended dose of CellCept oral suspension for renal transplant patients is 600 mg/m² body surface area twice daily (up to a maximum of 2 g daily).

Patients with a body surface area of 1.25 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).

The following adverse events, not mentioned above, were reported in clinical trials and in postmarketing experience in patients treated with CellCept:

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.

The adverse event profile associated with the use of immunosuppressive drugs is often difficult to establish owing to the presence of underlying disease and the concurrent use of many other medications. The principal adverse reactions associated with the administration of CellCept (mycophenolate mofetil) include diarrhea, leukopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections.

The adverse event profile associated with the administration of CellCept i.v. (mycophenolate mofetil hydrochloride for injection) has been shown to be similar to that observed after administration of oral dosage forms of CellCept.

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 infection such as tuberculosis and atypical mycobacterial infection.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases had risk factors for PML, including immunosuppressant therapies and impairment of immune function.

An increased risk of first trimester pregnancy loss and congenital malformations of heart, ear, face, hand, eye, vertebrae, oesophagus, and multiple congenital abnormalities have been reported in offspring of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressive agents.

The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with CellCept oral suspension 600 mg/m² twice daily (up to 1 g twice daily) were generally similar to those observed in adult patients dosed with CellCept capsules at a dose of 1 g twice daily. However, the following treatment-related adverse events occurred with a frequency of ≥10% in children and were more frequent in the pediatric population, particularly in children under 6 years of age, when the frequency of treatment-related adverse events were compared to adults: diarrhea, anemia, leucopenia, sepsis and infection.

The adverse event profile of CellCept i.v. was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral CellCept in renal transplant patients in the immediate post-transplant period (administered for the first 5 days). The potential venous irritation of CellCept i.v. was evaluated by comparing the adverse events attributable to peripheral venous infusion of CellCept i.v. with those observed in the IV placebo group; patients in this group received active medication by the oral route.

Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CellCept i.v.

In the active controlled study in hepatic transplant patients, 2 g/day of CellCept i.v. was administered in the immediate post-transplant period (up to 14 days). The safety profile of intravenous CellCept was similar to that of intravenous azathioprine.

CellCept is indicated for the prophylaxis of organ rejection in pediatric patients (2 to 18 years) receiving allogeneic renal transplants. CellCept should be used concomitantly with cyclosporine and corticosteroids.

The prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. CellCept should be used concomitantly with cyclosporine and corticosteroids.

Each oblong, blue/brown, two-piece hard gelatin capsule, printed in black with “CellCept 250” on the blue cap and “Roche” on the brown body, contains: mycophenolate mofetil 250 mg. Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, povidone (K-90) and pregelatinized starch; capsule shell: black iron oxide, gelatin, indigotine (FD&C blue #2) aluminum lake, potassium hydroxide, red iron oxide, shellac, titanium dioxide and yellow iron oxide. Blister packs of 10, boxes of 10.

Each vial of sterile, white to off-white lyophilized powder for i.v. infusion contains: the equivalent of mycophenolate mofetil 500 mg as the hydrochloride salt. Nonmedicinal ingredients: citric acid, polysorbate 80 and sodium hydroxide and/or hydrochloric acid to adjust pH. Sterile vials of 20 mL, cartons of 4. Each vial is intended for single use only.

Each lavender-colored, caplet-shaped, film coated tablet, engraved with “CellCept 500” on one side and “Roche” on the other, contains: mycophenolate mofetil 500 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, indigotine (FD&C blue #2) aluminum lake, iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90) and titanium dioxide. Blister packs of 10, boxes of 5.

Available as a white to off-white powder blend for reconstitution to a white to off-white fruit flavor suspension containing 200 mg/mL of mycophenolate mofetil. Each bottle of CellCept powder for oral suspension contains 35 g of MMF in a 110 g powder for oral suspension. Nonmedicinal ingredients: aspartame, citric acid, colloidal silicon dioxide, fruit flavor, methylparaben, sodium citrate, sorbitol, soybean lecithin and xanthan gum. Bottle of 225 mL with bottle adapter and 2 oral dispensers{*Oral dosing dispenser manufactured by F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.}. The deliverable volume after reconstitution is 165 mL.

Elderly patients may be at an increased risk of adverse events compared with younger individuals.

Administration of doses of CellCept greater than 1 g administered twice a day to renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m²) should be avoided and patients should be carefully observed (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency and Dosage and Administration, Dosage Adjustment, Renal Impairment).

No data are available for cardiac or hepatic transplant patients with severe chronic, renal impairment. CellCept should be used for cardiac or hepatic transplant patients with severe, chronic, renal impairment if the potential benefits outweigh the potential risks.

CellCept should be administered with caution in patients with active serious digestive system disease. Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac and in 5.4% of hepatic transplant patients treated with CellCept 3 g daily. CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, and rarely perforation (colon, gall bladder). Most patients receiving CellCept were also receiving other drugs that are known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil.

Safety and efficacy in children receiving allogeneic cardiac or hepatic transplants have not been established.

For pediatric patients receiving renal transplants also see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Pediatrics, Adverse Reactions, Pediatrics and Dosage and Administration, Pediatrics (2 to 18 years).

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections and sepsis. CellCept has been administered in combination with the following agents in clinical trials: anti-thymocyte globulin [equine] (Atgam) induction, muromonab-CD3 (Orthoclone OKT3), cyclosporine (Sandimmune, Neoral), and corticosteroids. The efficacy and safety of the use of CellCept in combination with other immunosuppressive agents has not been determined.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of CellCept therapy. In transplant patients however reduced immunosuppression may place the graft at risk.

In patients receiving CellCept (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients (see Adverse Reactions).

Severe neutropenia (absolute neutrophil count [ANC] <0.5×10³/µL) developed in up to 2.0% of renal, up to 2.8% of cardiac and up to 3.6% hepatic transplant patients receiving CellCept 3 g daily (see Adverse Reactions).

Patients receiving CellCept should be monitored for neutropenia (see Warnings and Precautions, Monitoring and Laboratory Tests and Dosage and Administration, Dosage Adjustment). The development of neutropenia may be related to CellCept itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC <1.3×10³/µL), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately. Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant for patients treated for prevention of renal, cardiac and hepatic rejection.

Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Patients receiving immunosuppressive regimes involving combinations of drugs, including CellCept, 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. As with all patients at an increased 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.

Lymphoproliferative disease or lymphoma developed in 0.4%-1% of patients receiving CellCept (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac and hepatic transplant patients (see Adverse Reactions).

Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year (see Warnings and Precautions, Immune and Dosage and Administration).

Because CellCept is an inosine monophosphate dehydrogenase (IMPDH) inhibitor, on theoretical grounds it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

There are no adequate and well-controlled studies in pregnant women. However, an increased risk of first trimester pregnancy loss and congenital malformations of heart, ear, face, hand, eye, vertebrae, oesophagus, and multiple congenital abnormalities have been reported in offspring of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. CellCept has been shown to have teratogenic effects in animals, it may cause fetal harm when administered to a pregnant woman. Therefore, CellCept should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus.

Women of childbearing potential should be instructed of the potential risks during pregnancy. Effective contraception must be used before beginning CellCept therapy, during therapy, and for 6 weeks following discontinuation of therapy, even where 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 (see Drug Interactions). If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy (see Information for the Patient).

Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 1 week prior to beginning therapy. It is recommended that CellCept therapy should not be initiated by the physician until a report of a negative pregnancy test has been obtained.

Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving CellCept (see Warnings and Precautions, Immune). Patients should be given complete dosage instructions and informed of the increased risk of lymphoproliferative disease and certain other malignancies.

Studies in rats have shown mycophenolate mofetil is excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see Information for the Patient).

CellCept Oral Suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine per mL suspension).

The mean (±SD) apparent volume of distribution of MPA in twelve healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following IV and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at ≥460 µg/mL with plasma proteins) increased the free fraction of MPA. At concentrations exceeding those encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100 µg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.

Following oral and IV administration, MMF undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. The parent drug MMF can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 µg/mL).

In 12 healthy volunteers, the mean absolute bioavailability of oral MMF relative to IV MMF (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of MMF up to a daily dose of 3 g (see Table 4 for pharmacokinetic parameters).

Effect of Food: Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of MMF when administered at doses of 1.5 g twice daily to renal transplant patients. However, MPA C_max was decreased by 40% in the presence of food (see Dosage and Administration).

Negligible amount of drug is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled MMF resulted 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 is not removed by hemodialysis. Similarly, MPAG concentrations normally encountered are unaffected by hemodialysis, however, at high MPAG plasma concentrations (>100 µg/mL), small amounts of this metabolite are removed. Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following IV administration, respectively.

Data obtained from several studies were pooled to examine any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC_0-12 for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) µg·h/mL while mean (±SD) MPA C_max was 9.96 (±6.19) in the males and 10.6 (±5.64) µg/mL in the females. These differences are not of clinical significance.

In patients with delayed renal graft function post-transplant, mean MPA AUC_0-12 was comparable, but MPAG AUC_0-12 was 2-3 fold higher, compared to that seen in post-transplant patients without delayed renal graft function. In the three pivotal studies of prevention of rejection, 298 of 1483 patients (20%) experienced delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving CellCept than azathioprine or placebo. No dose adjustment is recommended for these patients, however, they should be carefully observed. See Dosage and Administration, Dosage Adjustment, Delayed Renal Graft Function Post Transplant).

Following oral and intravenous dosing, MMF undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active.

In vivo, MPAG is converted to free MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of MMF to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Secondary peaks in the plasma MPA concentration-time profile are usually observed 6-12 hours post-dose. The coadministration of cholestyramine (4 g three times daily) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations.

Renal insufficiency has no consistent effect on MPA pharmacokinetics. Mean MPA AUC was increased by 50% in severe renal impairment (GFR <25 mL/min/1.73 m²), however, there was considerable variation about the mean. For MPAG, there is an increase (3-6 fold) in mean AUC (see Actions and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency).

The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving CellCept oral suspension at a dose of 600 mg/m² twice daily (up to a maximum of 1 g twice daily) after allogeneic renal transplantation. This dose achieved MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving CellCept capsules at a dose of 1g twice daily in the early post-transplant period. As observed in adults, early post-transplant MPA AUC values were approximately 45%-53% lower than those observed in the later post-transplant period (>3 months). MPA AUC values were similar in the early and late post-transplant period across the 1-18 year age range.

In a single dose (1 g, oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies may show a different effect. In a single-dose (1 g) intravenous study of 6 volunteers with alcoholic cirrhosis, MPA AUC was 44.1 µg·h/mL (±15.5).

Pharmacokinetics in the elderly has not been formally evaluated.

Mycophenolate mofetil (MMF) 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). MMF has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. MMF also inhibited proliferative arteriopathy in experimental models of aortic and heart allografts in rats, as well as in primate cardiac xenografts. MMF was used alone or in combination with other immunosuppressive agents in these studies. MMF 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.

MMF 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. MMF 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.

Pharmacokinetic Parameters for MPA [mean (±SD)] Following Administration of MMF to Healthy Volunteers (Single Dose), Renal, Cardiac and Hepatic Transplant Patients (Multiple Doses)

In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. The mean plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment (glomerular filtration rate [GFR] <25 mL/min/1.73 m²) was about 75% higher relative to the mean observed in healthy volunteers (GFR >80 L/min/1.73 m²). However, the mean single dose plasma MPAG AUC was 3-6 fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

Plasma MPA AUC observed after single dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m²) was 62.4 µg·h/mL (±19.3). Multiple dosing of MMF in patients with severe chronic renal impairment has not been studied (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

Subjects with severe chronic renal impairment who have received single doses of MMF showed higher mean plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy subjects. No data are available on the safety of long-term exposure to these levels of MPAG.

At clinically encountered concentrations, MPA is not removed by hemodialysis. Similarly, MPAG concentrations normally encountered are unaffected by hemodialysis, however, at high MPAG concentrations (>100 µg/mL), hemodialysis removes only small amounts of MPAG.