CELLCEPT Capsules, Tablets and Oral Suspension

CELLCEPT oral dosage forms (capsules, tablets or oral suspension) should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of CELLCEPT oral dosage forms and mycophenolic acid delayed-release tablets are not equivalent.

CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT capsules and oral suspension. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water.

The initial oral dose of CELLCEPT should be given as soon as possible following kidney, heart or liver transplant. It is recommended that CELLCEPT be administered on an empty stomach. In stable transplant patients, however, CELLCEPT may be administered with food if necessary [see Clinical Pharmacology (12.3)]. Once reconstituted, CELLCEPT Oral Suspension must not be mixed with any liquids prior to dose administration. If needed, CELLCEPT Oral Suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take CELLCEPT at the usual times.

CELLCEPT Intravenous

CELLCEPT Intravenous is recommended for patients unable to take oral CELLCEPT. CELLCEPT Intravenous should be administered within 24 hours following transplant. CELLCEPT Intravenous can be administered for up to 14 days; however, patients should be switched to oral CELLCEPT as soon as they can tolerate oral medication.

CELLCEPT Intravenous must be reconstituted before use [see Dosage and Administration (2.6)]. CELLCEPT Intravenous is incompatible with other intravenous infusion solutions and should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.

CELLCEPT Intravenous must not be administered as a bolus. 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, as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions (6.1)].

Adults

The recommended dosage for adult kidney transplant patients is 1 g orally or intravenously infused over no less than 2 hours, twice daily (total daily dose of 2 g).

Pediatrics (3 months and older)

Pediatric dosing is based on body surface area (BSA). The recommended dosage of CELLCEPT oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m2, administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral suspension). Pediatric patients with BSA ≥ 1.25 m2 may be dosed with capsules or tablets as follows:

Adults

The recommended dosage of CELLCEPT for adult heart transplant patients is 1.5 g orally or intravenously infused over no less than 2 hours administered twice daily (total daily dose of 3 g).

Pediatrics (3 months and older)

The recommended starting dosage of CELLCEPT oral suspension for pediatric heart transplant patients 3 months and older is 600 mg/m2, administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment.

Pediatric patients with BSA ≥1.25 m2 may be started on therapy with capsules or tablets as follows:

Adults

The recommended dosage of CELLCEPT for adult liver transplant patients is 1.5 g administered orally twice daily (total daily dose of 3 g) or 1 g infused intravenously over no less than 2 hours, twice daily (total daily dose of 2 g).

Pediatrics (3 months and older)

The recommended starting dosage of CELLCEPT oral suspension for pediatric liver transplant patients 3 months of age and older is 600 mg/m2, administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment.

Pediatric patients with BSA ≥1.25 m2 may be started on therapy with capsules or tablets as follows:

Renal Impairment

No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), do not administer doses of CELLCEPT greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3)].

Neutropenia

If neutropenia develops (ANC <1.3 × 103/µL), dosing with CELLCEPT should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

General Preparation Instructions Before Handling the Formulations

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans. Follow applicable special handling and disposal procedures1 [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), How Supplied/Storage and Handling (16.1)].

Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder or the constituted suspension because MMF has demonstrated teratogenic effects in humans. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table surface after reconstitution. If such contact occurs, wash hands thoroughly with soap and water; rinse eyes with water.

Alert patients that they and others should also avoid inhalation or contact of the skin or mucous membranes with the oral suspension. Advise them to wash the area thoroughly with soap and water if such contact occurs; if ocular contact occurs, rinse eyes with plain water.

CELLCEPT Oral Suspension

CELLCEPT Oral Suspension must be reconstituted by the pharmacist prior to dispensing to the patient. CELLCEPT Oral Suspension should not be mixed with any other medication. After reconstitution, the oral suspension contains 200 mg/mL MMF.

Before proceeding with the reconstitution steps read the general preparation instructions above [see General Preparation Instructions Before Handling the Formulations]. The following are the steps for reconstitution:

1. Tap the closed bottle several times to loosen the powder.
2. Measure 94 mL of water in a graduated cylinder.
3. Add approximately half the total amount of water for reconstitution to the bottle and shake the closed bottle well for about 1 minute.
4. Add the remainder of water and shake the closed bottle well for about 1 minute.
5. Remove the child-resistant cap and push bottle adapter into neck of bottle.
6. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
7. Write the date of expiration of the constituted suspension on the bottle label. (The shelf-life of the constituted suspension is 60 days.)
8. Dispense with the "Instruction for Use" and oral dispensers. Alert patients to read the important handling information described in the instructions for use.

Store reconstituted suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Storage in a refrigerator at 2°C to 8°C (36°F to 46°F) is acceptable. Do not freeze. Discard any unused portion 60 days after constitution.

CELLCEPT Intravenous

Before proceeding with the preparation steps for CELLCEPT Intravenous read the general preparation instructions [see General Preparation Instructions Before Handling the Formulations] and note the following:

• CELLCEPT Intravenous does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.
• 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 the diluent, the vial should not be used.

CELLCEPT Intravenous must be reconstituted and further diluted. A detailed description of the preparation is given below.

The administration of the infusion should be initiated within 4 hours of reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Discard unused portion of the reconstituted solutions.

CELLCEPT Injection should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.

CELLCEPT Oral

The incidence of adverse reactions for CELLCEPT was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies (14.1, 14.2 and 14.3)].

The three de novo kidney studies with 12-month duration compared two dose levels of oral CELLCEPT (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM®) induction therapy.

In the de novo heart transplantation study with 12-month duration, patients received CELLCEPT 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy.

In the de novo liver transplantation study with 12-month duration, patients received CELLCEPT 1 g twice daily intravenously for up to 14 days followed by CELLCEPT 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565.

Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ≥ 20% of patients in the CELLCEPT treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together.

In the three de novo kidney studies, patients receiving 2 g/day of CELLCEPT had an overall better safety profile than did patients receiving 3 g/day of CELLCEPT.

Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4% to 1% of patients receiving CELLCEPT (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2)]. Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant.

Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions (5.3)]. Severe neutropenia (ANC <0.5 × 103/µL) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving CELLCEPT 3 g daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5)].

The most common opportunistic infections in patients receiving CELLCEPT with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%. In patients receiving CELLCEPT (2 g or 3 g) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients [see Warnings and Precautions (5.3)].

The most serious gastrointestinal disorders reported were ulceration and hemorrhage, which are known risks associated with CELLCEPT. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials, while the most common gastrointestinal disorders were diarrhea, nausea and vomiting. Endoscopic investigation of patients with CELLCEPT-related diarrhea revealed isolated cases of intestinal villous atrophy [see Warnings and Precautions (5.5)].

The following adverse reactions were reported with 3% to <20% incidence in kidney, heart, and liver transplant patients treated with CELLCEPT, in combination with cyclosporine and corticosteroids.

CELLCEPT Intravenous

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

Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CELLCEPT Intravenous.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing CELLCEPT treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.

Risk Summary

Use of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems [see Human Data]. Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.01 to 0.05 times the recommended clinical doses in kidney and heart transplant patients) [see Animal Data].

Consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of CELLCEPT should be discussed with the pregnant woman.

The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Risk Summary

There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child [see Data]. Studies in rats treated with MMF have shown mycophenolic acid (MPA) to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CELLCEPT and any potential adverse effects on the breastfed infant from CELLCEPT or from the underlying maternal condition.

Data

Limited information is available from the National Transplantation Pregnancy Registry. Of seven infants reported by the National Transplantation Pregnancy Registry to have been breastfed while the mother was taking mycophenolate, all were born at 34-40 weeks gestation, and breastfed for up to 14 months. No adverse events were reported.

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of CELLCEPT should be discussed with the patient.

Pregnancy Testing

To prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting CELLCEPT. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible.

Contraception

Kidney Transplant

Use of CELLCEPT in this population is supported by evidence from adequate and well-controlled studies of CELLCEPT in adults with additional data from one open-label, pharmacokinetic and safety study of CELLCEPT in pediatric patients after receiving allogeneic kidney transplant (100 patients, 3 months to 18 years of age) [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

Heart Transplant and Liver Transplant

Use of CELLCEPT in pediatric heart transplant and liver transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult heart transplant and liver transplant patients. Additional supportive data include pharmacokinetic data in pediatric kidney transplant and pediatric liver transplant patients (8 liver transplant patients, 9 months to 5 years of age, in an open-label, pharmacokinetic and safety study) and published evidence of clinical efficacy and safety in pediatric heart transplant and pediatric liver transplant patients [see Dosage and Administration (2.3, 2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

Patients with Kidney Transplant

No dosage adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), no dose adjustments are necessary; however, doses greater than 1 g administered twice a day should be avoided.

Patients with Heart and Liver Transplant

No data are available for heart or liver transplant patients with severe chronic renal impairment. CELLCEPT may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

Patients with Kidney Transplant

No dosage adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dosage adjustments are needed for hepatic disease with other etiologies [see Clinical Pharmacology (12.3)].

Patients with Heart Transplant

No data are available for heart transplant patients with severe hepatic parenchymal disease.

Absorption

Following oral and intravenous administration, MMF undergoes complete conversion to MPA, the active metabolite. In 12 healthy volunteers, the mean absolute bioavailability of oral MMF relative to intravenous MMF was 94%. Two 500 mg CELLCEPT tablets have been shown to be bioequivalent to four 250 mg CELLCEPT capsules. Five mL of the 200 mg/mL constituted CELLCEPT oral suspension have been shown to be bioequivalent to four 250 mg capsules.

The mean (±SD) pharmacokinetic parameters estimates for MPA following the administration of MMF given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients, are shown in Table 10. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of MMF up to a daily dose of 3 g (1.5g twice daily) (see Table 10).

In the early post-transplant period (less than 40 days post-transplant), kidney, heart, and liver transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (i.e., 3 to 6 months post-transplant) (non-stationarity in MPA pharmacokinetics).

Mean MPA AUC values following administration of 1 g twice daily intravenous CELLCEPT over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.

In liver transplant patients, administration of 1 g twice daily intravenous CELLCEPT followed by 1.5 g twice daily oral CELLCEPT resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 g CELLCEPT twice daily.

Distribution

The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers was approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney 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 human serum albumin) and MPAG (at ≥ 460 mcg/mL with plasma proteins) increased the free fraction of MPA. MPA at concentrations as high as 100 mcg/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%.

Elimination

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 intravenous administration, respectively.

Specific Populations

Drug Interaction Studies

Adults

The three de novo kidney transplantation studies compared two dose levels of oral CELLCEPT (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) to prevent acute rejection episodes. One of the two studies with azathioprine (AZA) control arm also included anti-thymocyte globulin (ATGAM®) induction therapy. The geographic location of the investigational sites of these studies are included in Table 13.

In all three de novo kidney transplantation studies, the primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation. Treatment failure was defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection.

CELLCEPT, in combination with corticosteroids and cyclosporine, reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation (Table 13). Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death combined are summarized in Table 14. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.

No advantage of CELLCEPT at 12 months with respect to graft loss or patient death (combined) was established (Table 14). Numerically, patients receiving CELLCEPT 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving CELLCEPT 2 g/day experienced a better outcome than CELLCEPT 3 g/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year.

Pediatrics- De Novo Kidney transplantation PK Study with Long Term Follow-Up

One open-label, safety and pharmacokinetic study of CELLCEPT oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) in combination with cyclosporine and corticosteroids was performed at centers in the United States (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. CELLCEPT was well tolerated in pediatric patients [see Adverse Reactions (6.1)], and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g twice daily CELLCEPT capsules [see Clinical Pharmacology (12.3)]. The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant was similar to that observed in adult kidney transplant patients.

Pregnancy loss and malformations

• Inform females of reproductive potential and pregnant women that use of CELLCEPT during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. Advise that they must use an acceptable form of contraception [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].
• Encourage pregnant women to enroll in the Pregnancy Exposure Registry. This registry monitors pregnancy outcomes in women exposed to mycophenolate [see Use in Specific Populations (8.1)].

Contraception

• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential [see Use in Specific Populations (8.3)].
• Females of reproductive potential must use an acceptable form of birth control during the entire CELLCEPT therapy and for 6 weeks after stopping CELLCEPT, unless the patient chooses abstinence. CELLCEPT may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended [see Use in Specific Populations (8.3)].
• For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of CELLCEPT should be discussed with the patient.
• Advise sexually active male patients and/or their partners to use effective contraception during the treatment of the male patient and for at least 90 days after cessation of treatment. This recommendation is based on findings of animal studies [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].