WARNINGS
See
DESCRIPTION
: BOXED
WARNINGS
.
Patients receiving immunosuppressive regimens 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. Oversuppression of the immune system
can also increase susceptibility to infection, including
opportunistic infections, fatal infections and sepsis.
As usual for patients with 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.
CellCept has been administered in combination with the
following agents in clinical trials: antithymocyte globulin
(ATGAM®), OKT3 (Orthoclone OKT® 3), cyclosporine
(Sandimmune®, Neoral®) and corticosteroids. The
efficacy and safety of the use of CellCept in combination
with other immunosuppressive agents have not been determined.
Lymphoproliferative disease or lymphoma developed in
approximately 1% of patients receiving CellCept (2 g or
3 g) with other immunosuppressive agents in controlled
clinical trials of renal and cardiac transplant patients
(see ADVERSE REACTIONS).
Adverse effects on fetal development (including malformations)
occurred when pregnant rats and rabbits were dosed during
organogenesis. These responses occurred at doses lower
than those associated with maternal toxicity, and at doses
below the recommended clinical dose for renal or cardiac
transplantation. There are no adequate and well-controlled
studies in pregnant women. However, as 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 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.
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. If pregnancy does
occur during treatment, the physician and patient should
discuss the desirability of continuing the pregnancy (see
PRECAUTIONS
: Pregnancy and PATIENT INFORMATION).
In the four (three renal and one cardiac) controlled studies
for prevention of renal or cardiac transplant rejection,
similar rates of fatal infection/sepsis (<2%) occurred
in patients receiving CellCept (2 g or 3 g) or control
therapy in combination with other immunosuppressive agents
(see ADVERSE REACTIONS).
Severe neutropenia [absolute neutrophil count (ANC) <0.5
× 10³/µL] developed in up to 2.0% of
renal transplant patients and up to 2.8% of cardiac transplant
patients receiving CellCept (see ADVERSE REACTIONS). Patients
receiving CellCept should be monitored for neutropenia
(see
PRECAUTIONS
: Laboratory Tests). 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 (see DOSAGE AND ADMINISTRATION).
Neutropenia has been observed most frequently in the period
from 31 to 180 days posttransplant in patients treated
for prevention of renal and cardiac 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.
PRECAUTIONS
General
Gastrointestinal hemorrhage has been observed in approximately
3% of renal transplant patients and in 2.8% of cardiac
transplant patients treated with CellCept 3 g daily. Gastrointestinal
perforations have rarely been observed. Most patients
receiving CellCept were also receiving other drugs known
to be associated with these complications. Patients with
active peptic ulcer disease were excluded from enrollment
in studies with mycophenolate mofetil. Because CellCept
has been associated with an increased incidence of digestive
system adverse events, including infrequent cases of gastrointestinal
tract ulceration, hemorrhage, and perforation, CellCept
should be administered with caution in patients with active
serious digestive system disease.
Subjects with severe chronic renal impairment (GFR <25
mL/min/1.73 m² ) who have received single doses of
CellCept showed higher plasma MPA and MPAG AUCs relative
to subjects with lesser degrees of renal impairment or
normal healthy volunteers. No data are available on the
safety of long-term exposure to these levels of MPAG.
Doses of CellCept greater than 1 g administered twice
a day to renal transplant patients should be avoided and
they should be carefully observed (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
No data are available for cardiac transplant patients
with severe chronic renal impairment. CellCept may be
used for cardiac transplant patients with severe chronic
renal impairment if the potential benefits outweigh the
potential risks.
In patients with delayed renal graft function posttransplant,
mean MPA AUC0-12 was comparable, but MPAG AUC0-12 was
2-to 3-fold higher, compared to that seen in posttransplant
patients without delayed renal graft function. In the
three controlled studies of prevention of renal rejection,
there were 298 of 1483 patients (20%) with 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 CLINICAL
PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).
In cardiac transplant patients, the overall incidence
of opportunistic infections was approximately 10% higher
in patients treated with CellCept than in those receiving
azathioprme therapy, but this difference was not associated
with excess mortality due to infection/sepsis among patients
treated with CellCept (see ADVERSE REACTIONS).
There were more herpes virus (H simplex, H zoster, and
cytomegalovirus) infections in cardiac transplant patients
treated with CellCept compared to those treated with azathioprine
(see ADVERSE REACTIONS).
It is recommended that CellCept not be administered concomitantly
with azathioprme 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 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 (see DRUG INTERACTIONS).
On theoretical grounds, because CellCept is an IMPDH
(inosine monophosphate dehydrogenase) inhibitor, it should
be avoided in patients with rare hereditary deficiency
of hypoxanthineguanine phosphoribosyl-transferase (HGPRT)
such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
During treatment with CelICept, the use of live attenuated
vaccines should be avoided and patients should be advised
that vaccinations may be less effective (see DRUG INTERACTIONS:
Live Vaccines).
Phenylketonurics
CellCept Oral Suspension contains aspartame, a source
of phenylalanine (0.56 mg phenylalanine per mL suspension).
Therefore, care should be taken if CellCept Oral Suspension
is administered to patients with phenylketonuria.
CAUTION: CELLCEPT INTRAVENOUS SOLUTION
SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS
INJECTION.”
Information for Patients
See PATIENT INFORMATION section.
Laboratory Tests
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
, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis,Mutagenesis,Impairment of Fertility
In a 104-week oral carcinogenicity study in mice, mycophenolate
mofetil in daily doses up to 180 mg/kg was not tumorigenic.
The highest dose tested was 0.5 times the recommended
clinical dose (2 g/day) in renal transplant patients and
0.3 times the recommended clinical dose (3 g/day) in cardiac
transplant patients when corrected for differences in
body surface area (BSA). In a 104-week oral carcinogenicity
study in rats, mycophenolate mofetil in daily doses up
to 15 mg/kg was not tumorigenic. The highest dose was
0.08 times the recommended clinical dose in renal transplant
patients and 0.05 times the recommended clinical dose
in cardiac transplant patients when corrected for BSA.
While these animal doses were lower than those given to
patients, they were maximal in those species and were
considered adequate to evaluate the potential for human
risk (see
WARNINGS
).
Mycophenolate mofetil was not genotoxic, with or without
metabolic activation, in several assays: the bacterial
mutation assay, the yeast mitotic gene conversion assay,
the mouse micronucleus aberration assay, or the Chinese
hamster ovary cell (CHO) chromosomal aberration assay.
Mycophenolate mofetil had no effect on fertility of male
rats at oral doses up to 20 mg/kg/day. This dose represents
0.1 times the recommended clinical dose in renal transplant
patients and 0.07 times the recommended clinical dose
in cardiac transplant patients when corrected for BSA.
In a female fertility and reproduction study conducted
in rats, oral doses of 4.5 mg/kg/day caused malformations
(principally of the head and eyes) in the first generation
offspring in the absence of maternal toxicity. This dose
was 0.02 times the recommended clinical dose in renal
transplant patients and 0.01 times the recommended clinical
dose in cardiac transplant patients when corrected for
BSA. No effects on fertility or reproductive parameters
were evident in the dams or in the subsequent generation.
Pregnancy
Category C. In teratology studies
in rats and rabbits, fetal resorptions and malformations
occurred in rats at 6 mg/kg/day and in rabbits at 90 mg/kg/day,
in the absence of maternal toxicity. These levels are equivalent
to 0.03 to 0.92 times the recommended clinical dose in renal
transplant patients and 0.02 to 0.61 times the recommended
clinical dose in cardiac transplant patients on a BSA basis.
In a female fertility and reproduction study conducted in
rats, oral doses of 4.5 mg/kg/day caused malformations (principally
of the head and eyes) in the first generation offspring
in the absence of maternal toxicity. This dose was 0.02
times the recommended clinical dose in renal transplant
patients and 0.01 times the recommended clinical dose in
cardiac transplant patients when corrected for BSA.
There are no adequate and well-controlled studies in
pregnant women. CellCept should not be used in pregnant
women unless the potential benefit justifies the potential
risk to the fetus. Effective contraception must be used
before beginning CellCept therapy, during therapy and
for 6 weeks after CellCept has been stopped (see
WARNINGS
and PATIENT INFORMATION).
Nursing Mothers
Studies in rats treated with mycophenolate mofetil have
shown mycophenolic acid to be 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.
Pediatric Patients
Safety and effectiveness in pediatric patients have not
been established. Very limited pharmacokinetic data are
available in pediatric patients (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Geriatric Use
Clinical studies of CellCept did not include sufficient
numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other
reported clinical experience has not identified differences
in responses between the elderly and younger patients.
In general dose selection for an elderly patient should
be cautious, reflecting the greater frequency of decreased
hepatic, renal or cardiac function and of concomitant
or other drug therapy. Elderly patients may be at an increased
risk of adverse reactions compared with younger individuals
(see ADVERSE REACTIONS).
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