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The principal adverse reactions associated with the administration of CellCept include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections eg, opportunistic infection (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). The adverse event profile associated with the administration of CellCept Intravenous has been shown to be similar to that observed after administration of oral dosage forms of CellCept.

CellCept Oral

The incidence of adverse events for CellCept was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients.

Geriatrics

Elderly patients ( ≥ 65 years), particularly those who are receiving CellCept as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS).

Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than 1 year. Adverse events reported in ≥ 20% of patients in the CellCept treatment groups are presented below.

Table 9 : Adverse Events in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Allograft Rejection (Reported in ≥ 20% of Patients in the CellCept Group)

  Renal Studies Cardiac Study Hepatic Study
CellCept 2 g/day
(n=336)
%
CellCept 3 g/day
(n=330)
%
Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day
(n=326)
%
CellCept 3 g/day
(n=289)
%
Azathioprine 1.5 to 3 mg/kg/day
(n=289)
%
CellCept 3 g/day
(n=277)
%
Azathioprine 1 to 2 mg/kg/day
(n=287)
%
Body as a Whole
Pain 33 31.2 32.2 75.8 74.7 74 77.7
Abdominal pain 24.7 27.6 23 33.9 33.2 62.5 51.2
Fever 21.4 23.3 23.3 47.4 46.4 52.3 56.1
Headache 21.1 16.1 21.2 54.3 51.9 53.8 49.1
Infection 18.2 20.9 19.9 25.6 19.4 27.1 25.1
Sepsis 27.4 26.5
Asthenia 43.3 36.3 35.4 33.8
Chest pain 26.3 26
Back pain 34.6 28.4 46.6 47.4
Ascites 24.2 22.6
Hematologic and Lymphatic
Anemia 25.6 25.8 23.6 42.9 43.9 43 53
Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39
Thrombocytopenia 23.5 27 38.3 42.2
Hypochromic anemia 24.6 23.5
Leukocytosis 40.5 35.6 22.4 21.3
Urogenital
Urinary tract infection 37.2 37 33.7
Kidney function abnormal 21.8 26.3 25.6 28.9
Cardiovascular
Hypertension 32.4 28.2 32.2 77.5 72.3 62.1 59.6
Hypotension 32.5 36
Cardiovascular disorder 25.6 24.2
Tachycardia 20.1 18 22 15.7
Metabolic and Nutritional
Peripheral edema 28.6 27 28.2 64 53.3 48.4 47.7
Hyper­cholesteremia 41.2 38.4
Edema 26.6 25.6 28.2 28.2
Hypokalemia 31.8 25.6 37.2 41.1
Hyperkalemia 22 23.7
Hyperglycemia 46.7 52.6 43.7 48.8
Creatinine increased 39.4 36
BUN increased 34.6 32.5
Lactic dehydrogenase increased 23.2 17
Hypomagnesemia 39 37.6
Hypocalcemia 30 30
Digestive
Diarrhea 31 36.1 20.9 45.3 34.3 51.3 49.8
Constipation 22.9 18.5 22.4 41.2 37.7 37.9 38.3
Nausea 19.9 23.6 24.5 54 54.3 54.5 51.2
Dyspepsia 22.4 20.9
Vomiting 33.9 28.4 32.9 33.4
Anorexia 25.3 17.1
Liver function tests abnormal 24.9 19.2
Respiratory
Infection 22 23.9 19.6 37 35.3
Dyspnea 36.7 36.3 31 30.3
Cough increased 31.1 25.6
Lung disorder 30.1 29.1 22 18.8
Sinusitis 26 19
Pleural effusion 34.3 35.9
Skin and Appendages
Rash 22.1 18
Nervous System
Tremor 24.2 23.9 33.9 35.5
Insomnia 40.8 37.7 52.3 47
Dizziness 28.7 27.7
Anxiety 28.4 23.9
Paresthesia 20.8 18

The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥ 20% of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection.

The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of CellCept had an overall better safety profile than did patients receiving 3 g/day of CellCept.

The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved.

Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with CellCept compared to patients treated with azathioprine. The incidence of sepsis was comparable in CellCept and in azathioprine-treated patients in cardiac and hepatic studies.

In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving CellCept compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with CellCept or azathioprine.

Patients receiving CellCept alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see WARNINGS: Lymphoma and Malignancy). The incidence of malignancies among the 1483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥ 1 year was similar to the incidence reported in the literature for renal allograft recipients.

Lymphoproliferative disease or lymphoma 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 renal, cardiac, and hepatic transplant patients followed for at least 1 year (see WARNINGS: Lymphoma and Malignancy). 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 renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data.

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed.

Severe neutropenia (ANC < 0.5 x 103/μ L) developed in up to 2.0% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving CellCept 3 g daily (see WARNINGS: Neutropenia, PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION).

All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials:

Table 10 : Viral and Fungal Infections in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Transplant Rejection

  Renal Studies Cardiac Study Hepatic Study
CellCept 2 g/day
(n=336)
%
CellCept 3 g/day
(n=330)
%
Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day
(n=326)
%
CellCept 3 g/day
(n=289)
%
Azathioprine 1.5 to 3 mg/kg/day
(n=289)
%
CellCept 3 g/day
(n=277)
%
Azathioprine 1 to 2 mg/kg/day
(n=287)
%
Herpes simplex 16.7 20 19 20.8 14.5 10.1 5.9
CMV              
– Viremia/syndrome 13.4 12.4 13.8 12.1 10 14.1 12.2
– Tissue invasive disease 8.3 11.5 6.1 11.4 8.7 5.8 8
Herpes zoster 6 7.6 5.8 10.7 5.9 4.3 4.9
– Cutaneous disease 6 7.3 5.5 10 5.5 4.3 4.9
Candida 17 17.3 18.1 18.7 17.6 22.4 24.4
– Mucocutaneous 15.5 16.4 15.3 18 17.3 18.4 17.4

The following other opportunistic infections occurred with an incidence of less than 4% in CellCept patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii.

In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease.

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 WARNINGS: Serious Infections). In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with CellCept than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with CellCept.

The following adverse events were reported with 3% to < 20% incidence in renal, cardiac, and hepatic transplant patients treated with CellCept, in combination with cyclosporine and corticosteroids.

Table 11 : Adverse Events Reported in 3% to < 20% of Patients Treated With CellCept in Combination With Cyclosporine and Corticosteroids

Body System  
Body as a Whole abdomen enlarged, abscess, accidental injury, cellulitis, chills occurring with fever, cyst, face edema, flu syndrome, hemorrhage, hernia, lab test abnormal, malaise, neck pain, pelvic pain, peritonitis
Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia, petechia, polycythemia, prothrombin time increased, thromboplastin time increased
Urogenital acute kidney failure, albuminuria, dysuria, hydronephrosis, hematuria, impotence, kidney failure, kidney tubular necrosis, nocturia, oliguria, pain, prostatic disorder, pyelonephritis, scrotal edema, urine abnormality, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder
Cardiovascular angina pectoris, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiovascular disorder, congestive heart failure, extrasystole, heart arrest, heart failure, hypotension, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, pulmonary hypertension, supraventricular tachycardia, supraventricular extrasystoles, syncope, tachycardia, thrombosis, vasodilatation, vasospasm, ventricular extrasystole, ventricular tachycardia, venous pressure increased
Metabolic and abnormal healing, acidosis, alkaline phosphatase increased, alkalosis,
Nutritional bilirubinemia, creatinine increased, dehydration, gamma glutamyl transpeptidase increased, generalized edema, gout, hypercalcemia, hypercholesteremia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypochloremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypovolemia, hypoxia, lactic dehydrogenase increased, respiratory acidosis, SGOT increased, SGPT increased, thirst, weight gain, weight loss
Digestive anorexia, cholangitis, cholestatic jaundice, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, infection, jaundice, liver damage, liver function tests abnormal, melena, mouth ulceration, nausea and vomiting, oral moniliasis, rectal disorder, stomach ulcer, stomatitis
Respiratory apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, lung edema, lung disorder, neoplasm, pain, pharyngitis, pleural effusion, pneumonia, pneumothorax, respiratory disorder, respiratory moniliasis, rhinitis, sinusitis, sputum increased, voice alteration
Skin and Appendages acne, alopecia, fungal dermatitis, hemorrhage, hirsutism, pruritus, rash, skin benign neoplasm, skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, sweating, vesiculobullous rash
Nervous agitation, anxiety, confusion, convulsion, delirium, depression, dry mouth, emotional lability, hallucinations, hypertonia, hypesthesia, nervousness, neuropathy, paresthesia, psychosis, somnolence, thinking abnormal, vertigo
Endocrine Cushing's syndrome, diabetes mellitus, hypothyroidism, parathyroid disorder
Musculoskeletal arthralgia, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis
Special Senses abnormal vision, amblyopia, cataract (not specified), conjunctivitis, deafness, ear disorder, ear pain, eye hemorrhage, tinnitus, lacrimation disorder

Pediatrics

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 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with CellCept capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients.

CellCept Intravenous

The adverse event 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 renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of CellCept Intravenous was evaluated by comparing the adverse events attributable to peripheral venous infusion of CellCept Intravenous with those observed in the intravenous 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 Intravenous.

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

Postmarketing Experience

Congenital Disorders: Embryofetal Toxicity: Congenital malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy).

Digestive: Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.

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

Infections (see WARNINGS: Serious Infections, New or Reactivated Viral Infections):

  • Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally.
  • There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection.
  • Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with CellCept. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function.
  • Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including CellCept. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss.
  • Viral reactivation has been reported in patients infected with HBV or HCV.

Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving CellCept.