ADVERSE REACTIONS
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). 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 8 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 | CellCept
3 g/day | Azathioprine
1 to 2 mg/kg/day or
100 to 150 mg/day | CellCept
3 g/day | Azathioprine
1.5 to 3
mg/kg/day | CellCept
3 g/day | Azathioprine
1 to 2
mg/kg/day |
|---|
| (n=336) | (n=330) | (n=326) | (n=289) | (n=289) | (n=277) | (n=287) |
|---|
| % | % | % | % | % | % | % |
|---|
| Body as a Whole | | | | | | | |
| Pain | 33.0 | 31.2 | 32.2 | 75.8 | 74.7 | 74.0 | 77.7 |
| Abdominal pain | 24.7 | 27.6 | 23.0 | 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 | 26.0 | – | – |
| Back pain | – | – | – | 34.6 | 28.4 | 46.6 | 47.4 |
| Ascites | – | – | – | – | – | 24.2 | 22.6 |
| Hemic and Lymphatic | | | | | | | |
| Anemia | 25.6 | 25.8 | 23.6 | 42.9 | 43.9 | 43.0 | 53.0 |
| Leukopenia | 23.2 | 34.5 | 24.8 | 30.4 | 39.1 | 45.8 | 39.0 |
| Thrombocytopenia | – | – | – | 23.5 | 27.0 | 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 | 37.0 | 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 | 36.0 | – | – |
| Cardiovascular disorder | – | – | – | 25.6 | 24.2 | – | – |
| Tachycardia | – | – | – | 20.1 | 18.0 | 22.0 | 15.7 |
| Metabolic and Nutritional | | | | | | | |
| Peripheral edema | 28.6 | 27.0 | 28.2 | 64.0 | 53.3 | 48.4 | 47.7 |
| Hyper-cholesteremia | – | – | – | 41.2 | 38.4 | – | – |
| Edema | – | – | – | 26.6 | 25.6 | 28.2 | 28.2 |
| Hypokalemia | – | – | – | 31.8 | 25.6 | 37.2 | 41.1 |
| Hyperkalemia | – | – | – | – | – | 22.0 | 23.7 |
| Hyperglycemia | – | – | – | 46.7 | 52.6 | 43.7 | 48.8 |
| Creatinine increased | – | – | – | 39.4 | 36.0 | – | – |
| BUN increased | – | – | – | 34.6 | 32.5 | – | – |
| Lactic dehydrogenase increased | – | – | – | 23.2 | 17.0 | – | – |
| Hypomagnesemia | – | – | – | – | – | 39.0 | 37.6 |
| Hypocalcemia | – | – | – | – | – | 30.0 | 30.0 |
| Digestive | | | | | | | |
| Diarrhea | 31.0 | 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 | 54.0 | 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 | 22.0 | 23.9 | 19.6 | 37.0 | 35.3 | – | – |
| Dyspnea | – | – | – | 36.7 | 36.3 | 31.0 | 30.3 |
| Cough increased | – | – | – | 31.1 | 25.6 | – | – |
| Lung disorder | – | – | – | 30.1 | 29.1 | 22.0 | 18.8 |
| Sinusitis | – | – | – | 26.0 | 19.0 | – | – |
| Pleural effusion | – | – | – | – | – | 34.3 | 35.9 |
| Skin and Appendages | | | | | | | |
| Rash | – | – | – | 22.1 | 18.0 | – | – |
| Nervous System | | | | | | | |
| Tremor | – | – | – | 24.2 | 23.9 | 33.9 | 35.5 |
| Insomnia | – | – | – | 40.8 | 37.7 | 52.3 | 47.0 |
| Dizziness | – | – | – | 28.7 | 27.7 | – | – |
| Anxiety | – | – | – | 28.4 | 23.9 | – | – |
| Paresthesia | – | – | – | 20.8 | 18.0 | – | – |
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). 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). 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 × 103/µL) 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, 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). Table 9 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials:
Table 9 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 | CellCept
3 g/day | Azathioprine
1 to 2 mg/kg/day or
100 to 150 mg/day | CellCept
3 g/day | Azathioprine
1.5 to 3
mg/kg/day | CellCept
3 g/day | Azathioprine
1 to 2
mg/kg/day |
|---|
| (n=336) | (n=330) | (n=326) | (n=289) | (n=289) | (n=277) | (n=287) |
|---|
| % | % | % | % | % | % | % |
|---|
| Herpes simplex | 16.7 | 20.0 | 19.0 | 20.8 | 14.5 | 10.1 | 5.9 |
| CMV | | | | | | | |
| – Viremia/ syndrome | 13.4 | 12.4 | 13.8 | 12.1 | 10.0 | 14.1 | 12.2 |
| – Tissue invasive disease | 8.3 | 11.5 | 6.1 | 11.4 | 8.7 | 5.8 | 8.0 |
| Herpes zoster | 6.0 | 7.6 | 5.8 | 10.7 | 5.9 | 4.3 | 4.9 |
| – Cutaneous disease | 6.0 | 7.3 | 5.5 | 10.0 | 5.5 | 4.3 | 4.9 |
| Candida | 17.0 | 17.3 | 18.1 | 18.7 | 17.6 | 22.4 | 24.4 |
| – Mucocutaneous | 15.5 | 16.4 | 15.3 | 18.0 | 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).
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 10 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 |
| Hemic 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 Nutritional | abnormal healing, acidosis, alkaline phosphatase increased, alkalosis, 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
Congenital malformations including ear malformations have been reported in offspring of patients exposed to mycophenolate mofetil during pregnancy (see WARNINGS: Pregnancy).
Digestive
Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.
Resistance Mechanism Disorders
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 serious infections such as tuberculosis and atypical mycobacterial infection.
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.
|
REPORTS OF SUSPECTED CELLCEPT SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Cellcept. The information is not vetted and should not be considered as verified clinical evidence.
Possible Cellcept side effects / adverse reactions in 48 year old female
Reported by a physician from United States on 2011-10-28
Patient: 48 year old female
Reactions: Renal Failure, Nausea, Mouth Ulceration, Anaemia, Squamous Cell Carcinoma of Skin, Neutropenia, Rash, Accidental Exposure
Suspect drug(s):
Dapsone
Dosage: titrated up to 100 mg twice daily, titrated up to 50 mg daily
Indication: Behcet's Syndrome
Arava
Dosage: 20 mg daily
Indication: Behcet's Syndrome
Imuran
Dosage: titrated up to 150 mg daily
Indication: Behcet's Syndrome
Plaquenil
Dosage: 300 mg daily, 200 mg daily, 200 mg twice daily, oral
Administration route: Oral
Indication: Behcet's Syndrome
Enbrel
Dosage: 25 mg twice weekly
Indication: Behcet's Syndrome
Methotrexate
Dosage: 7.5 mg per week, titrated up to 20 mg per week
Indication: Behcet's Syndrome
Cytoxan
Dosage: 250 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, intravenous
Indication: Behcet's Syndrome
Cyclosporine
Indication: Behcet's Syndrome
End date: 2001-01-06
Remicade
Dosage: 200 mg, 300 mg, 400 mg, intravenous
Indication: Behcet's Syndrome
Leukeran
Dosage: titrated up to 4 mg daily, 3 mg daily, 3 mg daily
Indication: Behcet's Syndrome
Colchicine
Dosage: 6 mg twice daily, 6 mg twice daily
Indication: Behcet's Syndrome
Cellcept
Dosage: 1000 mg twice daily
Indication: Behcet's Syndrome
Rituxan
Dosage: 1000 mg, 1000 mg, intravenous
Indication: Behcet's Syndrome
End date: 2006-07-05
Prednisone
Dosage: 10 mg daily
Indication: Behcet's Syndrome
Other drugs received by patient: Terbutaline Sulfate; (Esomeprazole); Pregabalin; Acyclovir; (Fentanyl); Erythromycin; Sertraline Hydrochloride; Theophylline; Pentoxifylline; Furosemide; Folic Acid; Fluticasone Propionate/salmeterol; Ipratropium Bromide and Albuterol Sulfate
Possible Cellcept side effects / adverse reactions in 58 year old female
Reported by a pharmacist from United States on 2011-11-14
Patient: 58 year old female weighing 85.0 kg (187.0 pounds)
Reactions: Confusional State, Loss of Consciousness, Convulsion
Adverse event resulted in: life threatening event, hospitalization
Suspect drug(s):
Cellcept
Other drugs received by patient: Alendronate Sodium; Oyster Shell Calcium; Allopurinol; Glimepiride; Enoxaparin; Prednisone; Warfarin Sodium; Fluticasone Propionate; Lansoprazole; Certirizine; Amlodipine; Sertraline Hydrochloride
Possible Cellcept side effects / adverse reactions in 55 year old male
Reported by a consumer/non-health professional from United States on 2011-11-21
Patient: 55 year old male weighing 75.7 kg (166.6 pounds)
Reactions: Economic Problem, Diarrhoea, Crohn's Disease, Quality of Life Decreased, Emotional Disorder, Asthenia, Abdominal Pain Upper
Adverse event resulted in: life threatening event, hospitalization
Suspect drug(s):
Cellcept
|
