A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cellcept Side Effects, and Drug Interactions - Mycophenolate Mofetil
Cellcept Side Effects, and Drug Interactions - Mycophenolate Mofetil
SIDE EFFECTS
The principal adverse reactions associated with the administration of
CellCept 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 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 three
randomized, comparative, double-blind trials in prevention of rejection
in renal transplant patients, and in one randomized, comparative, double-blind
trial in cardiac transplant patients.
Elderly patients, particularly those who are receiving CellCept as part
of a combination immunosuppressive regimen, may be at increased risk of
certain infections (including CMV tissue invasive disease) and possibly
gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals
(see PRECAUTIONS).
Safety data are summarized below for all renal transplant patients in
the double-blind prevention studies; approximately 53% of these patients
have been treated for more than 1 year. Adverse events that were reported
in ³10% of patients in either CellCept
treatment group are presented below for the two active-controlled studies
combined (USA and Europe/Canada/Australia) and for the one European placebo-controlled
study. Because of the lower overall reporting of events in the European
placebo-controlled study, these data were not combined with the other
two active-controlled prevention trials, but are instead presented separately.
|
Adverse Events in Controlled Studies in Prevention
of Renal Allograft Rejection
|
| |
USA Study Combined with Europe/ Canada/ Australia
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)
% |
| Body as a Whole |
| Pain |
33.0 |
31.2 |
32.2 |
| Abdominal pain |
24.7 |
27.6 |
23.0 |
| Fever |
21.4 |
23.3 |
23.3 |
| Headache |
21.1 |
16.1 |
21.2 |
| Infection |
18.2 |
20.9 |
19.9 |
| Sepsis |
17.6 |
19.7 |
15.6 |
| Asthenia |
13.7 |
16.1 |
19.9 |
| Chest pain |
13.4 |
13.3 |
14.7 |
| Back pain |
11.6 |
12.1 |
14.1 |
| Hemic and Lymphatic |
| Anemia |
25.6 |
25.8 |
23.6 |
| Leukopenia |
23.2 |
34.5 |
24.8 |
| Thrombocytopenia |
10.1 |
8.2 |
13.2 |
| Hypochromic anemia |
7.4 |
11.5 |
9.2 |
| Leukocytosis |
7. 1 |
10.9 |
7.4 |
| Urogenital |
| Urinary tract infection |
37. 2 |
37. 0 |
33. 7 |
| Hematuria |
14.0 |
12.1 |
11.3 |
| Kidney tubular necrosis |
6.3 |
10.0 |
5. 8 |
| Cardiovascular |
| Hypertension |
32.4 |
28.2 |
32.2 |
| Metabolic and Nutritional |
| Peripheral edema |
28.6 |
27.0 |
28.2 |
| Hypercholesteremia |
12.8 |
8. 5 |
11.3 |
| Hypophosphatemia |
12.5 |
15.8 |
11.7 |
| Edema |
12.2 |
11.8 |
13.5 |
| Hypokalemia |
10.1 |
10.0 |
8. 3 |
| Hyperkalemia |
8.9 |
10.3 |
16.9 |
| Hyperglycemia |
8.6 |
12.4 |
15.0 |
| Digestive |
| Diarrhea |
31.0 |
36.1 |
20.9 |
| Constipation |
22.9 |
18.5 |
22.4 |
| Nausea |
19.9 |
23.6 |
24.5 |
| Dyspepsia |
17.6 |
13.6 |
13.8 |
| Vomiting |
12. 5 |
13. 6 |
9. 2 |
| Nausea and vomiting |
10. 4 |
9. 7 |
10. 7 |
| Oral moniliasis |
10. 1 |
12. 1 |
11. 3 |
| Respiratory |
| Infection |
22.0 |
23.9 |
19.6 |
| Dyspnea |
15.5 |
17.3 |
16.6 |
| Cough increased |
15. 5 |
13. 3 |
15. 0 |
| Pharyngitis |
9. 5 |
11. 2 |
8. 0 |
| Skin and Appendages |
| Acne |
10.1 |
9. 7 |
6.4 |
| Rash |
7.7 |
6. 4 |
10.4 |
| Nervous System |
| Tremor |
11.0 |
11.8 |
12.3 |
| Insomnia |
8.9 |
11.8 |
10.4 |
| Dizziness |
5.7 |
11.2 |
11.0 |
| |
Europe Study
|
CellCept
2 g/day
(n= 165)
% |
CellCept
3 g/day
(n= 160)
% |
Placebo
(n= 166)
% |
| Body as a Whole |
| Sepsis |
21.8 |
17.5 |
13.9 |
| Infection |
12.7 |
15.6 |
13.3 |
| Abdominal pain |
12.1 |
11.9 |
11.4 |
| Hemic and Lymphatic |
| Leukopenia |
11.5 |
16.3 |
4. 2 |
| Urogenital |
| Urinary tract infection |
45. 5 |
44. 4 |
37. 3 |
| Urinary tract disorder |
6.7 |
10.6 |
4. 2 |
| Cardiovascular |
| Hypertension |
17.6 |
16.9 |
19.3 |
| Digestive |
| Diarrhea |
16.4 |
18.8 |
13.9 |
| Respiratory |
| Infection |
15.8 |
13.1 |
9. 0 |
| Bronchitis |
8.5 |
11. 9 |
8. 4 |
| Pneumonia |
3. 6 |
10.6 |
10.8 |
In the randomized, double-blind, comparative trial in cardiac transplant
recipients, approximately 65% of patients have been treated for more than
1 year. Adverse events reported in ³ 10%
of patients in the group treated with CellCept are provided below.
| Adverse Events in the Controlled
Studies in Prevention of Cardiac Allograft Rejection |
| |
CellCept
3 g/day
(n= 289)
% |
Azathioprine
1.5 to 3 mg/kg/day
(n= 289)
% |
| Body as a Whole |
| Pain |
75.8 |
74.7 |
| Abdominal pain |
33.9 |
33.2 |
| Fever |
47.4 |
46.4 |
| Headache |
54.3 |
51.9 |
| Infection |
25.6 |
19.4 |
| Sepsis |
18.7 |
18.7 |
| Asthenia |
43.3 |
36.3 |
| Chest pain |
26.3 |
26.0 |
| Back pain |
34.6 |
28.4 |
| Accidental injury |
19.0 |
14.9 |
| Chills |
11.4 |
11.4 |
| Hemic and Lymphatic |
| Anemia |
42.9 |
43.9 |
| Leukopenia |
30.4 |
39.1 |
| Thrombocytopenia |
23.5 |
27.0 |
| Hypochromic anemia |
24.6 |
23.5 |
| Leukocytosis |
40.5 |
35.6 |
| Ecchymosis |
16.6
|
8.0
|
| Urogenital |
| Urinary tract infection |
13.1 |
11.8 |
| Kidney function abnormal |
21.8 |
26.3 |
| Oliguria |
14.2 |
12.8 |
| Cardiovascular |
| Hypertension |
77.5 |
72.3 |
| Hypotension |
32.5 |
36.0 |
| Cardiovascular disorder |
25.6 |
24.2 |
| Tachycardia |
20.1 |
18.0 |
| Arrhythmia |
19.0 |
18.7 |
| Bradycardia |
17.3 |
17.3 |
| Pericardial effusion |
15.9 |
13.5 |
| Heart failure |
11.8 |
8.7 |
| Metabolic and Nutritional |
| Peripheral edema |
64.0 |
53.3 |
| Hypercholesteremia |
41.2 |
38.4 |
| Edema |
26.6 |
25.6 |
| Hypokalemia |
31.8 |
25.6 |
| Hyperkalemia |
14.5 |
19.7 |
| Hyperglycemia |
46.7 |
52.6 |
| Creatinine increased |
39.4 |
36.0 |
| BUN increased |
34.6 |
32.5 |
| Lactic dehydrogenase increased |
23.2 |
17.0 |
| Bilirubinemia |
18.0 |
21.8 |
| Hypervolemia |
16.6 |
22.8 |
| Generalized edema |
18.0 |
20.1 |
| Hyperuricemia |
16.3 |
17.6 |
| SGOT increased |
17.3 |
15.6 |
| Hypomagnesemia |
18.3 |
12.8 |
| Acidosis |
14.2 |
16.6 |
| Weight gain |
15.6 |
15.2 |
| SGPT increased |
15.6 |
12.5 |
| Hyponatremia |
11.4 |
11.8 |
| Hyperlipemia |
10.7 |
9.3 |
| Digestive |
| Diarrhea |
45.3 |
34.3 |
| Constipation |
41.2 |
37.7 |
| Nausea |
54.0 |
54.3 |
| Dyspepsia |
18.7 |
19.4 |
| Vomiting |
33.9 |
28.4 |
| Nausea and vomiting |
11.1 |
7.6 |
| Oral moniliasis |
11.4 |
11.8 |
| Flatulence |
13.8 |
15.6 |
| Respiratory |
| Infection |
37.0 |
35.3 |
| Dyspnea |
36.7 |
36.3 |
| Cough increased |
31.1 |
25.6 |
| Pharyngitis |
18.3 |
13.5 |
| Lung disorder |
30.1 |
29.1 |
| Sinusitis |
26.0 |
19.0 |
| Rhinitis |
19.0 |
15.6 |
| Pleural effusion |
17.0 |
13.8 |
| Asthma |
11.1 |
11.4 |
| Pneumonia |
10.7 |
10.4 |
| Skin and Appendages |
| Acne |
12.1 |
9. 3 |
| Rash |
22.1 |
18.0 |
| Skin disorder |
12.5 |
8. 7 |
| Nervous System |
| Tremor |
24.2 |
23.9 |
| Insomnia |
40.8 |
37.7 |
| Dizziness |
28.7 |
27.7 |
| Anxiety |
28.4 |
23.9 |
| Paresthesia |
20.8 |
18.0 |
| Hypertonia |
15.6 |
14.5 |
| Depression |
15.6 |
12.5 |
| Agitation |
13.1 |
12.8 |
| Somnolence |
11.1 |
10.4 |
| Confusion |
13.5 |
7.6 |
| Nervousness |
11.4 |
9.0 |
| Musculoskeletal System |
| Leg Cramps |
16.6 |
15.6 |
| Myasthenia |
12.5 |
9.7 |
| Myalgia |
12.5 |
9.3 |
| Special Senses |
| Amblyopia |
14.9 |
6.6 |
| Endocrine System |
12.1 |
12.8 |
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.
Sepsis, which was generally CMV viremia, was slightly more common in those
renal patients treated with CellCept, with an incidence of 18% to 22%,
compared to 16% in patients receiving azathioprine and 14% in patients
receiving placebo. In the controlled cardiac transplant study, there was
no difference in the incidence of sepsis (18.7%) between patients treated
with CellCept and control patients. In the digestive system, diarrhea
was increased in renal and cardiac patients receiving CellCept, with an
incidence of up to 36%, compared to 21% for patients receiving azathioprine
and 14% for patients receiving placebo in the renal transplant studies.
In the controlled cardiac transplant study, an incidence of diarrhea up
to 45.3% in the patients treated with CellCept was reported compared to
34.3% for patients receiving azathioprine. The types of adverse events
in the cardiac transplant patients studied in the multicenter controlled
trial were qualitatively similar to those observed in renal transplant
patients.
The incidence of malignancies among the 1483 patients treated in controlled
trials for the prevention of renal allograft rejection who were followed
for ³1 year was similar to the incidence
reported in the literature for renal allograft recipients. 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 WARNINGS).
The following table summarizes the incidence of malignancies observed
in the controlled renal and cardiac trials.
| Malignancies Observed in Renal and
Cardiac Transplant Trials |
| |
Renal Trials |
Cardiac Trial |
| |
CellCept
2 g/day |
CellCept
3 g/day |
Placebo |
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 |
| |
(n= 501) |
(n= 490) |
(n= 166) |
(n= 326) |
(n= 289) |
(n= 289) |
Lymphoma/
lymphoproliferative
disease |
0.6% |
1.0% |
0.0% |
0.3% |
0.7% |
2.1% |
Non- melanoma skin
carcinoma |
4.0% |
1.6% |
0.0% |
2.4% |
4.2% |
2.8% |
| Other malignancy |
0.8% |
1.4% |
1.8% |
1.8% |
2.1% |
2.1% |
Up to 2.0% of patients receiving CellCept 3 g daily for prevention of
renal rejection developed severe neutropenia [absolute neutrophil count
(ANC) <0.5 × 10³/µL]. Up to 2.8% of cardiac transplant patients receiving
CellCept 3 g daily developed severe neutropenia (see WARNINGS
, PRECAUTIONS : Laboratory Tests
and DOSAGE AND ADMINISTRATION).
The following tables show the incidence of opportunistic infections that
occurred in the renal and cardiac transplant populations in the controlled
prevention trials:
| Opportunistic Infections in Prevention
of Renal Rejection Trials |
| |
USA Study Combined with
Europe/ Canada/ Australia Study
|
CellCept
2 g/day |
CellCept
3 g/day |
Azathioprine
1 to 2 mg/kg/day or
100 to 150 mg/day |
(n= 336)
% |
(n= 330)
% |
(n= 326)
% |
| Herpes simplex |
16.7 |
20.0 |
19.0 |
CMV
viremia/syndrome |
13.4 |
12.4 |
13.8 |
| tissue invasive disease |
8.3 |
11.5 |
6.1 |
| Herpes zoster |
6.0 |
7.6 |
5.8 |
Candida
fungemia/disseminated |
0.6 |
0.6 |
0.3 |
| tissue invasive disease |
0.6 |
0.6 |
0.3 |
| Aspergillus/Mucor invasive
disease |
0.3 |
0.9 |
0.3 |
| Pneumocystis carinii |
0.3 |
0.0 |
1.2 |
| |
Europe Study |
CellCept
2 g/day |
CellCept
3 g/day |
Placebo |
(n= 165)
% |
(n= 160)
% |
(n= 166)
% |
| Herpes simplex |
15.2 |
12.5 |
6.0 |
CMV
viremia/syndrome |
15.2 |
15.0 |
13.3 |
| tissue invasive disease |
3.6 |
7.5 |
2.4 |
| Herpes zoster |
6.7 |
6.9 |
2.4 |
Candida
fungemia/disseminated |
0.0 |
0.6 |
0.0 |
| tissue invasive disease |
0.0 |
0.6 |
0.0 |
| Pneumocystis carinii |
0.0 |
0.0 |
2.4 |
| Opportunistic Infections
in Prevention of Cardiac Rejection Trial |
|
|
CellCept
3 g/ day
(n=289)
%
|
Azathioprine
1.5 to 3 mg/ kg/ day
(n= 289)
%
|
|
Herpes simplex
|
20.8
|
14.5
|
|
CMV
|
|
|
| viremia/ syndrome |
12.1
|
10.0
|
|
tissue invasive disease
|
11.4
|
8.7
|
|
CMV infection
|
2.8
|
2.8
|
|
CMV urine
|
2.4
|
2.8
|
|
CMV nasal secretions
|
0.3
|
0.0
|
|
CMV saliva
|
0.3
|
0.0
|
|
Herpes zoster
|
10.7
|
5.9
|
|
Herpes zoster cutaneous disease
|
10.0
|
5.5
|
|
Herpes zoster visceral disease
|
0.7
|
0.3
|
|
Candida
|
18.7
|
17.6
|
|
mucocutaneous
|
18.0
|
17.3
|
|
urnary tract infection
|
0.7
|
1.0
|
|
fungemia/ disseminated disease
|
0.7
|
0.3
|
| invasive tissue disease |
0.0
|
0.3 |
| Cryptococcosis |
0.7 |
0.3 |
| Aspergillus/ Mucor |
2.1 |
2.1 |
| Aspergillus pulmonary or sinus invasive |
0.7 |
1.4 |
| Aspergillus disseminated or metastatic |
0.3 |
1.0 |
| Aspergillus cutaneous |
0.7 |
0.0 |
| Aspergillus sputum |
0.3 |
0.3 |
| Pneumocystis carinii |
0.0 |
1.7 |
|
Listeriosis
|
0.0
|
0.7
|
In controlled studies for prevention of renal or cardiac rejection, similar
rates of fatal infection/sepsis (<2%) occurred in patients receiving CellCept
(2 g or 3 g) (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, not mentioned in any of the tables above,
were reported with ³3% incidence in both
renal and cardiac transplant patients treated with CellCept, in combination
with cyclosporine and corticosteroids.
Body as a Whole: abdomen enlarged, chills occurring with
fever, cyst, face edema, flu syndrome, hemorrhage, pelvic pain, malaise
Urogenital: dysuria, impotence, urinary frequency
Cardiovascular: angina pectoris, atrial fibrillation, palpitation,
peripheral vascular disorder, postural hypotension
Metabolic and Nutritional: alkaline phosphatase increased,
dehydration, hypervolemia, hypocalcemia, hypoglycemia, hypoproteinemia
Digestive: anorexia, esophagitis, gastritis, gastroenteritis,
gingivitis, gum hyperplasia, infection, liver function tests abnormal,
rectal disorder
Respiratory: lung edema
Skin and Appendages: fungal dermatitis, pruritus, skin
benign neoplasm, skin hypertrophy, skin ulcer, sweating
Endocrine: diabetes mellitus
Musculoskeletal: arthralgia, joint disorder
Special Senses: conjunctivitis
The following adverse events, not mentioned in any of the tables above
were reported with ³3% incidence in renal
transplant patients only treated with CellCept, in combination with other
immunosuppressive agents:
Body as a Whole: accidental injury, hernia
Hemic and Lymphatic: ecchymosis, polycythemia
Urogenital: albuminuria, hydronephrosis, pain, pyelonephritis,
urinary tract disorder
Cardiovascular: cardiovascular disorder, hypotension, tachycardia,
thrombosis, vasodilatation
Metabolic and Nutritional: acidosis, creatinine increased,
gamma glutamyl transpeptidase increased, hypercalcemia, hyperlipemia,
hyperuricemia, lactic dehydrogenase increased, SGOT increased, SGPT increased,
weight gain
Digestive: flatulence, gastrointestinal hemorrhage, gastrointestinal
moniliasis, hepatitis, ileus, mouth ulceration
Respiratory: asthma, lung disorder, pleural effusion, rhinitis,
sinusitis
Skin and Appendages: alopecia, hirsutism, rash, skin disorder
Nervous: anxiety, depression, hypertonia, paresthesia,
somnolence
Endocrine: parathyroid disorder
Musculoskeletal: leg cramps, myalgia, myasthenia
Special Senses: amblyopia, cataract (not specified)
The following adverse events, not mentioned in any of the tables above,
were reported with ³3% incidence in cardiac
transplant patients treated with CellCept, in combination with other immunosuppressive
agents:
Body as a Whole: neck pain, cellulitis
Hemic and Lymphatic: prothrombin increased, thromboplastin
decreased, petechia
Urogenital: nocturia, kidney failure, urine abnormality,
hematuria, urinary incontinence, prostatic disorder, urinary retention
Cardiovascular: ventricular extrasystole, congestive heart
failure, supraventricular tachycardia, ventricular tachycardia, atrial
flutter, pulmonary hypertension, heart arrest, venous pressure increased,
syncope, supraventricular extrasystoles, extrasystoles, pallor, vasospasm
Metabolic and Nutritional: hypoxia, hypophosphatemia, gout,
abnormal healing, alkalosis, weight loss, hypochloremia, thirst, respiratory
acidosis
Digestive: gastrointestinal disorder, melena, liver damage,
dysphagia, jaundice, stomatitis
Respiratory: atelectasis, hiccup, pneumothorax, sputum
increased, respiratory disorder, epistaxis, apnea, voice alteration, pain,
hemoptysis, neoplasm
Skin and Appendages: hemorrhage, skin carcinoma
Nervous: emotional lability, neuropathy, convulsion, hallucinations,
thinking abnormal, vertigo
Endocrine: Cushing's syndrome, hypothyroidism
Special Senses: ear pain, deafness, ear disorder, tinnitus,
abnormal vision, lacrimation disorder, eye hemorrhage
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 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 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
Intravenous.
Postmarketing Experience
Digestive: colitis (sometimes caused by cytomegalovirus),
pancreatitis
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.
DRUG INTERACTIONS
Drug interaction studies with mycophenolate mofetil have been conducted
with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral
contraceptives, and trimethoprim/sulfamethoxazole. Drug interaction studies
have not been conducted with other drugs that may be commonly administered
to renal or cardiac transplant patients. CellCept has not been administered
concomitantly with azathioprine.
Acyclovir: Coadministration of mycophenolate mofetil (1
g) and acyclovir (800 mg) to twelve healthy volunteers resulted in no
significant change in MPA AUC and Cmax . However, 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 the two drugs
to compete for tubular secretion, further increasing the concentrations
of both drugs.
Antacids With Magnesium and Aluminum Hydroxides: Absorption
of a single dose of mycophenolate mofetil (2 g) was decreased when administered
to ten rheumatoid arthritis patients also taking Maalox® TC (10 mL qid).
The Cmax and AUC0-24 for MPA were 33% 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.
Cholestyramine: Following single-dose administration of
1.5 g mycophenolate mofetil to twelve healthy volunteers pretreated with
4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately
40%. This decrease is consistent with interruption of enterohepatic recirculation
which may be due to binding of recirculating MPAG with cholestyramine
in the intestine. 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.
Cyclosporine: Cyclosporine (Sandimmune®) pharmacokinetics
(at doses of 275 to 415 mg/day) were unaffected by single and multiple
doses of 1.5 g bid of mycophenolate mofetil in ten stable renal transplant
patients. The mean (± SD) AUC0-12 and Cmax 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.
Ganciclovir: 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 Cmax (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
Cmax 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. Because MPAG plasma concentrations are
increased in the presence of renal impairment, as are ganciclovir concentrations,
the two drugs will compete for tubular secretion and thus further increases
in concentrations of both drugs may occur. In patients with renal impairment
in which MMF and ganciclovir are coadministered, patients should be monitored
carefully.
Oral Contraceptives: A study of coadministration of CellCept
(1 g bid) and combined oral contraceptives containing ethinylestradiol
(0.02 to 0.04 mg) and levonorgestrel (0.05 to 0.20 mg), desogestrel (0.15
mg) or gestodene (0.05 to 0.10 mg) was conducted in 18 women with psoriasis
over 3 consecutive menstrual cycles. Mean AUC(0-24) was similar
for ethmylestradiol and 3-keto desogestrel; however, mean levonorgestrel
AUC(0-24) significantly decreased by about 15%. There was large
inter-patient variability (% CV in the range of 60-70%) in the data, especially
for ethinylestradiol. Mean serum level of LH, FSH and progesterone were
not significantly affected. CellCept may not have any influence on the
ovulation-suppressing action of the studied oral contraceptives. However,
it is recommended that oral contraceptives are coadministered with CellCept
with caution and additional birth control methods be considered (see PRECAUTIONS:
Pregnancy).
Trimethoprim/sulfamethoxazole: Following single-dose administration of
mycophenolate mofetil (1.5 g) to twelve healthy male volunteers on day
8 of a 10 day course of BactrimTM DS
(trimethoprim 160 mg/sulfamethoxazole 800 mg) administered bid, no effect
on the bioavailability of MPA was observed. The mean (± SD) AUC and Cmax
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) and 34.2
(± 10.7), respectively, after administration of mycophenolate mofetil
alone.
Other Interactions: 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 results in a three-fold increase in plasma MPAG AUC and a two-fold
increase in plasma MPA AUC. 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.
Live Vaccines: During treatment with CellCept,
the use of live attenuated vaccines should be avoided and patients should
be advised that vaccinations may be less effective (see PRECAUTIONS:
General).
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