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
Imuran Side Effects, and Drug Interactions - Azathioprine
Imuran Side Effects, and Drug Interactions - Azathioprine
SIDE EFFECTS
The principal and potentially
serious toxic effects of azathioprine
are hematologic and gastrointestinal. The risks of secondary
infection and neoplasia
are also significant (see
WARNINGS). The frequency
and severity of adverse reactions depend on the dose
and duration of azathioprine
as well as on the patient's underlying disease or concomitant
therapies. The incidence
of hematologic toxicities and neoplasia encountered in groups of renal
homograft recipients is
significantly higher than that in studies employing azathioprine
for rheumatoid arthritis.
The relative incidences in clinical
studies are summarized below:
|
Toxicity
|
Renal Homograft
|
Rheumatoid Arthritis
|
| Leukopenia |
|
|
| Any
degree |
>50%
|
28%
|
| <2500/mm3
|
16%
|
5.3%
|
| infections
|
20%
|
<1%
|
| Neoplasia
|
|
|
| Lymphoma
|
0.5%
|
*
|
| Others
|
2.8%
|
|
*Data on the rate and risk
of neoplasia among persons
with rheumatoid arthritis treated with azathioprine
are limited.
The incidence of lymphoproliferative
disease in patients with RA
appears to be significantly higher than that in the general population.
In one completed study, the rate
of lymphoproliferative
disesse in RA patients receiving
higher than recommended doses of azathioprine
(5 mg/kg/day) was 1.8 cases per
1000 patient years of follow-up
compared with 0.8 cases per 1000 patient
years of follow-up, in those not receiving azathioprine. However, the
proportion of the increased risk
attributable to the azathioprine
dosage or to other therapies (i.e., alkylating agents) received by azathioprine-treated
patients cannot be determined.
Hematologic: Leukopenia and/or thrombocytopenia
are dose dependent and may occur late in the course of azathioprine
therapy. Dose reduc1ion or temporary withdrawal
allows reversal of these
toxicities. Infection may occur as a secondary
manitestation of bone marrow
suppression or leukopenia,
but the incidence of infection
in renal homotransplantation
is 30 to 60 times that in rheumatoid
arthritis. Macrocytic anemia
and/or bleeding have been reported in two patients on azathioprine.
Gastrointestinal: Nausea and vomiting
may occur within the first few months of azathiaprine therapy,
and occurred in approximately 12% of 676 rheumatoid
arthritis patients. The
frequency of gastric
disturbance can be reduced by administration
of the drug in divided doses
and/or after meals. However, in some patients, nausea
and vomiting may be severe
and may be accompanied by symptoms such as dierrhea, fever,
malaise, and myalgias (see
PRECAUTIONS). Vomiting with
abdominal pain
may occur rarely with a hypersensitivity
pancreatitis. Hepstotoxicity manifest
by elevation of serum
alkaline phosphatase, bilirubin
and/or serum transaminases is
known to occur following azathioprine
use, primarily in allograft
recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumstoid
arthritis patients. Hepatotoxicity
following transplantation most often occurs within 6 months of transplantation
and is generally reversible after interruption of azathioprine. A rare,
but life-threatening hepatic veno-occlusive disease
associated with chronic administration
of azathioprine has been described in transplant
patients and in one patient
receiving azathioprine for panuveitis. Periodic measurement of serum
transaminases, alkaline phosphatase
and bilirubin is indicated
for early detection of hepatotoxicity. If hepatic
veno-occlusive disease
is clinically suspected, azathioprine should be permanently withdrawn.
Others: Additional side
effects of low frequency
have been reported. These include skin
rashes (approximately 2%), alopecia, fever, arthrelgias, diarrhea,
steatorrhea and negative
nitrogen balance (all less
than 1%),
DRUG INTERACTIONS
Use with Allopurinol: The principal
pathway for detoxification
of azathioprine is inhibited
by allopurinol. Patients receiving azathioprine and allopurinol
concomitantly should have a dose
reduction of azathioprine,
to approximately 1/3 to 1/4 the usual dose.
Use with Other Agents Affecting Myelopoesis: Drugs which
may affect leukocyte
production, including co-trimoxazole, may lead
to exaggerated leukopenia,
especially in renal transplant
recipients.
Use with Angiotensln Converting Enzyme Inhibitors: The
use of angiotensin converting
enzyme inhibitors to control
hypertension in patients on azathioprine
has been reported to induce severe leukopenia.
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