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 Warnings, Precautions, Pregnancy, Nursing, Abuse - Azathioprine
Imuran Warnings, Precautions, Pregnancy, Nursing, Abuse - Azathioprine
WARNINGS
Severe leukopenia
and/or thrombocytopenia may occur in patients on azathioprine.
Macrocytic anemia and severe
bone marrow
depression may also occur. Hematologic toxicities are dose
related and may be more severe in renal
transplant patients whose
homagraft is undergoing rejection. It is suggested that patients on azathioprine
have complete blood counts,
including platelet counts,
weekly during the first month, twice monthly for the second and third
months of treatment, then
monthly or more frequently if dosage
alterations or other therapy
changes are necessary. Delayed hematologic suppression may occur. Prompt
reduction in dosage
or temporary withdrawal of the drug
may be necessary if there is a rapid fall
in, or persistently low leukocyte
count or other evidence
of bone marrow
depression. Leukopenia does not correlate with therapeutic
effect; therefore the dose should
not be increased intentionally to lower the white
blood cell
count.
Serious infections are a constant
hazard for patients on chronic
immunosuppression, especially for homograft
recipients. Fungal, viral, bacterial and protozoal
infections may be fatal and
shouldbe treated vigorously. Reduction of azathioprine
dosage and/or use of other
drugs should be considered.
Azathioprine is mutagenic in animals and humans, carcinogenic
in animals, and may increase the patient's risk
of neoplasia. Renal transplant
patients are known to have an increased risk
of malignancy, predominantly
skin cancer and reticulum
cell or lymphomatous
tumors. The risk of post-transplant
lymphomas may be increased in patients who receive aggressive treatment
with immunosuppressive drugs. The degree
of immunosuppression
is determined not only by the immunosuppressive regimen
but also by a number of other
patient factors. The number
of immunosuppressive agents may not necessarfly increase the risk
of post-transpfant lymphomas. However, transplant
patients who receive multiple
immunosuppressive agents may be at risk
for over- immunosuppressant; therefore, immunosuppressive drug
therapy should be maintained
at the lowest effective levels. Information is available on the spontaneous
neoplasia risk
in rheumatoid arthritis,
and on neoplasia following immunosuppressive therapy
of other autoimmune diseases. It has not been possible to define the precise
risk of neoplasia
due to azathioprine. The data suggest the risk
may be elevated in patients with rheumatoid
arthritis, though lower than for renal
transplant patients. However,
acute myelogenous leukemia as
well as solid tumors have been
reported in patients with rheumatoid arthritis who have received azathioprine.
Data on neoplasia in patients
receiving azathioprine
can be found under ADVERSE REACTIONS.
Azathioprine has been reported to cause
temporary depression in
spermatogenesis and reduction
in sperm viability
and sperm count
in mice at doses 10 times the human
therapeutic dose, a reduced
percentage of fertile mating
s occurred when animals received 5 mg/kg.
Pregnancy
"Pregnancy Category D": Azathioprine can cause
fetal harm when administered to a pregnant
woman. Azathioprine should not be given during pregnancy
without careful weighing of risk
versus benefit. Whenever possible, use of azathioprine
in pregnant patients should
be avoided. This drug should
not be used for treating rheumatoid
arthritis in pregnant women.
Azathioprine is teratogenic
in rabbits and mice when given in doses equivalent to the human
dose (5 mg/kg daily). Abnormalities
included skeletal malformations and visceral
anomalies.
Limited immunologic and other abnormalities have occurred in a few infants
born of renal allograft
recipients on azathioprine. In
a detailed case report, documented lymphopenia, diminished IgG
and IgM levels, CMV
infection, and a decreased thymic
shadow were noted in an infant
born to a mother receiving 150 mg
azathioprine and 30 mg
prednisone daily throughout
pregnsncy. At ten weeks most features
were normalized. DeWitte et al reported pancylopenia and severe immune
deficiency in a pre-term
infant whose mother
received 125 mg azathioprine
and 12.5 mg prednisone
daily. There have been two published reports of abnormal
physical findings. Williamson
and Karp described an infant born with preaxial
polydactyly whose mother
received azathioprine 200 mg daily
and prednisone 20 mg
every other day during pregnancy. Tallent et al described cinfant with
a large myelomeningocele
in the upper lumbar region, bilateral
dislocated hips, and bilateral
talipes equinovarus. The father
was on long-term azathioprine
therapy.
Benefit versus risk must be
weighed carefully before use of arathioprine in patients of reproductive
potential. There are no adequate
and well-controlled studies in pregnant
women. If this drug is used during
pregnancy or if the patient
becomes pregnant while taking
this drug, the patient
should be apprised of the potential
hazard to the fetus. Women of childbearing age should be advised to avoid
becoming pregnant.
PRECAUTIONS
General
A gastrointestinal
hypersensitivity
reaction characterized by
severe nausea and vomiting
has been reported. These symptoms may also be accompanied by diarrhea,
rash, fever,
malaise, myalgias, elevations
in liver enzymes, and occasionally,
hypotension. Symptoms of gastrointestinal
toxicity most otlen develop
within the first several weeks of azathioprine
therapy and are reversible
upon discontinuation of the drug. The reaction
can recur within hours after rechallenge with a single dose
of azathioprine.
Information for Patients
Patients being started on azathioprine
should be informed of the necessity of periodic
blood counts while they are
receiving the drug and should
be encouraged to report any
unusual bleeding or bruising
to their physician. They should be informed of the danger of infection
while receiving azathioprine and encouraged to report
signs and symptoms of infection
to their physician. Careful dosage
instructions should be given to the patient,
especially when azathioprine
is being administered in the presence of impaired renal function or concomitantly
with allopurinol (see
DOSAGE AND ADMINISTRATION
and DRUG INTERACTIONS). Patients
should be advised of the potential
risks of the use of azathioprine
during pregnancy and during
the nursing period. The increased
risk of neoplasia
following azathioprine
therapy should be explained
to the patient.
Laboratory Tests - See WARNINGS
and ADVERSE REACTIONS.
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.
Carcinogenesls, Mutagenesis, Impairment of Fertility See WARNINGS
section.
Pregnancy
Teratogenic Effect. Pregnancy Category D See WARNINGS
section.
Nursing Mothers
The use of azathioprine
in nursing mothers is not
recommended. Azathioprine or its metabolites are transferred at low levels,
both transplacentally and in breast
milk. Because of the potential
for tumorigenicity shown for azathioprine, a decision should be made whether
to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and efficacy of azathioprine
in children have not been established.
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