AZATHIOPRINE
DESCRIPTION:
WARNING: Chronic immunosuppression with
this purine antimetabolite increases Risk
Of Neoplasia in humans. Physicians using
this drug should be very familiar with this
risk as well as with the mutagenic
potential to both men and women and with
possible hematologic toxicities. See
WARNINGS.
Azathioprine, an immunosuppressive antimetabolite, is available in tablet form
for oral administration. Each scored tablet contains 50 mg azathioprine and the
inactive ingredients anhydrous lactose, starch (corn), povidone, magnesium
stearate and stearic acid.
Azathioprine is chemically 6-((1-methyl- 4-nitroimidazol-5-yl)thio)purine.
It is an imidazolyl derivative of 6-mercaptopurine and many of its biological
effects are similar to those of the parent compound.
Azathioprine is insoluble in water, but may be dissolved with addition of one
molar equivalent of alkali. The sodium salt of azathioprine is sufficiently
soluble to make a 10 mg/mL water solution which is stable for 24 hours of 59 deg
to 77 deg F (15 deg to 25 deg C). Azathioprine is stable in solution at neutral
or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide
(0.1N), especially on warming. Conversion to mercaptopurine also occurs in the
presence of sulfhydryl compounds such as cysteine, glutathione and hydrogen
sulfide.
ACTIONS/CLINICAL PHARMACOLOGY:
CLINICAL PHARMACOLOGY AND ACTIONS
Metabolism (REF. 1): Azathioprine is well absorbed following oral
administration. Maximum serum radioactivity occurs at one to two hours after
oral (REF. 35) S-azathioprine and decays with a half-life of five hours. This is
not an estimate of the half-life of azathioprine itself but is the decay rate of
all (REF. 35) S- containing metabolites of the drug. Because of extensive
metabolism, only a fraction of the radioactivity is present as azathioprine.
Usual doses produce blood levels of azathioprine, and of mercaptopurine derived
from it, which are low (<1 mcgm/mL). Blood levels are of little predictive value
for therapy since the magnitude and duration of clinical effects correlate with
thiopurine nucleotide levels in tissues rather than with plasma drug levels.
Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and
are partially dialyzable.
Azathioprine is cleaved In Vitro to mercaptopurine. Both compounds are rapidly
eliminated from blood and are oxidized or methylated in erythrocytes and liver;
no azathioprine or mercaptopurine is detectable in urine after eight hours.
Conversion to inactive 6-thiouric acid by xanthine oxidase is an important
degradative pathway, and the inhibition of this pathway in patients receiving
allopurinol is the basis for the azathioprine dosage reduction required in these
patients (see DRUG INTERACTIONS under PRECAUTIONS). Proportions of metabolites
are different in individual patients, and this presumably accounts for variable
magnitude and duration of drug effects. Renal clearance is probably not
important in predicting biological effectiveness or toxicities, although dose
reduction is practiced in patients with poor renal function.
Homograft Survival (REF. 1, 2): Summary information from transplant centers and
registries indicates relatively universal use of azathioprine with or without
other immunosuppressive agents. (REF. 3, 4, 5) Although the use of azathioprine
for inhibition of renal homograft rejection is well established, the
mechanism(s) for this action are somewhat obscure. The drug suppresses
hypersensitivities of the cell-mediated type and causes variable alterations in
antibody production. Suppression of T-cell effects, including ablation of T-cell
suppression is dependent on the temporal relationship to antigenic stimulus or
engraftment. This agent has little effect on established graft rejections or
secondary responses.
Alterations in specific immune responses or immunologic functions in transplant
recipients are difficult to relate specifically to immunosuppression by
azathioprine. These patients have subnormal responses to vaccines, low numbers
of T-cells, and abnormal phagocytosis by peripheral blood cells, but their
mitogenic responses, serum immunoglobulins and secondary antibody responses are
usually normal.
Immuno inflammatory Response: Azathioprine suppresses disease manifestations as
well as underlying pathology in animal models of auto- immune disease. For
example, the severity of adjuvant arthritis is reduced by azathioprine.
The mechanisms whereby azathioprine affects auto- immune diseases are not known.
Azathioprine is immunosuppressive, delayed hypersensitivity and cellular
cytotoxicity tests being suppressed to a greater degree than are antibody
responses. In the rat model of adjuvant arthritis, azathioprine has been shown
to inhibit the lymph node hyperplasia which preceded the onset of the signs of
the disease. Both the immunosuppressive and therapeutic effects in animal models
are dose- related. Azathioprine is considered a slow-acting drug and effects may
persist after the drug has been discontinued.
INDICATIONS AND USAGE:
Azathioprine is indicated as an adjunct for the prevention of rejection in renal
homotransplantation. It is also indicated for the management of severe, active
rheumatoid arthritis unresponsive to rest, aspirin or other nonsteroidal anti-
inflammatory drugs, or to agents in the class of which gold is an example.
Renal Homotransplantation: Azathioprine is indicated as an adjunct for the
prevention of rejection in renal homotransplantation. Experience with over
16,000 transplants shows a five-year patient survival of 35% to 55%, but this is
dependent on donor, match of HLA antigens, antidonor or anti B-cell alloantigen
antibody and other variables. The effect of azathioprine on these variables has
not been tested in controlled trials.
Rheumatoid Arthritis (REF. 6, 7): Azathioprine is indicated only in adult
patients meeting criteria for classic or definite rheumatoid arthritis as
specified by the American Rheumatism Association. (REF. 8) Azathioprine should
be restricted to patients with severe, active and erosive disease not responsive
to conventional management including rest, aspirin or other non-steroidal drugs
or to agents in the class of which gold is an example. Rest, physiotherapy and
salicylates should be continued while azathioprine is given, but it may be
possible to reduce the dose of corticosteroids in patients on azathioprine. The
combined use of azathioprine with gold, antimalarials or penicillamine has not
been studied for either added benefit or unexpected adverse effects. The use of
of azathioprine with these agents cannot be recommended.
CONTRAINDICATIONS:
Azathioprine should not be given to patients who have shown hypersensitivity to
the drug.
Azathioprine should not be used to treating rheumatoid arthritis in pregnant
women.
Patients with rheumatoid arthritis previously treated with alkylating agents
(cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive
risk of neoplasia if treated with azathioprine. (REF. 9)
WARNINGS:
WARNING: Chronic immunosuppression with
this purine antimetabolite increases Risk
Of Neoplasia in humans. Physicians using
this drug should be very familiar with this
risk as well as with the mutagenic
potential to both men and women and with
possible hematologic toxicities. See
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 homograft 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 should be 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. (REF. 10) The risk of post-transplant
lymphomas may be increased in patients who receive aggressive treatment with
immunosuppressive drugs. (REF. 11) 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 necessarily increase the
risk of post-transplant lymphomas. However, transplant patients who receive
multiple immunosuppressive agents may be at risk for over- immunosuppression;
therefore, immunosuppressive drug therapy should be maintained at the lowest
effective levels. Information is available on the spontaneous neoplasia risk in
rheumatoid arthritis, (REF. 12, 13) and on neoplasia following immunosuppressive
therapy of other autoimmune diseases. (REF. 14, 15) It has not been possible to
define the precise risk of neoplasia due to azathioprine. (REF. 16) The data
suggest the risk may be elevated in patients with rheumatoid arthritis, though
lower than for renal transplant patients. (REF. 11, 13) 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 dose17; a reduced percentage of fertile matings 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. (REF. 19)
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. (REF. 18)
Limited immunologic and other abnormalities have occurred in a few infants born
of renal allograft recipients on azathioprine. In a detailed case report, 20
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 pregnancy. At ten weeks
most features were normalized. DeWitte et al (REF. 21) reported pancytopenia 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 (REF. 22) 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 (REF. 23)
described an infant 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 azathioprine 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. (REF. 24, 25, 26) These symptoms may also
be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver
enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity
most often 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 under
PRECAUTIONS). 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 Myelopoiesis: Drugs which may effect leukocyte
production, including co-trimoxazole, may lead to exaggerated leukopenia,
especially in renal transplant recipients. (REF. 27)
Use With Angiotensin Converting Enzyme Inhibitors: The use of angiotensin
converting enzyme inhibitors to control hypertension in patients on azathioprine
has been reported to induce severe leukopenia. (REF. 28)
CARCINOGENESIS, 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. (REF. 29, 30, 31) 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.
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 effect leukocyte
production, including co-trimoxazole, may lead to exaggerated leukopenia,
especially in renal transplant recipients. (REF. 27)
Use With Angiotensin Converting Enzyme Inhibitors: The use of angiotensin
converting enzyme inhibitors to control hypertension in patients on azathioprine
has been reported to induce severe leukopenia. (REF. 28)
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
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 hemograft
recipients is significantly higher than that in studies employing azathioprine
for rheumatoid arthritis. The relative incidences in clinical studies are
summarized below:
Renal Rheumatoid
Toxicity Homograft Arthritis
-----------------------------------------------------------------------------------------------------------
Leukopenia
Any Degree >50% 28%
<2500/mm(cubed) 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. (REF. 12) In one completed study, the rate of
lymphoproliferative disease 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. (REF. 13) 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 reduction or temporary
withdrawal allows reversal of these toxicities. Infection may occur as a
secondary manifestation 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
azathioprine 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 diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with
abdominal pain may occur rarely with a hypersensitivity pancreatitis.
Hepatotoxicity 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 rheumatoid 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. (REF. 32, 33, 34) 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 recorded. These
include skin rashes (approximately 2%), alopecia, fever, arthralgias, diarrhea,
steatorrhea and negative nitrogen balance (all less than 1%).
OVERDOSAGE:
The oral LD50s for single doses of azathioprine in mice and rats are 2500 mg/kg
and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to
marrow hypoplasia, bleeding, infection, and death. About 30% of azathioprine is
bound to serum proteins, but approximately 45% is removed during an 8 hour
hemodialysis. (REF. 35) A single case has been reported of a renal transplant
patient who ingested a single dose of 7500 mg azathioprine. The immediate toxic
reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia, and
mild abnormalities in liver function. The white blood cell count, SGOT, and
bilirubin returned to normal six days after the overdose.
DOSAGE AND ADMINISTRATION:
RENAL HOMOTRANSPLANTATION: The dose of azathioprine required to prevent
rejection and minimize toxicity will vary with individual patients; this
necessitates careful management. Initial dose is usually 3 to 5 mg/kg daily,
beginning at the time of transplant. Azathioprine is usually given as a single
daily dose on the day of, and in a minority of cases one to three days before,
transplantation. Azathioprine is often initiated with the intravenous
administration of the sodium salt, with subsequent use of tablets (at the same
dose level) after the post-operative period. Intravenous administration of the
sodium salt is indicated only in patients unable to tolerate oral medications.
Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible.
The dose of azathioprine should not be increased to toxic levels because of
threatened rejection. Discontinuation may be necessary for severe hematologic or
other toxicity, even if rejection of the homograft may be a consequence of drug
withdrawal.
RHEUMATOID ARTHRITIS: Azathioprine is usually given on a daily basis. The
initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single
dose or on a twice daily schedule. The dose may be increased, beginning at six
to eight weeks and thereafter by steps at four-week intervals, if there are no
serious toxicities and if initial response is unsatisfactory. Dose increments
should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg/day. Therapeutic
response occurs after several weeks of treatment, usually six to eight; an
adequate trial should be a minimum of 12 weeks. Patients not improved after
twelve weeks can be considered refractory. Azathioprine may be continued long-
term in patients with clinical response, but patients should be monitored
carefully, and gradual dosage reduction should be attempted to reduce risk of
toxicities.
Maintenance therapy should be at the lowest effective dose, and the dose given
can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg
daily every four weeks while other therapy is kept constant. The optimum
duration of maintenance azathioprine has not been determined. Azathioprine can
be discontinued abruptly, but delayed effects are possible.
USE IN RENAL DYSFUNCTION: Relatively oliguric patients, especially those with
tubular necrosis in the immediate post-cadaveric transplant period, may have
delayed clearance of azathioprine or its metabolites, may be particularly
sensitive to this drug and may require lower doses.
Procedures for proper handling and disposal of this immunosuppressive
antimetabolite drug should be considered. Several guidelines on this subject
have been published. (REF. 36-42) There is no general agreement that all of the
procedures recommended in the guidelines are necessary or appropriate.
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