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Azasan
Overview
What is Azasan?
AZASAN
, an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 75 mg or 100 mg azathioprine and the inactive ingredients lactose monohydrate, pregelatinized starch, povidone, corn starch, magnesium stearate, and stearic acid.
Azathioprine is chemically 1
-purine, 6-[(1-methyl-4-nitro-1
-imidazol5-yl)thio]-. The structural formula of azathioprine is:
Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. 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.
What does Azasan look like?
What are the available doses of Azasan?
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What should I talk to my health care provider before I take Azasan?
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How should I use Azasan?
AZASAN
is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.
Renal Homotransplantation:
Rheumatoid Arthritis:
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZASAN
Renal Homotransplantation:
Rheumatoid Arthritis:
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 4 weeks while other therapy is kept constant. The optimum duration of maintenance AZASAN
has not been determined. AZASAN
can be discontinued abruptly, but delayed effects are possible.
Use in Renal Dysfunction:
Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.
There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
What interacts with Azasan?
AZASAN should not be given to patients who have shown hypersensitivity to the drug.
AZASAN should not be used for 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 malignancy if treated with AZASAN .
What are the warnings of Azasan?
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
Malignancy
Patients receiving immunosuppressants, including AZASAN
, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with AZASAN
. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Serious infections
Effect on Sperm in Animals:
Pregnancy: Pregnancy Category D
AZASAN
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 AZASAN
. 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 pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm 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 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 AZASAN
in patients of reproductive potential. There are no adequate and wellcontrolled 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.
What are the precautions of Azasan?
General:
Information for Patients:
Laboratory Tests: Complete Blood Count (CBC) Monitoring:
TPMT Testing:
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZASAN
Drug Interactions:
Use with Aminosalicylates:
Use with Other Agents Affecting Myelopoesis:
Use with Angiotensin-Converting Enzyme Inhibitors:
Use with Warfarin:
Use with ribavirin:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Pregnancy:
Nursing Mothers:
Pediatric Use:
What are the side effects of Azasan?
The principal and potentially serious toxic effects of AZASAN
are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see
). The frequency and severity of adverse reactions depend on the dose and duration of AZASAN
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 AZASAN
for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:
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 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. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.
Hematologic:
TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from AZASAN
. See
,
and
. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving
azathioprine.
Gastrointestinal:
Others:
| Toxicity | Renal Homograft | Rheumatoid Arthritis |
| Lekopenia | ||
| Any Degree | >50% | 28% |
| <2500 cell/mm | 16% | 5.3% |
| Infections | 20% | <1% |
| Neoplasia | * | |
| Lymphoma | 0.5% | |
| Others | 2.8% |
What should I look out for while using Azasan?
AZASAN
should not be given to patients who have shown hypersensitivity to the drug.
AZASAN
should not be used for 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 malignancy if treated with AZASAN
.
Malignancy
Patients receiving immunosuppressants, including AZASAN
, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with AZASAN
. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
®
ADVERSE REACTIONS
®
Cytopenias:
Serious infections
Effect on Sperm in Animals:
Pregnancy: Pregnancy Category D
AZASAN
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 AZASAN
. 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 pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm 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 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 AZASAN
in patients of reproductive potential. There are no adequate and wellcontrolled 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.
What might happen if I take too much Azasan?
The oral LD
s for single doses of AZASAN
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 AZASAN
is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.
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 6 days after the overdose.
How should I store and handle Azasan?
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP. AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-231-41) 15 count samples (NDC 65649-231-51) 100 mg, diamond-shaped, yellow, scored tablets, 100 count bottles (NDC 65649-241-41) 15 count samples (NDC 65649-241-51) Rx only. Store at 20° to 25°C (68° to 77° F) [See USP Controlled Room Temperature] Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral
S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the halflife of azathioprine itself, but is the decay rate for all
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 mcg/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. See
.
Azathioprine is metabolized to 6-mercaptopurine (6-MP). 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 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites (See
). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.
6-MP undergoes two major inactivation routes (
). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism.
For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT nonfunctional alleles (homozygous) for low or absent TPMT activity. Nonfunctional alleles are less common in Asians. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of AZASAN
. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of AZASAN
.
TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing AZASAN® toxicity.
Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See
,
,
and
sections.
Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA.
GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthineguanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU: Thiouric acid; XO: Xanthine oxidase (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.)
Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol is the basis for the azathioprine dosage reduction required in these patients (see
).
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:
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.
Immunoinflammatory Response:
The mechanisms whereby azathioprine affects autoimmune 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 precedes 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.
Non-Clinical Toxicology
AZASAN should not be given to patients who have shown hypersensitivity to the drug.AZASAN should not be used for 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 malignancy if treated with AZASAN .
Malignancy Patients receiving immunosuppressants, including AZASAN , are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with AZASAN . As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
®
ADVERSE REACTIONS
®
Cytopenias:
Serious infections
Effect on Sperm in Animals:
Pregnancy: Pregnancy Category D
AZASAN 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 AZASAN . 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 pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm 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 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 AZASAN in patients of reproductive potential. There are no adequate and wellcontrolled 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.
General:
Information for Patients:
Laboratory Tests: Complete Blood Count (CBC) Monitoring:
TPMT Testing:
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZASAN
Drug Interactions:
Use with Aminosalicylates:
Use with Other Agents Affecting Myelopoesis:
Use with Angiotensin-Converting Enzyme Inhibitors:
Use with Warfarin:
Use with ribavirin:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Pregnancy:
Nursing Mothers:
Pediatric Use:
The principal and potentially serious toxic effects of AZASAN are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see ). The frequency and severity of adverse reactions depend on the dose and duration of AZASAN 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 AZASAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:
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 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. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.
Hematologic:
TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from AZASAN . See , and . Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving
azathioprine.
Gastrointestinal:
Others:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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