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- Azathioprine Sodium
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Generic: 100 mg (1 ea)
Azasan: 75 mg, 100 mg [scored]
Imuran: 50 mg [scored]
Generic: 50 mg
Brand Names: U.S.
- Immunosuppressant Agent
Azathioprine is an imidazolyl derivative of mercaptopurine; metabolites are incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis (Taylor 2005). The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine’s immunosuppressive and toxic effects.
Oral: Well absorbed
Hepatic; metabolized to 6-mercaptopurine via glutathione S-transferase (GST) reduction. Further metabolized (in the liver and GI tract) via three major pathways: Hypoxanthine guanine phosphoribosyltransferase (to active metabolites: 6-thioguanine-nucleotides, or 6-TGNs), xanthine oxidase (to inactive metabolite: 6-thiouric acid), and thiopurine methyltransferase (TPMT) (to inactive metabolite: 6-methylmercaptopurine)
Urine (primarily as metabolites)
Onset of Action
Immune thrombocytopenia (oral): Initial response: 30 to 90 days; Peak response: 30 to 120 days (Neunert 2011)
Time to Peak
Oral: 1 to 2 hours (including metabolites)
Azathioprine and mercaptopurine: Variable: ~2 hours (Taylor 2005)
Special Populations: Renal Function Impairment
Clearance (azathioprine and metabolites) may be delayed in oliguric patients, particularly in those with tubular necrosis in the immediate post-transplant phase (cadaveric transplant).
Use: Labeled Indications
Renal transplantation: Adjunctive therapy in prevention of rejection of kidney transplants
Rheumatoid arthritis: Treatment of active rheumatoid arthritis (RA), to reduce signs and symptoms
Adjunct in prevention of rejection of solid organ (nonrenal) transplants; remission maintenance or reduction of steroid use in Crohn disease (CD) and in ulcerative colitis (UC); dermatomyositis/polymyositis; erythema multiforme; pemphigus vulgaris, lupus nephritis (maintenance), chronic refractory immune thrombocytopenia (ITP), relapsed/remitting multiple sclerosis
Hypersensitivity to azathioprine or any component of the formulation; pregnancy (in patients with rheumatoid arthritis [see Pregnancy Considerations]); patients with rheumatoid arthritis and a history of treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of malignancy with azathioprine treatment
Note: Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity receiving conventional azathioprine doses are at risk for developing severe, life-threatening myelotoxicity. Dosage reductions are recommended for patients with reduced TPMT activity; consider discontinuing in patients with abnormal blood counts that do not respond to dose reduction.
Renal transplantation (treatment usually started the day of transplant; however, has been initiated [rarely] 1 to 3 days prior to transplant):
Oral: Initial: 3 to 5 mg/kg once daily (usually given as a single daily dose), then 1 to 3 mg/kg once daily maintenance
IV: Initial: 3 to 5 mg/kg once daily; Maintenance: dose reduction to 1 to 3 mg/kg once daily is usually possible. Note: IV is indicated only in patients unable to tolerate oral medications (dosing should be transitioned from IV to oral as soon as tolerated).
Initial: 1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily; after 6 to 8 weeks, may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks
Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities).
IV: Note: IV is indicated only in patients unable to tolerate oral medications (dosing should be transitioned from IV to oral as soon as tolerated):
Initial: ~1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily; after 6 to 8 weeks, may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks.
Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities)
Crohn disease, remission maintenance or reduction of steroid use (off-label use): Oral: 2 to 3 mg/kg/day (Lichtenstein 2009)
Dermatomyositis/polymyositis, adjunctive management (off-label use): Oral: 50 mg/day in conjunction with prednisone; increase by 50 mg/week to total dose of 2 to 3 mg/kg/day (Briemberg 2003); Note: Onset of beneficial effects may take 3 to 6 months; however, may be preferred over methotrexate in patients with pulmonary or hepatic toxicity.
Immune thrombocytopenia, chronic (refractory or relapsed) (off-label use): Oral: 1 to 2 mg/kg/day; maximum dose: 150 mg/day (Provan 2010). Initial response is observed at 30 to 90 days; may take up to 6 months for peak response (Neunert 2011; Provan 2010)
Lupus nephritis, maintenance (off-label use): Oral: Initial: 2 mg/kg/day; may reduce to 1.5 mg/kg/day after 1 month (if proteinuria <1 g/day and serum creatinine stable) (Moroni 2006) or target dose: 2 mg/kg/day (Hahn 2012; Houssiau 2010)
Pericarditis, recurrent (off-label use): Oral: 150 mg once daily for 2 to 3 months, then 100 mg once daily to suppress clinical symptoms (Marcolongo 1995)
Ulcerative colitis, remission maintenance or reduction of steroid use (off-label use): Oral: 1.5 to 2.5 mg/kg/day (Kornbluth 2010)
Dosage adjustment for concomitant use with allopurinol: Reduce azathioprine dose to one-third or one-fourth the usual dose when used concurrently with allopurinol. Patients with low or absent TPMT activity may require further dose reductions or discontinuation.
Refer to adult dosing.
Dosing: Renal Impairment
There are no specific dosage adjustments provided in the manufacturer’s labeling; however, oliguric patients, particularly those with tubular necrosis in the immediate post-transplant period (cadaveric transplant) may have delayed clearance and typically receive lower doses. The following adjustments have been recommended (Aronoff 2007):
CrCl >50 mL/minute: No adjustment recommended.
CrCl 10 to 50 mL/minute: Administer 75% of normal dose.
CrCl <10 mL/minute: Administer 50% of normal dose.
Hemodialysis (partially dialyzable; ~45% removed in 8 hours): Administer 50% of normal dose; supplement: 0.25 mg/kg.
CRRT: Administer 75% of normal dose.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling.
Dosing: Adjustment for Toxicity
Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment.
Severe toxicity (hematologic or other) in renal transplantation: May require discontinuation.
Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease): Permanently discontinue.
Injection: Add 10 mL of sterile water for injection, and swirl until solution is clear. May further dilute into NS or dextrose for infusion.
Canadian product: Reconstitute with 5 to 10 mL sterile water for injection (adding 5 mL will result in a 10 mg/mL solution). May further dilute in NS for infusion.
A 50 mg/mL oral suspension may be prepared with tablets. Crush one-hundred-twenty 50 mg tablets in a mortar and reduce to a fine powder. Add 40 mL of either cherry syrup (diluted 1:4 with Simple Syrup, USP); a 1:1 mixture of Ora-Sweet and Ora-Plus; or a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and mix to a uniform paste. Mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well", "refrigerate", and "protect from light". Stable for 60 days refrigerated.Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.8862208
Oral: Administering tablets after meals or in divided doses may decrease adverse GI events.
IV: Infusion is usually administered over 30 to 60 minutes, although may be infused over 5 minutes up to over 8 hours.
See Trissel’s IV Compatibility Database
Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Reconstituted solution should be used within 24 hours.
Tablet: Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.
5-ASA Derivatives: May decrease the metabolism of Thiopurine Analogs. Monitor therapy
ACE Inhibitors: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy
Allopurinol: May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Management: Reduce the azathioprine dose to one third to one quarter of the usual dose if used concomitantly with allopurinol, and monitor closely for systemic toxicity (particularly hematologic toxicity, nausea, and vomiting). Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Cyclophosphamide: AzaTHIOprine may enhance the hepatotoxic effect of Cyclophosphamide. Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Febuxostat: May increase the serum concentration of AzaTHIOprine. Avoid combination
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Mercaptopurine: AzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine. Avoid combination
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Ribavirin (Oral Inhalation): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients extra closely for signs/symptoms of myelosuppression. Consider therapy modification
Ribavirin (Systemic): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients closely for signs/symptoms of myelosuppression. Consider therapy modification
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Sulfamethoxazole: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Trimethoprim: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): AzaTHIOprine may enhance the adverse/toxic effect of Vaccines (Live). AzaTHIOprine may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose azathioprine (3 mg/kg/day or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns and is not a contraindication for administration of zoster vaccine. Higher doses of azathioprine should be avoided. Consider therapy modification
Vitamin K Antagonists (eg, warfarin): AzaTHIOprine may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
TPMT phenotyping results may not be accurate following recent blood transfusions.
Frequency not always defined; dependent upon dose, duration, indication, and concomitant therapy.
Central nervous system: Malaise
Gastrointestinal: Nausea and vomiting (rheumatoid arthritis: 12%), diarrhea
Hematologic & oncologic: Leukopenia (renal transplant: >50%; rheumatoid arthritis: 28%), neoplasia (renal transplant 3% [other than lymphoma], 0.5% [lymphoma]), thrombocytopenia
Hepatic: Hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases
Infection: Increased susceptibility to infection (renal transplant 20%; rheumatoid arthritis <1%; includes bacterial, fungal, protozoal, viral, opportunistic, and reactivation of latent infections)
Neuromuscular & skeletal: Myalgia
<1% (Limited to important or life-threatening): Abdominal pain, acute myelocytic leukemia, alopecia, anemia, arthralgia, bone marrow depression, hemorrhage, hepatic veno-occlusive disease, hepatosplenic T-cell lymphomas, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hypersensitivity, hypotension, interstitial pneumonitis (reversible), JC virus infection, macrocytic anemia, malignant lymphoma, malignant neoplasm of skin, negative nitrogen balance, pancreatitis, pancytopenia, progressive multifocal leukoencephalopathy, skin rash, steatorrhea, Sweet's syndrome (acute febrile neutrophilic dermatosis)
Concerns related to adverse effects:
• Gastrointestinal toxicity: The frequency of gastrointestinal adverse effects (nausea and vomiting) may be decreased with dividing dose or administering after meals. Gastrointestinal hypersensitivity with severe nausea and vomiting has been reported; diarrhea, rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities may also occur. Symptoms usually develop within the first several weeks of treatment and are generally reversible upon discontinuation; may recur upon rechallenge.
• Hematologic toxicity: Dose-related hematologic toxicities (leukopenia, thrombocytopenia, and anemias, including macrocytic anemia and/or pancytopenia) may occur; may be severe and/or delayed. Thiopurine methyltransferase (TPMT) genotyping or phenotyping may help to identify patients who are at an increased risk for developing azathioprine toxicity. Patients with intermediate TPMT activity may be at increased risk for hematologic toxicity at conventional azathioprine doses; patients with low or absent TPMT activity are at risk for severe, life-threatening myelotoxicity. Myelosuppression may be more severe with renal transplants undergoing rejection. Monitor CBC with differential and platelets weekly during the first month, then twice a month for 2 months, then monthly (or more frequently if clinically indicated). May require treatment interruption or dose reduction. Leukopenia does not correlate with therapeutic effect and the dose should not be increased intentionally to lower the white blood cell count.
• Hepatotoxicity: Hepatotoxicity (transaminase, bilirubin, and/or alkaline phosphatase elevations) may occur, usually in renal transplant patients. Usually occurs within 6 months of transplant and is normally reversible with discontinuation. Monitor liver function periodically. Rarely, hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported; discontinue if hepatic SOS is suspected.
• Infections: Chronic immunosuppression increases the risk of serious, sometimes fatal, infections (bacterial, viral, fungal, protozoal, and opportunistic), including reactivation of latent infections.
• Malignancy: [US Boxed Warning]: Chronic immunosuppression with azathioprine (a purine antimetabolite), increases the risk of malignancy. Malignancies reported have included post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Health care providers using this medication should be very familiar with this risk, as well as with the mutagenic potential to both men and women, and with possible hematologic toxicities. Patients should be informed of the risk for malignancy development. HSTCL is a rare white blood cell cancer that is usually fatal and has predominantly occurred in adolescents and young adults treated for Crohn disease or ulcerative colitis and receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. Most cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents, although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy. Renal transplant patients are known to be at increased risk for malignancy (eg, skin cancer, lymphoma), the risk is increased with aggressive immunosuppression. Limit sun and ultraviolet light exposure and use appropriate sun protection.
• Progressive multifocal leukoencephalopathy: Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including azathioprine (some cases have been fatal). Risk factors for PML include treatment with immunosuppressants and immune system impairment. Consider a diagnosis of PML in any patient presenting with new-onset neurological manifestations; consultation with a neurologist as clinically indicated may be warranted. Consider decreasing the degree of immunosuppression with respect to the risk of organ rejection in transplant patients.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment; dosage reductions may be necessary.
• TPMT deficiency: Patients with genetic deficiency of TPMT are more sensitive to myelosuppressive effects. Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity are at risk for developing severe and life-threatening hematologic toxicity. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity. Consider TPMT testing in patients with abnormally low CBC unresponsive to dose reduction. TPMT testing does not substitute for CBC monitoring.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Mercaptopurine: Azathioprine is metabolized to mercaptopurine; concomitant use may result in profound myelosuppression and should be avoided.
• TPMT or xanthine oxidase inhibitors: Patients on concurrent therapy with drugs which may inhibit TPMT (eg, olsalazine) or xanthine oxidase (eg, allopurinol) may be sensitive to myelosuppressive effects. Dose adjustment of azathioprine may be recommended when used concurrently with allopurinol; patients with low or absent TPMT activity may require further dose reductions or discontinuation.
• Vaccines: Immune response to vaccines may be diminished.
• Experienced health care provider: [U.S. Boxed Warning]: Should be prescribed by health care providers familiar with the risks, including hematologic toxicities and mutagenic potential.
CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly; monitor more frequently with dosage modifications), total bilirubin, liver function tests, creatinine clearance, TPMT genotyping or phenotyping (consider TPMT testing in patients with abnormally low CBC unresponsive to dose reduction); monitor for signs/symptoms of infection.
For use as immunomodulatory therapy in CD or UC (Kornbluth 2010; Lichtenstein 2009), monitor CBC with differential weekly for 1 month, then biweekly for 1 month, followed by monitoring every 1 to 2 months throughout the course of therapy; monitor more frequently if symptomatic. LFTs should be assessed every 3 months. Monitor for signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Pregnancy Risk Factor
Adverse events have been observed in animal reproduction studies. Azathioprine crosses the placenta in humans; congenital anomalies, immunosuppression, hematologic toxicities (lymphopenia, pancytopenia), and intrauterine growth retardation have been reported. Women of childbearing potential should avoid becoming pregnant during treatment.
Intrauterine growth retardation and preterm delivery are also reported in pregnancies following a kidney transplant. Stable immunosuppression is required in pregnant women who have had a kidney transplant and an increased risk of fetal malformations has not been observed with azathioprine; doses ≤2 mg/kg/day are recommended (Durst 2015; Hou 2013).
Although contraindicated by the manufacturer, available guidelines suggest that use of azathioprine is acceptable for the treatment of rheumatoid arthritis (Flint 2016). Azathioprine may also be used for the adjunctive treatment of lupus nephritis in pregnant women (Hahn 2012). Both guidelines recommend doses ≤2 mg/kg/day during pregnancy (Flint 2016; Hahn 2012). Agents other than azathioprine are recommended for the treatment of immune thrombocytopenia (Neunert 2011) and inflammatory bowel disease (van der Woude 2015) in pregnant women.
The National Transplantation Pregnancy Registry (NTPR) is a registry which follows pregnancies which occur in maternal transplant recipients or those fathered by male transplant recipients. The NTPR encourages reporting of pregnancies following solid organ transplant by contacting them at 877-955-6877 or NTPR@giftoflifeinstitute.org.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), angina, severe nausea, vomiting, loss of strength and energy, bruising, bleeding, severe dizziness, passing out, diarrhea, muscle pain, night sweats, excessive weight loss, mole changes, skin growths, or signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
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