The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC, please click here:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009053s032lbl.pdf
Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11
Introduction and Mechanism of Action
Azathioprine (AZA), is immunosuppressive antimetabolite, is available in tablet form for oral administration. It is an imidazolyl derivative of 6-mercaptopurine (6MP) and many of its biological effects are similar to those of the parent compound. 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.
Therapeutic indications
Ulcerative Colitis and Crohn's Disease:
AZA and 6MP are immune-modulators used to avoid prolonged steroid use (steroid sparing agents) by maintaining patients in remission. They are indicated following 2 or more steroid courses in 12 months; steroid-dependent patients; and those with severe disease especially with adverse prognostic factors. They are also used to augment anti-TNF therapy, in-part by reducing immunogenicity of biologic agents.
Dosing, administration, and monitoring
Dosing, administration
- The recommended dose is calculated to reach 2-2.5 mg/Kg/d for AZA and 1-1.5 mg/Kg/d for 6MP given orally once daily.
- Reduce the dose by 50% if the TPMT level is low, but do not use thiopurines if TPMT very low/absent (increased risk of developing severe, life-threatening myelotoxicity). TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING THIOPURINES.
- Use 25% of the dose in patients taking allopurinol. Doses should be reduced in renal impairment.
Monitoring
- Monitor patients regularly (blood count, LFT, U&E). For example, weekly for 4 weeks, alternate weekly for 2 months, then 2-3 monthly.
- Recommend stopping therapy and obtain urgent blood tests if unexpected bleeding, bruising or fever.
If patients relapse on therapy, optimise dose:
- Review compliance
- Optimise dose based on:
- Metabolite testing (6-TGN and MMP)
- Bone marrow parameters (aim lymphocyte > 0.5x109/L; MCV <115 fL)
- Doses of AZA > 2.5 mg/kg/d or 6MP > 1.5 mg/kg/d may be required.
- Thereafter, consider methotrexate (for CD), anti-TNF or surgery (according to ECCO Statements).
Retreatment
If therapy is interrupted, restarting treatment with thiopurines can be considered. In case of Intolerance or idiosyncratic reaction (e.g. pancreatitis) a new drug challenge is formally contraindicated.
Dose interruption and discontinuation
Thiopurines treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, anaemia and hepatotoxicity or pancreatitis. It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.
Contraindications
Hypersensitivity to the active substance or to any of the excipients
Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections
Severe hepatic impairment (Dose adjustments may be necessary)
Adverse effects
The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal (GI). Switch from AZA to 6MP with GI intolerance, unless these are severe pancreatitis or severe leucopenia.
Combination with other therapies
Thiopurines are used in combination with biologics mostly TNF antagonists, to optimize efficacy (e.g. based on the SONIC trial with infliximab) and reduce the risk of developing antibodies against the drug, however with the possibility of increased immunosuppression, increased risk of infection and higher incidence of adverse events.
Serious infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving thiopurines. The risk of opportunistic infections is higher in Asian geographic regions.
Thiopurines should not be initiated in patients with active infections, including localized infections.
The risks and benefits of treatment should be considered prior to initiating thiopurines in patients:
• with recurrent infections,
• with a history of a serious or an opportunistic infection,
• who have resided or travelled in areas of endemic mycoses,
• who have underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with thiopurines. Treatment should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with thiopurines should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.
Tuberculosis
The risks and benefits of treatment should be considered prior to initiating thiopurines in patients:
• who have been exposed to TB,
• who have resided or travelled in areas of endemic TB.
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of thiopurines. Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering thiopurines.
Antituberculosis therapy should also be considered prior to administration of thiopurines in patients who test negative for TB but who have a past history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection. Consultation with a healthcare professional with expertise in the treatment of TB is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral infections
EBV – as fatal cases in EBV naïve male patients due to hemophagocytosis syndrome have been described in the literature. The thiopurines indication should be carefully proofed and discussed with this group of patients.
HV - Corticosteroid use and thiopurines were associated with an elevated Herpes Zoster risk.
Malignancy and lymphoproliferative disorder
The possibility exists for thiopurines to affect host defences against malignancies. The risks and benefits of thiopurine treatment should be considered prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing thiopurines in patients who develop a malignancy. Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, urinary tract/renal cancer
Lymphoma
Increase in lymphoma have been reported in patients treated with thiopurines on monotherapy or in particular combination with anti-TNF agents, however the prevalence remains very low (5/12’000).
Hepatosplenic T-cell lymphoma
Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with thiopurines. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with thiopurines as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.
Non-melanoma skin cancer
Increase in non-melanoma skin cancer have been reported in patients treated with thiopurines. Advise patients to avoid excess exposure and use high-factor sunscreen. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Pancreatitis
Rare side effect (<5%). Occurs within the first two months of use. Discontinue drug immediately. Re-challenge not recommended as pancreatitis often recurs.
Liver enzymes
Treatment with thiopurines could be associated with an increased incidence of liver enzyme elevation in some patients (see monitoring section). Caution should be exercised when considering initiation of thiopurines treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Following initiation, routine monitoring of liver tests should be performed as some “Shunts” towards MMP metabolites in case of high TMPT activity could lead to drug induced- hepatitis. If this shunting phenomenon is suspected a combination of a very low dose (one fourth) of azathioprine and allopurinol can be done. If drug-induced liver injury is suspected, the administration of thiopurines should be interrupted until this diagnosis has been excluded.
Gastro-intestinal Intolerance and other adverse events
Flu-like symptoms, nausea, headache occur in ≈10%. Many respond to taking drug twice daily, dose reduction, or switching from AZA to 6MP.
Laboratory parameters and Monitoring
Bone marrow toxicity (is dose dependent - please refer also to monitoring section)
Neutrophils
Leucopenia is common, and may be associated with improved drug efficacy.
Severe leucopenia (neutrophil < 1x109/L or lymphocytes < 0.5x109/L) is associated with adverse outcomes (infection). Stop drug; consider lower dose on rechallenge once blood parameters normalized.
Lymphocytes
Treatment with thiopurines was associated with an increased incidence of lymphopenia compared to placebo. Lymphocyte counts less than 750 cells/mm3 were associated with an increased incidence of serious infections.
Haemoglobin
Treatment with thiopurines has been associated with decreases in haemoglobin levels. It is not recommended to initiate thiopurines treatment in patients with a haemoglobin value less than 9 g/dL.
Vaccinations
Prior to initiating thiopurines, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. Immunization with live vaccines should rather not be given concurrently with thiopurines. The decision to use live vaccines prior to thiopurines treatment should take into account the pre-existing immunosuppression in a given patient.
Interactions with other Drugs
Red flag interactions with the following medications:
- Allopurinol/ oxipurinol/ thiopurinol: Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol are given concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine should be reduced to one-quarter of the original dose.
- Neuromuscular blocking agents: Azathioprine can potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine and can reduce the blockade produced by non-depolarising agents such as tubocurarine. There is considerable variation in the potency of this interaction.
- Warfarin: Inhibition of the anticoagulant effect of warfarin, when administered with azathioprine, has been reported.
- Aminosalicylate derivatives: As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Azathioprine therapy (see Special Warnings and Special Precautions for Use).
- Furosemide: Furosemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.
Special situations (e.g. pregnancy)
Pregnancy
Thiopurines are considered safe to use in pregnancy, following discussion as to their risk / benefit.
Breast-feeding
6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving thiopurine treatment. Low dose excretion occurs into breast milk for four hours following ingestion; therefore, consider advising expressing and wasting milk during this time period.
Fertility
Thiopurine use doesn’t seem to affect human fertility.
Surgery
Thiopurines do not increase the risk of peri- or post-operative complications.
Elderly
Although the available data do not provide evidence that the incidence of side effects among elderly patients is significantly higher than that among other patients treated with thiopurines, it is recommended that the dosages used should be at the lower end of the range.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
Renal and/or hepatic insufficiency
It has been suggested that the toxicity of thiopurines may be enhanced in the presence of renal insufficiency, but controlled studies have not supported this suggestion. Nevertheless, it is recommended that the dosages used should be at the lower end of the normal range and that haematological response should be carefully monitored. Dosage should be further reduced if haematological toxicity occurs.
Caution is necessary during the administration of thiopurines to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of thiopurines may be impaired, and the dosage of thiopurines should therefore be reduced if hepatic or haematological toxicity occurs.
Limited evidence suggests that thiopurines is not beneficial to patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive thiopurines.