How to use it
Starting dose. Enter the drug, weight, TPMT, NUDT15, kidney function, regimen and pregnancy status. The tool gives a once-daily dose rounded to Canadian tablets, the monitoring schedule and the cautions that apply. Age, sex and EBV status are optional: fill them in to get targeted lymphoma and EBV advice.
Metabolites. Enter 6-TGN and 6-MMP from the report, after at least 4 weeks on a stable dose. Say whether the patient is also on an anti-TNF, has active disease, or takes allopurinol.
Check TPMT before starting; the advanced therapy screening checklist lists it with the other baseline tests.
Starting dose
| Result | Starting dose |
|---|---|
| TPMT and NUDT15 normal | Azathioprine 2–2.5 mg/kg/day or mercaptopurine 1–1.25 mg/kg/day, full dose from day 1 (BSG 2019) |
| Intermediate (one gene) | 50% of that: azathioprine 1–1.25, mercaptopurine 0.5–0.63 mg/kg/day (BSG 2019; BSG 2025 gives 30–80% for NUDT15; CPIC 30–80% for azathioprine) |
| Intermediate for both genes | No figure from CPIC: individualise |
| Poor (either gene) | Avoid; use another drug class (CPIC 2018; BSG) |
| TPMT not known | Wait for the result (BSG 2019) |
| With allopurinol 100 mg daily | 25–33% of the standard dose (BSG 2019 and 2025) |
| Creatinine clearance 10–50 or below 10 mL/min | 75% or 50% of the dose (BSG 2019) |
Why 1–1.25 mg/kg for mercaptopurine? BSG 2019 gives 1–1.25 mg/kg/day. The often-quoted 1.5 mg/kg/day comes from CPIC’s oncology-weighted “normal starting dose”. The tool uses the BSG range.
Rounding. Every oral azathioprine and mercaptopurine product marketed in Canada is a scored 50 mg tablet. The tool picks the highest whole-tablet dose inside the range, then a half tablet if needed. It never rounds up past the top of the range. The Canadian azathioprine patient leaflets say not to break the tablet, so check with the pharmacist before prescribing half tablets.
NUDT15 testing is not yet widely available (BSG 2025). CPIC allows dosing on TPMT alone when only one gene is tested, with the caveat that the other result is missing. The tool does this but does not show the dose as green.
IBD is off-label. In Canada, azathioprine is authorized for renal transplant and rheumatoid arthritis and mercaptopurine for acute lymphoblastic leukemia.
Monitoring
- The tool follows BSG 2019 and 2025: CBC, creatinine and liver tests at weeks 2, 4, 8 and 12, then at least every 3 months. The screening checklist uses the same schedule.
- The Canadian Imuran monograph is stricter: CBC with platelets weekly for the first month, twice monthly in months 2 and 3, then monthly. The tool shows it as a secondary note.
- Withhold if white cells are below 3.5 or neutrophils below 2 × 10⁹/L until they recover (BSG 2019).
- Check metabolites from 4 weeks, and especially with allopurinol (BSG 2025).
Reading metabolites
Units: pmol/8 × 10⁸ red cells. Use these cut-offs only when the report uses these units and quotes a 6-TGN range of about 235–450.
| 6-TGN; 6-MMP | Meaning | Action (BSG 2025 Table 8 unless stated) |
|---|---|---|
| Both undetectable | Non-adherence | Explore adherence; rarely poor absorption |
| Undetectable; detectable but ≤5700 | Likely non-adherence or partial adherence (Dr. Squirell; see below) | Check adherence first; consider shunting only if adherence is confirmed and a repeat shows the same |
| <235; ≤5700, ratio ≤11 | Underdosing or variable adherence | Increase the dose by 25–33%; repeat in 4 weeks |
| <235; >5700 or ratio >11 | Hypermethylator (“shunter”) | Reduce to 25–33% and add allopurinol 100 mg; repeat in 4 weeks |
| 235–450; ≤5700 | Correct dose | Continue if responding; if not, change drug class |
| 235–450; >5700 | Possibly too high | Reduce the dose; repeat in 4 weeks; consider allopurinol |
| >450; any | Myelotoxicity risk | Check CBC (Simsek 2017); reduce the dose; repeat in 4 weeks (Table 8 gives this for 6-MMP >5700) |
With an anti-TNF, a 6-TGN of at least 125 may be enough, although 235–450 may better prevent antibodies to the anti-TNF (BSG 2025).
Where sources differ
- 6-TGN threshold: 235 (Dubinsky 2000; BSG) or 230 (Osterman 2006 meta-analysis tested 230–260). The tool uses 235.
- Undetectable 6-TGN with a low 6-MMP: the ratio rule would call any detectable 6-MMP with no 6-TGN “shunting”. The tool reads it as non-adherence (or partial adherence) first, as Dr. Squirell advises, and considers shunting only if adherence is confirmed and a repeat test after 4 weeks of regular dosing shows the same pattern. Undetectable 6-TGN with 6-MMP above 5700 is still read as shunting, after an adherence check.
- Shunting ratio: BSG uses 6-MMP:6-TGN above 11 (Derijks 2004). New Zealand studies use above 20 (Gardiner 2011; van Egmond 2012). The tool uses 11 and notes a ratio above 20.
- Allopurinol dose reduction: 25–33% (BSG), 25–50% (Sparrow 2007), a quarter (Imuran monograph), one-third to one-quarter (Canadian mercaptopurine monographs). The tool uses 25–33%.
- Intermediate TPMT on mercaptopurine: BSG 2019 halves the dose. CPIC 2018 reduces it to 30–80% only when the normal dose is 1.5 mg/kg/day or more, and says reduction may not be needed below that. The BSG target (1–1.25 mg/kg/day) is below it, so the CPIC range is shown for azathioprine only.
- EBV: BSG 2025 suggests testing everyone before a thiopurine; ECCO 2023 suggests testing young adult men.
- Live vaccines: CAG 2021 makes no low-dose exception. The Canadian Immunization Guide allows varicella vaccine to be considered at azathioprine ≤3 mg/kg/day or mercaptopurine ≤1.5 mg/kg/day, and advises consulting an expert when low-dose immunosuppressants are combined (for example, with an anti-TNF).
Pitfalls
- Laboratory methods differ. The Dervieux method gives 6-TGN about 2.6 times the Lennard method (Simsek 2017). Don’t apply these cut-offs to another method or convert between them; use the lab’s range.
- Too early. Metabolites need about 4 weeks on a stable dose. TPMT enzyme activity is unreliable after a recent transfusion and falsely low while on a thiopurine; use genotype instead.
- Never add allopurinol to a full thiopurine dose. Avoid febuxostat altogether.
- A normal TPMT doesn’t prevent myelosuppression. NUDT15 variants and other causes exist. Keep to the blood count schedule.
- Pancreatitis usually occurs in the first month (about 4%). Do not rechallenge.
- Pregnancy: don’t start a thiopurine in pregnancy, but continue one that is working. See the IBD in pregnancy tool.
- Lymphoma and skin cancer: the risk of lymphoproliferative disorders is about 5 times higher while on a thiopurine (CESAME). Hepatosplenic T-cell lymphoma has mostly occurred in men under 35 after 2 or more years. Advise sun protection and skin checks.