Table 2.
Overview of recommendations that can be considered in patients starting AzaAllo or 6-TG therapy. These guidelines and positions are intended to support daily practice. This guideline is based on the medication guideline IBD (allopurinol in combination with azathioprine/mercaptopurine) of the Dutch Gastroenterology Society [52]
| Brand names |
Mercaptopurine (Puri-Nethol®) Tablet 50 mg Azathioprine (Imuran®) Tablet 25 mg, 50 mg Allopurinol Tablet 100 mg Thioguanine (Thiosix®, Lanvis®) Tablet 20 mg, 40 mg |
| Dosages |
AZA monotherapy 1.0–3.0 mg/kg/day MP monotherapy 1.0–1.5 mg/kg/day Thiopurine-allopurinol combination: Mercaptopurine 1 od 0.25–0.375 mg/kg/day usually 25 mg increase dose based on 6-TGN level Azathioprine 1 od 0.5–0.70 mg/kg/day usually 50 mg, increase dose based on 6-TGN level Allopurinol 1 od 100 mg/day Thioguanine monotherapy Thioguanine 1 od (0.2–0.3 mg/kg/day) usually 20 mg (up to 40 mg/day), no dose adjustments necessary based on 6-TGN level |
| Therapeutic effect | 2–3 months |
| Interactions |
• 5-ASA: higher 6-TGN levels/bone marrow depression [53] • Allopurinol: higher 6-TGN levels (active metabolite) and lower 6-MMP levels (side-metabolite). [28] • Ribavirine: (increased likelihood of bone marrow depression) [54] |
| Fertility |
• Fertility: no adverse effects, based on current literature [55] • Pregnancy: sparse data available. Caution is advised [56, 57] • Lactation: Allopurinol passes into breast milk. Consequences not clear. Be very cautious with the use of allopurinol. [58, 59] |
| Lab prior to therapy |
• Hb, MCV, leukocytes + differentiation, trombocytes • Kreatinine + eGFR • ASAT, ALAT, alkaline phosphatase, gamma-GT, bilirubin (total) • In case of low Hb: ferritin and transferrin saturation • Hepatitis B and C screening and EBV status • On indication: CMV • Feces calprotectine and/or endoscopy |
| Lab during therapy |
Weeks 1. 2, 4, 6, 8, and 12: Hb, MCV [48] (might be increased during thiopurine usage), trombocytes, leukocytes + differentiation, kreatinine, alkaline phosphatase, bilirubin (total), gamma-GT, ASAT, ALAT Afterwards, every three months during first year: Hb, MCV, trombocytes, leukocytes + differentiation, kreatinine, alkaline phosphatase, bilirubin (total), gamma-GT, ASAT, ALAT After first year of thiopurine usage, every six months: Hb, MCV, trombocytes, leukocytes + differentiation, kreatinine, alkaline phosphatase, bilirubin (total), gamma-GT, ASAT, ALAT |
| Drug levels |
AZA/6-MP Therapeutic levels 6-TGN: 235–450 pmol/8*108 RBC (Lennard Method) 6-TGN: 300–600 pmol/8*108 RBC (Dervieux Method) Toxic levels 6-MMP: > 5700 pmol/8*108 RBC In case of low 6-TGN and high 6-MMP: 25% of current dosage and add 100 mg allopurinol under frequent follow-up of general lab and 6-TGN levels 6-TG Therapeutic levels 6-TGN: 235–1000 pmol/8*108 RBC (Lennard Methode) 6-TGN: 300–1250 pmol/8*108 RBC (Dervieux Methode) Toxic levels 6-TGN: > 2000 pmol/8*108 RBC (Lennard Method) 6-TGN: > 2600 pmol/8*108 RBC (Dervieux Method) |
| TPMT |
AZA/6-MP TPMT intermediate metabolizer Start with 50% of the standard dose [60] TPMT poor metabolizer 1. 10% of standard dosage [60] 2. Choose other alternative Thiopurine-allopurinol combination Only use in TPMT normal metabolizer [61] Thioguanine therapy TPMT intermediate metabolizer Start with 50% of the standard dose (0.1–0.15 mg/kg/day) [60] TPMT poor metabolizer 1. TG 20 mg every week [62] 2. Choose other alternative * It must be noted that the evidence of the use of genotyping in TG therapy is not clear |
| NUDT15 |
AZA/6-MP NUDT15 intermediate metabolizer Start with 25% to 50% of the standard dose NUDT15 poor metabolizer 1. Avoid thiopurines, or 2. If cannot be avoided use 10% of standard dosage Thiopurine-allopurinol combination Only use in NUDT15 normal metabolizer Thioguanine therapy NUDT15 intermediate metabolizer Start with 25% to 50% of the standard dose NUDT15 poor metabolizer 1. Avoid TG, Or if cannot be avoided, 2. Use 25% to 50% of standard dose TG every week |
AZA Azathioprine, MCV mean corpuscular volume, MP mercaptopurine, NUDT15 nudix hydrolase 15, TDM therapeutic drug monitoring, TG thioguanine, TPMT thiopurine S-methyltransferase, 6-MMP 6-methyl mercaptopurine ribonucleotides, 6-TGN 6-thioguanine nucleotides