Thiopurines

Azathioprine and mercaptopurine 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.

Active disease

  • Slow onset of action means they are not established therapy for induction of remission, though can induce remission, with a NNT = 4 in studies lasting more than 16 weeks (NNH=14).
  • Some studies suggest that early introduction (within the first few months of diagnosis) can improve success rates. Meta-analysis provides indirect support for their use in perianal disease.
ECCO statement 6D (CD 2016)

Immunosupressive naïve patients who are dependent on corticosteroids should be treated with a thiopurine [EL1] or methotrexate [EL2] or anti-TNF based strategy [EL1]. Surgical options should also be discussed [EL4]

Maintaining remission

  • Immunomodulators (azathioprine/mercaptopurine/methotrexate) are effective (NNT=3)
  • Introduction early in disease course may improve success rates though this has not been definitively assessed in adults.
  • Azathioprine more effective than 4 g/d mesalazine at preventing clinical relapse in those with moderate or severe lesions, with greater improvement in endoscopic appearances; but more patients withdraw taking azathioprine.
  • Thiopurines have a steroid sparing effect (successful in 87% taking azathioprine vs. 53% on placebo); albeit with increased risk of side-effects.
ECCO statement 6C (CD 2016)

For patients with extensive disease, thiopurines are recommended for maintenance of remission [EL1]. In patients with aggressive/severe disease course or poor prognostic factors, an anti-TNF-based strategy should be considered [EL5]

Prevention of post-surgical recurrence

  • Azathioprine for 1 year with Metronidazole for 3 months is more effective at reducing endoscopic post-operative recurrence than metronidazole alone.
  • Meta-analysis of 4 controlled trials assessing azathioprine to prevent clinical post-operative recurrence demonstrated it to be:
    • More effective than comparators (by 8% @ 1 y {NNT = 13} and 13% @ 2 y {NNT = 8})
    • With greater benefit when compared to placebo alone (by 13% for clinical {NNT = 7} and 23% for endoscopic {NNT = 4} recurrence @ 1 y).
  • Compared to all comparators, it was more effective at preventing severe endoscopic recurrence (i2-4, by 15%, NNT = 7) but not very severe recurrence (i3-4).
  • Adverse events requiring drug withdrawal occurred in 17% (10% in comparators).

Stopping therapy

  • As of 2013, therapeutic efficacy has been demonstrated for at least four years, therefore consider stopping azathioprine after 4 years of remission.
  • Some patients remain in long term remission, with relapse rates of 14%, 53% and 63% @ 1, 3 and 5 y respectively.
  • Remission can be re-induced by re-starting thiopurines in most of those who, having previously responded, relapse.
ECCO statement 6G (CD 2016)

For patients in long term remission on thiopurine maintenance therapy, cessation of treatment may be considered in the absence of objective signs of inflammation [EL2]. No recommendation can be given for the duration of treatment with methotrexate. Prolonged use of anti-TNF agents may be considered if needed [EL3]

Dosing, administration and monitoring

Before treatment

Dosing

  • Azathioprine 2-2.5 mg/kg/d or Mercaptopurine 1-1.5 mg/kg/d.
  • Reduce the dose by 50% if the TPMT level is low, but do not use thiopurines if TPMT very low/absent.
  • Use 25% of the dose in patients taking allopurinol.
  • Doses should be reduced in renal impairment.

Follow-up

  • 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 azathioprine > 2.5 mg/kg/d or mercaptopurine > 1.5 mg/kg/d may be required.
  • Thereafter, consider methotrexate, anti-TNF or surgery.

ECCO statement 6E (CD 2016)

Patients receiving thiopurines who relapse should be evaluated for adherence to therapy, and objective signs of inflammation [EL5]. Dose optimisation may improve response rates [EL4]. Where appropriate, therapy should be changed to methotrexate [EL2] or anti-TNF therapy [EL1]. Surgery should always be considered as an option in localised disease [EL4]

Red flag interactions

Interaction with other medicinal products and other forms of interaction

  • 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.

Adverse effects

  • Switch to Mercaptopurine with intolerance / severe adverse effects to azathioprine, unless these are severe pancreatitis or severe leucopenia.
  • Bone marrow toxicity
    • 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 normalised.
  • Abnormal liver function
    • Discontinue if transaminases > 2xULN, until liver function normalises
    • Hepatic toxicity can be abrogated taking 25% of the daily dose together with 100mg of allopurinol, which requires frequent blood monitoring (similar to those newly commenced on thiopurines +/- thiopurine metabolite monitoring); or switching to alternate thiopurine.
  • Pancreatitis
    • Rare side effect. Occurs within the first two months of use.
    • Discontinue drug. Re-challenge not recommended as pancreatitis often recurs.
  • Lymphoma
  • Other malignancy
    • Increased non-melanoma skin cancer.
    • Advise patients to avoid excess exposure and use high-factor sunscreen.
  • Flu-like symptoms, nausea, headache
    • Occur in ≈10%. Many respond to taking drug twice daily, dose reduction, or switching to alternative thiopurine.
  • National Formulary should be consulted to review adverse drug reactions and drug interactions.

Special situations

Pregnancy

  • Thiopurines are considered safe to use in pregnancy, following discussion as to their risk / benefit.
  • Low dose excretion occurs into breast milk for four hours following ingestion, therefore consider advising expressing and wasting milk during this time period.
  • One study of 50 pregnancies in which fathers used MP within 3 months of conception demonstrated a higher rate of complications.

Breastfeeding

  • 6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.

Surgery

  • Thiopurines do not increase the risk of peri- or post-operative complications.

Paediatrics

Please see Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease: Guidelines

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 azathiopurine, 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 azathiopurine 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 azathiopurine to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of azathiopurine may be impaired, and the dosage of azathiopurine should therefore be reduced if hepatic or haematological toxicity occurs.

Limited evidence suggests that azathiopurine 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 azathiopurine.

Despite widespread use in UC, there is little high quality data for thiopurines. They are indicated as maintenance therapy in steroid-dependent and steroid-refractory patients, in severe UC patients treated with ciclosporin, and as adjunctive treatment with anti-TNF.

Active disease

There is very little data assessing response rates in active UC, as thiopurines have slow-onset of action. They are mainly used to maintain remission.

Maintaining remission

The evidence for the use of thiopurines is weak in UC. A 2009 meta-analysis reported a NNT of 5, although the controlled studies of maintenance of remission only included 124 thiopurine treated patients (mean efficacy of 60% vs. 37% in controls (OR = 2.56; 95% CI = 1.51-4.34)). There is no evidence to support concomitant 5-ASA therapy. Azathiopurine is effective in steroid-dependent UC, with remission remaining in >50% on steroid withdrawal (≈20% in those given 3.2 g/d 5-ASA). In the large Oxford cohort of patients treated with AZA, 87% were in remission at 6 months; 62% remained in remission at 5 years. Predicting response was uncertain other than suppression of the leukocyte count < 5x109/L. The median time to relapse after stopping AZA was 18 months, independent of prior duration of azathioprine.

Based on a subset analysis of a very large population based study (CESAME cohort), thiopurines might reduce advanced neoplasia (cancer or high grade dysplasia) in patients at high risk, however this finding needs to be confirmed.

ECCO statement 8J (UC 2017)

Chemoprevention with mesalamine compounds may reduce the incidence of colorectal cancer in ulcerative colitis [EL2]. There is insufficient evidence to recommend for or against chemoprevention with thiopurines

Dosing, administration and monitoring

Before treatment

Dosing

  • Azathioprine 2-2.5 mg/kg/d or Mercaptopurine 1-1.5 mg/kg/d.
  • Reduce the dose by 50% if the TPMT level is low, but do not use thiopurines if TPMT very low/absent.
  • Use 25% of the dose in patients taking allopurinol.
  • Doses should be reduced in renal impairment.
Dosing when renal and/or hepatic insufficiency
  • It has been suggested that the toxicity of azathiopurine 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 azathiopurine to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of azathiopurine may be impaired, and the dosage of azathiopurine should therefore be reduced if hepatic or haematological toxicity occurs.
  • Limited evidence suggests that azathiopurine 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 azathiopurine.

Follow-up

  • 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 azathioprine > 2.5 mg/kg/d or mercaptopurine > 1.5 mg/kg/d may be required.
  • Thereafter, consider methotrexate, anti-TNF or surgery.

Red flag interactions

Interaction with other medicinal products and other forms of interaction

  • 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.

Adverse effects

  • Switch to Mercaptopurine with intolerance / severe adverse effects to azathioprine, unless these are severe pancreatitis or severe leucopenia.
  • Bone marrow toxicity
    • 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 normalised.
  • Abnormal liver function
    • Discontinue if transaminases > 2xULN, until liver function normalises
    • Hepatic toxicity can be abrogated taking 25% of the daily dose together with 100mg of allopurinol, which requires frequent blood monitoring (similar to those newly commenced on thiopurines +/- thiopurine metabolite monitoring); or switching to alternate thiopurine.
  • Pancreatitis
    • Rare side effect. Occurs within the first two months of use.
    • Discontinue drug. Re-challenge not recommended as pancreatitis often recurs.
  • Lymphoma
  • Other malignancy
    • Increased non-melanoma skin cancer.
    • Advise patients to avoid excess exposure and use high-factor sunscreen.
  • Flu-like symptoms, nausea, headache
    • Occur in ≈10%. Many respond to taking drug twice daily, dose reduction, or switching to alternative thiopurine.
  • National Formulary should be consulted to review adverse drug reactions and drug interactions.

Special situations

Pregnancy

  • Thiopurines are considered safe to use in pregnancy, following discussion as to their risk / benefit.
  • Low dose excretion occurs into breast milk for four hours following ingestion, therefore consider advising expressing and wasting milk during this time period.
  • One study of 50 pregnancies in which fathers used MP within 3 months of conception demonstrated a higher rate of complications.

Breastfeeding

  • 6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.

Surgery

  • Thiopurines do not increase the risk of peri- or post-operative complications.

Paediatrics

Please see:

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 azathiopurine, 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.

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