Chemical: Drug
thioguanine

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Prescribing Info (2) Drug Labels (2) Clinical Annotations (10)

Available Prescribing Info

Dosing Guidelines

Annotation of CPIC Guideline for thioguanine and TPMT
Annotation of DPWG Guideline for thioguanine and TPMT

last updated 03/15/2017

1. Annotation of CPIC Guideline for thioguanine and TPMT

Summary

Start with reduced doses of thioguanine for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles; adjust dose based on degree of myelosuppression and disease-specific guidelines. Consider alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles.

Annotation

This annotation is based on the CPIC® guideline for thiopurines and TPMT.

May 2016 Update on PharmGKB

Several studies have reported that individuals who carry low-function alleles for NUDT15 are unable to tolerate usual doses of thiopurines. [Articles:25108385, 25624441, 26033531, 26076924, 26405151, 26503813, 26590936, 26735160, 26878724] These alleles are more common among those of Asian ancestry and Hispanic ethnicity than others. [Articles:25624441, 26878724] The dose tolerated by those with two low-function alleles is only ~ 10% that tolerated by those with no low-function NUDT15 or TPMT alleles. [Articles:25624441, 26878724] CPIC is planning a guideline to address NUDT15 variants and possible dosing recommendations for thiopurines.

April 2013 Update

Advance online publication January 2013.

The 2013 update of CPIC guidelines regarding azathioprine, thioguanine and mercaptopurine, have been published in Clinical Pharmacology and Therapeutics. Literature published between June 2010-November 2012 was reviewed and there is no new evidence that would change the original guidelines. Therefore, the dosing recommendations in the original publication remain clinically current.
These guidelines are applicable to:
- pediatric patients
- adult patients
Download and read:
- Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update
- 2013 supplement

March 2011

Advance online publication January 2011.

Guidelines regarding the use of pharmacogenomic tests in dosing for azathioprine, thioguanine and mercaptopurine were published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Excerpt from the 2011 thiopurine dosing guidelines:
- "Thiopurines are most commonly used to treat nonmalignant conditions but are also critical anticancer agents. The approach to dosing adjustments based on TPMT status may differ depending on the clinical indication and the propensity to initiate therapy at higher vs. lower starting doses. We and others advocate testing for TPMT status prior to initiating thiopurine therapy, so that starting dosages can be adjusted accordingly."
Download and read:
- Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing
- 2011 supplement

Table 1: Recommended dosing of thioguanine by TPMT phenotype

Adapted from Tables 1 and 2 of the 2011 guideline manuscript.

Phenotype (Genotype)	Examples of diplotypes	Implications for pharmacologic measures after thioguanine	Dosing recommendations for thioguanine	Classification of recommendations
Homozygous wild-type or normal, high activity (two functional *1 alleles)	1/1	Lower concentrations of TGN metabolites, but note that TGN after thioguanine are 5-10x higher than TGN after mercaptopurine or azathioprine	Start with normal starting dose. Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine . Allow 2 weeks to reach steady state after each dose adjustment.	Strong
Heterozygote or intermediate activity (one functional allele - 1, plus one nonfunctional allele - 2, 3A, 3B, 3C, or 4)	1/2, 1/3A, 1/3B, 1/3C, 1/4	Moderate to high concentrations of TGN metabolites; but note that TGN after thioguanine are 5-10x higher than TGN after mercaptopurine or azathioprine	Start with reduced doses (reduce by 30-50%) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.	Medium
Homozygous variant, mutant, low, or deficient activity (two nonfunctional alleles - 2, 3A, 3B, 3C, or *4)	3A/3A, 2/3A, 3C/3A, 3C/4, 3C/2, 3A/4	Extremely high concentrations of TGN metabolites; fatal toxicity possible without dose decrease	Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy.	Strong

last updated 08/10/2011

2. Annotation of DPWG Guideline for thioguanine and TPMT

Summary

Select an alternative drug rather than thioguanine for intermediate and poor TPMT metabolizers.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for thioguanine based on TPMT genotype [Article:21412232]. They recommend selecting an alternative drug for patients carrying inactive alleles.

Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical Relevance
IM (one inactive allele: 2, 3, 4-18)	Select alternative drug. Insufficient data to allow calculation of dose adjustment.	Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.	Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10⁹/l; leucopenia 1.0-2.0x10⁹/l; thrombocytopenia 25-50x10⁹/l; severe diarrhea.
PM (two inactive alleles: 2, 3, 4-18)	Select alternative drug. Insufficient data to allow calculation of dose adjustment.	Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series.	Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.

*See Methods or [Article:18253145] for definition of "moderate" quality.
S: statistically significant difference.

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Annotated Labels

Annotation of FDA Label for thioguanine and TPMT
Annotation of HCSC Label for thioguanine and TPMT

last updated 10/25/2013

1. Annotation of FDA Label for thioguanine and TPMT

On FDA Biomarker List

Actionable PGx

Summary

The drug label states that substantial dosage reductions may be required in individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) to avoid the development of life-threatening bone marrow suppression. Prescribers should be aware that some laboratories offer testing for TPMT deficiency.

Annotation

The pharmacogenomic releationship between thioguanine and TPMT is well described. See the TPMT VIP and Thiopurines Pathway for more details. Recent work by the Clinical Pharmacogenomics Implementation Consortium (CPIC) has published guidelines for dosing of thioguanine in individuals with TPMT variants.

Excerpt from the Thioguanine (Tabloid) drug label:

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Prescribers should be aware that some laboratories offer testing for TPMT deficiency. Since bone marrow suppression may be associated with factors other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Thioguanine (Tabloid) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

Drug Toxicity
- Precautions section
- source: PHONT
Leukemia
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Neoplasms
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Warnings section, Adverse reactions section, Precautions section
- source: PHONT
TPMT
- metabolism/PK, Dosage & administration section, Warnings section, Precautions section
- source: U.S. Food and Drug Administration

2. Annotation of HCSC Label for thioguanine and TPMT

Actionable PGx

Summary

The product monograph for thioguanine (LANVIS) notes that individuals with deficiency of the thiopurine methyltransferase (TPMT) enzyme may be at increased risk of developing myelosuppression when receiving the drug, and that testing for TPMT deficiency is available.

Annotation

Thioguanine (LANVIS) is indicated for treatment of acute leukemia, as well as chronic granulocytic leukemia. Excerpt from the thioguanine (LANVIS) product monograph:

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of thioguanine and prone to developing rapid bone marrow depression following the initiation of treatment with LANVIS(R). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore, close monitoring of blood counts is still necessary.

For the complete product monograph text with sections containing pharmacogenetic information highlighted, see the thioguanine product monograph.

*Disclaimer: The contents of this page have not been endorsed by HCSC and are the sole responsibility of PharmGKB.

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.