Tioguanine


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Acute myeloid leukaemia; Acute lymphoblastic leukaemia; Chronic myeloid leukaemia Usual dose: 100-200 mg/m2/day. Dose and duration of treatment depends on the combination of other cytotoxic drugs used. Rare cases, as monotherapy: Initial: 2 mg/kg/day for 4 weeks, may be increased to 3 mg/kg/day if response is inadequate and no leukocyte or platelet depression. Refer to currently published protocols for dose, method and sequence of administration.
Dosage Details
Oral
Acute lymphoblastic leukaemia, Acute myeloid leukaemia, Chronic myeloid leukaemia
Adult: Usual dose: 100-200 mg/m2 daily given at various stages of treatment in short-term cycles. Dose and duration of treatment depends on the combination of other cytotoxic drugs used. Rare cases, as single agent therapy: Initially, 2 mg/kg daily for 4 weeks, may be increased to 3 mg/kg daily with careful monitoring if response is inadequate and no leukocyte or platelet depression. Refer to currently published protocols for dose, method and sequence of administration.
Child: Same as adult dose.
Special Patient Group
Pharmacogenomics:

Tioguanine is metabolised by 2 main pathways: metabolism by hypoxanthine (guanine) phosphoribosyl transferase to form thioguanine nucleotides (TGN) and metabolism by thiopurine S-methyltransferase (TPMT) to form inactive methylthioguanine base. Furthermore, nudix hydrolase 15 (nucleotide diphosphatase [NUDT15]) catalyses the conversion of cytotoxic tioguanine triphosphate metabolites to less toxic tioguanine monophosphate. TPMT and NUDT15 significantly affects the pharmacokinetics and cytotoxic effects of tioguanine.

Individuals with inherited deficiencies in TPMT or NUDT15 enzyme (known as homozygous deficient or poor metabolisers) may be unusually sensitive to myelosuppressive effects of tioguanine and prone to developing rapid bone marrow suppression. The prevalence of TPMT poor metabolisers is approx 0.3% in European or African ancestry, while NUDT15 risk alleles are common in Asians and Hispanic populations. Approx 2% of the East Asian ancestry (e.g. Chinese, Japanese, Vietnamese) have 2 loss-of-function alleles, and approx 21% have 1 loss-of-function NUDT15 alleles; <1% of European or African ancestry were detected to be NUDT15 deficient. TPMT genotyping or phenotyping, and NUDT15 variant genotyping may be considered prior to initiating tioguanine treatment.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline recommendations as of October 2018:

TPMT phenotypes

TPMT normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have lower levels of TGN metabolites and with normal risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with the normal starting dose (e.g. 40-60 mg/m2 daily), then adjust doses and of other combination agents without emphasis on tioguanine. After each dose adjustment, allow 2 weeks to reach steady-state concentrations.

TPMT intermediate metabolisers and possible intermediate metabolisers
TPMT intermediate metabolisers are carriers of 1 normal function allele and 1 no function allele (e.g. *1/*2, *1/*3A, *1/*3B, *1/*3C, *1/*4) while TPMT possible intermediate metabolisers are carriers of 1 uncertain/unknown function allele and 1 no function allele (e.g. *2/*8, *3A/*7). These phenotypes and genotypes have moderate to high levels of TGN metabolites resulting in increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with lowered doses at 50-80% of normal dose if the normal starting dose is ≥40-60 mg/m2 daily (e.g. 20-48 mg/m2 daily), then adjust doses according to the degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 2-4 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing tioguanine dose over other agents depending on other therapy.

TPMT poor metabolisers
Carriers of 2 no function alleles (e.g. *3A/*3A, *2/*3A, *3A/*3C, *3C/*4, *2/*3C, *3A/*4) have extremely high levels of TGN metabolites resulting in possible fatal toxicity without dose reduction and greatly increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with drastically reduced doses and frequency (e.g. reduce daily dose by 10-fold and give 3 times weekly instead of daily), then adjust doses according to the degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 4-6 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing tioguanine dose over other agents. Consider alternative non-thiopurine immunosuppressant treatment for non-malignant conditions.

NUDT15 phenotypes

NUDT15 normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have normal risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with the normal starting dose (e.g. 40-60 mg/m2 daily), then adjust doses and of other combination agents without emphasis on tioguanine. After each dose adjustment, allow 2 weeks to reach steady-state concentrations.

NUDT15 intermediate metabolisers and possible intermediate metabolisers
NUDT15 intermediate metabolisers are carriers of 1 normal function allele and 1 no function allele (e.g. *1/*2, *1/*3) while NUDT15 possible intermediate metabolisers are carriers of 1 uncertain function allele and 1 no function allele (e.g. *2/*5, *3/*6). These phenotypes and genotypes have increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with lowered doses at 50-80% of normal dose if the normal starting dose is ≥40-60 mg/m2 daily, then adjust doses according to the degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 2-4 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing tioguanine dose over other agents depending on other therapy.

NUDT15 poor metabolisers
Carriers of 2 no function alleles (e.g. *2/*2, *2/*3, *3/*3) have greatly increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Dose reduction to 25% of normal dose, then adjust doses according to the degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 4-6 weeks to reach steady-state concentration. If myelosuppression occurs, emphasise on reducing tioguanine dose over other agents. Consider alternative non-thiopurine immunosuppressant treatment for non-malignant conditions.
Renal Impairment
Dose reduction may be necessary.
Hepatic Impairment
Dose reduction may be necessary.
Administration
Should be taken on an empty stomach.
Contraindications
Prior resistance to tioguanine or mercaptopurine. Pregnancy and lactation. Immunisation with live vaccines.
Special Precautions
Patients with TPMT and NUDT15 deficiency (e.g. TPMT and NUDT15 intermediate, possible intermediate, and poor metabolisers); Lesch-Nyhan syndrome. Not recommended for maintenance therapy or long-term continuous treatment. Renal and hepatic impairment.
Adverse Reactions
Significant: Bone marrow suppression (e.g. leucopenia, thrombocytopenia, anaemia), hepatoxicity manifested as hepatic veno-occlusive disease/hepatic sinusoidal obstruction syndrome (e.g. hyperbilirubinaemia, hepatomegaly, weight gain caused by fluid retention and ascites), portal hypertension (e.g. splenomegaly, oesophageal varices), hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, periportal fibrosis, elevated liver enzymes; secondary malignancies, tumour lysis syndrome, hyperuricaemia, photosensitivity.
Blood and lymphatic system disorders: Pancytopenia.
Gastrointestinal disorders: Stomatitis, nausea, vomiting, diarrhoea. Rarely, intestinal necrosis or perforation.
Hepatobiliary disorders: Jaundice. Rarely, hepatic necrosis.
Investigations: Increased blood alkaline phosphatase and gamma glutamyl transferase.
Metabolism and nutrition disorders: Anorexia.
Renal and urinary disorders: Hyperuricosuria, urate nephropathy.
Potentially Fatal: Infections and bleeding due to granulocytopenia and thrombocytopenia.
Patient Counseling Information
Avoid excessive exposure to sunlight, wear protective clothing and use sunscreen.
MonitoringParameters
Consider TPMT genotypic or phenotypic tests, and NUDT15 genotypic tests to identify deficiency prior to treatment initiation. Monitor CBC with differential and platelet count frequently; LFTs weekly at the beginning of treatment and monthly thereafter (more frequently in patients with hepatic disease or concomitantly receiving other hepatotoxic drugs); serum uric acid. Monitor for signs and symptoms of hepatotoxicity, tumour lysis syndrome and myelosuppression. Monitor adherence.
Overdosage
Symptoms: Immediate nausea, vomiting, malaise, hypotension, diaphoresis; or delayed myelosuppression and azotaemia. Management: Supportive treatment. Administer appropriate blood transfusions (e.g. platelet or granulocyte transfusion) for bleeding and antibiotics for sepsis. May induce emesis for early detection of ingestion.
Drug Interactions
Increased risk of bone marrow suppression with other myelotoxic drugs or radiation therapy. May increase risk of TPMT deficiency with aminosalicylate derivatives (e.g. olsalazine, mesalazine, sulfasalazine). Increased risk of nodular regenerative hyperplasia, portal hypertension and oesophageal varices with busulfan.
Potentially Fatal: May diminish therapeutic effect of live vaccines and increase risk of infection.
Food Interaction
May increase risk of hepatotoxicity with alcohol.
Action
Description: Tioguanine is a sulfhydryl purine analogue of guanine and acts as a purine antimetabolite. It is converted to ribonucleotides which are incorporated into deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) resulting in the inhibition of synthesis and metabolism of purine nucleotides.
Synonym: Thioguanine.
Pharmacokinetics:
Absorption: Incompletely and variably absorbed from the gastrointestinal tract. Time to peak plasma concentration: 8 hours.
Distribution: Penetrates into CSF. Crosses the placenta.
Metabolism: Rapidly and extensively metabolised in the liver mainly via methylation by thiopurine S-methyltransferase (TPMT) into active (2-amino-6-methylthiogunaine) and inactive metabolites; to a lesser extent via deamination to form thioxanthine, and oxidation by xanthine oxidase to form thiouric acid.
Excretion: Via urine, mainly as metabolites. Terminal elimination half-life: 5-9 hours.
Chemical Structure

Chemical Structure Image
Tioguanine

Source: National Center for Biotechnology Information. PubChem Database. Thioguanine, CID=2723601, https://pubchem.ncbi.nlm.nih.gov/compound/Thioguanine (accessed on Apr. 27, 2020)

Storage
Store between 15-25°C. Protect from light and moisture. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01BB03 - tioguanine ; Belongs to the class of antimetabolites, purine analogues. Used in the treatment of cancer.
References
Dean, L. Thioguanine Therapy and TPMT Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). Accessed 08/11/2019. PMID: 28520351

Relling M, Schwab M, Whirl-Carrillo M et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. CPIC Update. 2018 May;105(5):1095-1105. doi: 10.1002/cpt.1304. Accessed 08/11/2019

Annotation of CPIC Guideline for Thioguanine and NUDT15, TPMT. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 08/11/2019.

Anon. NUDT15 - Thioguanine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 23/04/202023/04/2020.

Anon. Thioguanine. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 08/11/2019.

Anon. Thioguanine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/11/2019.

Anon. TPMT - Thioguanine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 23/04/2020.

Buckingham R (ed). Tioguanine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/11/2019.

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 08/11/2019.

Joint Formulary Committee. Tioguanine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/03/2020.

Tabloid Tablet (Aspen Global Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 08/11/2019.

Disclaimer: This information is independently developed by MIMS based on Tioguanine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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