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thioguanine
It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase).
Not completely elucidated, crosses the placenta
| Cross blood brain barrier? | Trace |
| PPB | No information found |
Predominantly in liver and other tissues; extensively metabolised by methylation, oxidation and deamination. Metabolism is not inhibited by xanthine oxidase inhibitors.
| Active metabolites | 2-amino-6-methylmercaptopurine |
| Inactive metabolites | yes |
Mainly in urine
| Urine | 24-46% within 24 hours (little unchanged) |
| Half-life | 5 - 9 hours |
Emetogenic Potential:
The following adverse effects include those reported for use of thioguanine as a component of combination chemotherapy, so some of these effects may be due to other chemotherapy drugs.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Dermatological | Photosensitivity (rare) | E | |||
| Rash (rare) | E | ||||
| Gastrointestinal | Anorexia (less common) | E | |||
| Colitis (rare) | E D | ||||
| Diarrhea (common) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (common) | E | ||||
| Nausea, vomiting (less common) | I | ||||
| Hematological | Myelosuppression ± infection, bleeding (common, includes pancytopenia; may be severe - nadir 7-14 days, recovery 21 days) | E | |||
| Hepatobiliary | ↑ LFTs (may be severe) | E | |||
| Portal hypertension (may be severe) | E | ||||
| Veno-occlusive disease (may be severe) | E | ||||
| Metabolic / Endocrine | Hyperuricemia (during periods of active cell lysis - common) | I | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The primary toxicity of thioguanine is dose-related myelosuppression.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas) can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
Unlike mercaptopurine, thioguanine's metabolism is not inhibited by the xanthine oxidase inhibitor allopurinol. However, toxicity is markedly increased in patients with inherited deficiencies of TPMT and HGPRT.
Prolonged maintenance use may be associated with veno-occlusive disease or portal hypertension, with thrombocytopenia and abnormal liver function tests and is common in children and males. In some cases, portal hypertension may persist for 5 to 9 years after treatment cessation. Liver toxicity may be reversible. Nodular regenerative hyperplasia and centrilobular hepatic necrosis has been reported rarely.
Photosensitivity may lead to an increased risk of skin cancer. Patients should limit sun exposure, wear protective clothing and use sunscreen with an SPF ≥ 30.
Refer to the local protocol by which the patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.
Thioguanine should not be used in patients with mercaptopurine-resistant disease and is not recommended for maintenance treatment due to the high risk of liver toxicity.
Genotypic or phenotypic tests of TPMT are recommended prior to starting treatment as patients with TPMT deficiency may need significant starting dose reductions.
Calculate doses to nearest 20 mg. Take as a single dose, on an empty stomach.
Induction:
2 mg/kg/day p.o, may increase to 3 mg/kg/day if no response after 4 weeks
Suggested dose adjustments per TPMT geno/phenotype:
| TPMT geno/phenotype | thioguanine dose |
| Homozygous wild type or high activity (2 functional *1 alleles) | No change in starting dose. Adjust doses per protocol for myelosuppression. Allow 2 weeks to reach steady state after each dose adjustment. |
| Heterozygous or intermediate activity (one functional *1 allele, plus one non-functional allele *2, *3A, *3B, *3C or *4) | Reduce starting dose by 30-50% and adjust doses per protocol for myelosuppression. Allow 2-4 weeks to reach steady state after each dose adjustment. Reduce thioguanine dose first vs. other drugs. |
| Homozygous, mutant or low activity (2 non-functional alleles *2, *3A, *3B, *3C or *4) | Reduce starting dose 10-fold and dose 3 times weekly. Adjust dose per protocol for myelosuppression. Allow 4-6 weeks to reach steady state after each dose adjustment. Reduce thioguanine dose first vs. other drugs. |
Hepatic impairment may increase thioguanine exposure; consider reducing the starting dose. Dose should be held with evidence of hepatotoxicity or biliary stasis.
No data are available in renal impairment; consider reducing the starting dose.
There are limited safety data in patients aged 65 and older. Dose selection should be cautious, starting at the lower end of the protocol dosing range, reflecting the increased risk with reduced hepatic, renal or cardiac function, co-morbidities and co-administered drugs.
See specific protocols for doses and dose modifications. Liver toxicity has been observed in children receiving thioguanine as part of maintenance therapy.
- Patients with hypersensitivity to this drug or any of its components
- Patients those disease has demonstrated prior resistance to this drug or mercaptopurine; thioguanine is cross-resistant with mercaptopurine
- Thioguanine is not recommended as maintenance treatment due to the high incidence of liver toxicity and veno-occlusive disease
- Live vaccines
- Patients with inherited deficiencies of thiopurine methyltransferase (TPMT) or hypoxanthine guanine phosphoribosyltransferase (Lesch Nyhan syndrome) are at risk for excessive toxicity, as are patients taking drugs that inhibit TPMT such as sulfasalazine.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
Yes
-
Teratogenicity:
Yes
-
Fetotoxicity:
Yes
Thioguanine should not be used in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
-
Excretion into breast milk:
Likely
Breastfeeding is not recommended.
-
Fertility effects:
Likely
Unlike mercaptopurine, thioguanine’s metabolism is not inhibited by the xanthine oxidase inhibitor allopurinol. It is unclear whether thioguanine dose reduction is required when given in combination with allopurinol.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Busulfan | Hepatotoxicity, esophageal varices, portal hypertension | Unknown | Monitor if given together for long-term therapy |
| TPMT inhibitors (sulfasalazine, mesalazine, olsalazine | ↑ toxicity | ↓ TPMT | Caution with concomitant use |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
TPMT geno/phenotype testing |
Before starting treatment |
CBC |
Baseline and at least weekly |
Liver function tests |
Baseline and at each visit |
Renal function tests |
Baseline and at each visit |
Clinical toxicity assessment for infection, bleeding, GI, skin and liver toxicity |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Lanvis® (thioguanine) product monograph. Concord, Ontario; Triton Pharma Inc.; Sept 21, 2017.
June 2019 Updated emetic risk category.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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