Thioguanine (Monograph)

Brand name: Thioguanine Tabloid
Drug class: Antineoplastic Agents
VA class: AN300
CAS number: 154-42-7

Medically reviewed by Drugs.com on Feb 20, 2024. Written by ASHP.

Introduction

Antineoplastic agent; antimetabolite, synthetic purine antagonist.^{103 b}

Uses for Thioguanine

Acute Myeloid Leukemia (AML)

Remission induction (in combination with other antineoplastic agents) in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).^{103 104 115 116}

Has been used with other antineoplastic agents in regimens of consolidation therapy for AML following induction of a complete remission; optimal regimen of such therapy in prolonging remissions remains to be established but is typically administered short-term.^{115 b}

Not recommended for maintenance or long-term continuous therapy.¹⁰³ (See Hepatic Effects under Cautions.)

Thioguanine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.^{103 b}

• Individualize dosage according to clinical and hematologic response and tolerance of the patient.¹⁰³

Administration

Oral Administration

Calculate total daily dose to the nearest multiple of 20 mg and administer orally once daily.^b

Dosage

Consult currently published protocols for dosages used in combination regimens and method and sequence of administration.¹⁰³

Dosage reduction may be necessary if used concomitantly with other myelosuppressive agents.¹⁰³ (See Specific Drugs under Interactions.)

When initiating thioguanine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) activity are at increased risk of life-threatening myelotoxicity; substantial dosage reduction may be required.¹⁰³ (See Hematologic Effects under Cautions.)

Pediatric Patients

Acute Myeloid Leukemia

Induction and Consolidation Therapy

Oral

If monotherapy is appropriate, initially, approximately 2 mg/kg daily.¹⁰³ If there is no clinical improvement and no leukocyte or platelet count depression after 4 weeks on initial dosage, dosage may be cautiously increased to 3 mg/kg daily.¹⁰³

Thioguanine should not be part of maintenance therapy.¹⁰³ (See Hepatic Effects under Cautions.)

Adults

Acute Myeloid Leukemia

Induction and Consolidation Therapy

Oral

If monotherapy is appropriate, initially, approximately 2 mg/kg daily.¹⁰³ If there is no clinical improvement and no leukocyte or platelet count depression after 4 weeks on initial dosage, dosage may be cautiously increased to 3 mg/kg daily.¹⁰³

Thioguanine should not be part of maintenance therapy.¹⁰³ (See Hepatic Effects under Cautions.)

Special Populations

Hepatic Impairment

Consider dosage reduction; however, no specific dosage recommendations at this time.¹⁰³ (See Hepatic Effects under Cautions.)

Renal Impairment

Consider dosage reduction; however, no specific dosage recommendations at this time.¹⁰³

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹⁰³

Cautions for Thioguanine

Contraindications

• If a diagnosis of AML has not been adequately established and there is no responsible clinician knowledgeable in assessing response to chemotherapy.¹⁰³

• Patients whose disease was resistant to prior therapy with the drug.¹⁰³ Consider that there is complete cross-resistance between thioguanine and mercaptopurine.¹⁰³

Warnings/Precautions

Warnings

Toxicity

Highly toxic; low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.^b Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.^{103 b}

Hepatic Effects

Risk of hepatotoxicity associated with vascular endothelial damage; usually manifested as hepatic veno-occlusive disease (e.g., hyperbilirubinemia, hepatomegaly, ascites) or portal hypertension (e.g., splenomegaly, thrombocytopenia out of proportion with neutropenia, esophageal varices).¹⁰³

Possible jaundice and increases in serum aminotransferases (AST, ALT), alkaline phosphatase, and γ glutamyl transferase concentrations.¹⁰³ Hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis reported.¹⁰³

Discontinue immediately if evidence of hepatotoxicity (e.g., jaundice) occurs; signs and symptoms generally reversible after discontinuance of the drug.¹⁰³

Hepatic function must be carefully monitored.¹⁰³ Serum transaminase, alkaline phosphatase, and bilirubin concentrations should be determined weekly during initiation of therapy and monthly thereafter.¹⁰³ More frequent testing in patients with preexisting liver disease and in those receiving other hepatotoxic drugs.¹⁰³

Hematologic Effects

Risk of myelosuppression (manifested as anemia, leukopenia, and/or thrombocytopenia); usually dose related.¹⁰³ Hematologic status must be carefully monitored.¹⁰³

Discontinue temporarily at the first sign of an abnormally large or rapid decrease in leukocytes, platelets, or hemoglobin concentration or abnormal depression of bone marrow, unless induction of bone marrow hypoplasia is desired.^{103 b} Bone marrow examination (aspiration and/or biopsy) may be helpful in distinguishing between progression of leukemia, resistance to therapy, and marrow hypoplasia induced by therapy.^{103 b}

Perform CBC, including platelet count and leukocyte differential, at least once weekly during therapy; more frequent blood counts may be required, particularly during remission induction therapy and with concomitant therapy with other antineoplastic agents.^{103 b}

When initiating thioguanine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) activity are at increased risk for life-threatening myelotoxicity; substantial dosage reduction may be required.¹⁰³ Concomitant use with drugs that inhibit TPMT (e.g., olsalazine, mesalamine, sulfasalazine) may exacerbate such toxicity.¹⁰³ Consider testing for TPMT deficiency prior to initiating therapy.¹⁰³

Infectious Complications and Hemorrhagic Complications

Life-threatening infections due to granulocytopenia may occur.¹⁰³ Anti-infectives or granulocyte transfusions may be needed.¹⁰³

Bleeding due to thrombocytopenia may occur.¹⁰³ Platelet transfusions may be needed.¹⁰³

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.¹⁰³

Avoid pregnancy during therapy.¹⁰³ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹⁰³

Major Toxicities

GI Effects

Possible nausea, vomiting, anorexia, and stomatitis.¹⁰³

General Precautions

Hyperuricemia

Hyperuricemia occurs frequently because of extensive purine catabolism accompanying rapid cellular destruction.¹⁰³ Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of urine, and/or administration of allopurinol.¹⁰³

Immunization

Effects of thioguanine on immunocompetence are unknown.¹⁰³ Avoid live virus vaccines in immunocompromised patients.¹⁰³

Specific Populations

Pregnancy

Category D.¹⁰³ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether thioguanine is distributed into milk.¹⁰³ Discontinue nursing or the drug.¹⁰³

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.¹⁰³

Common Adverse Effects

Myelosuppression, hyperuricemia, hepatotoxicity.¹⁰³

Drug Interactions

Specific Drugs

Thioguanine Pharmacokinetics

Absorption

Bioavailability

Absorption from GI tract is variable and incomplete; approximately 30% of an oral dose may be absorbed.¹⁰³

Distribution

Extent

Incorporated into the DNA and RNA of bone marrow cells.¹⁰³

Does not reach therapeutic concentrations in the CSF.¹⁰³

Thioguanine crosses the placenta; not known whether distributed into milk.¹⁰³

Elimination

Metabolism

Rapidly and extensively metabolized in the liver and other tissues, principally to the less toxic and less active methylated derivative 2-amino-6-methylthiopurine.¹⁰³

Elimination Route

Excreted principally in urine as metabolites.^{103 b}

Half-life

Biphasic; terminal half-life averages 11 hours.^b

Stability

Storage

Oral

Tablets

15–25°C.¹⁰³

Actions

• Converted intracellularly to ribonucleotides that result in a sequential blockade of the synthesis and utilization of purine and guanine nucleotides.^{103 b}

• Thioguanine ribonucleotides incorporate into DNA and RNA; cytotoxic effects may be related primarily to substitution of ribonucleotides into DNA.^{103 b}

• Usually complete cross-resistance between thioguanine and mercaptopurine.^{103 b}

Advice to Patients

• Advise patients that the major toxicities of the drug are related to myelosuppression, hepatotoxicity, and GI toxicity.¹⁰³

• Importance of taking the drug only under medical supervision.¹⁰³

• Importance of patients informing their clinicians if fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia occur.¹⁰³

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.¹⁰³

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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