Thioguanine Tabloid

Generic Name: Thioguanine
Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 154-42-7

Introduction

Antineoplastic agent; antimetabolite, synthetic purine antagonist.103 b

Uses for Thioguanine Tabloid

Acute Myeloid Leukemia (AML)

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

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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 Tabloid 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 Tabloid

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

Interactions for Thioguanine Tabloid

Specific Drugs

Drug

Interaction

Comments

Allopurinol

Pharmacokinetic interactions not expected103

Dosage adjustments not required103

Aminosalicylates (e.g., olsalazine, mesalamine, sulfasalazine)

Potential pharmacokinetic interaction; increased risk of thioguanine myelotoxicity103 (see Hematologic Effects under Cautions)

Use concomitantly with caution103

Myelosuppressive agents

Possible additive myelosuppressive effects103

Reduced thioguanine dosage may be necessary with concomitant therapy103

Thioguanine Tabloid 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.

Thioguanine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

40 mg

Thioguanine Tabloid (scored)

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tabloid 40MG Tablets (GLAXO SMITH KLINE): 25/$247.98 or 50/$489.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Ann Intern Med. 1976; 85:578-82. [IDIS 65468] [PubMed 1068643]

101. Gill RA, Onstad GR, Cardamone JM et al. Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med. 1982; 96:58-60. [IDIS 142618] [PubMed 7053705]

102. Krivoy N, Raz R, Carter A et al. Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med. 1982; 96:788. [IDIS 152653] [PubMed 7091946]

103. GlaxoSmithKline. Tabloid brand thioguanine 40-mg scored tablets prescribing information. Research Triangle Park, NC; 2004 Dec.

104. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Aug 22.

105. Thiersch JB. Effect of 2-6 diaminopurine (2-6 DP): 6 chlorpurine (CIP) and thioguanine (ThG) on rat litter in utero. Proc Soc Exp Biol Med. 1957; 94:40-3. [PubMed 13400865]

107. Key NS, Kelly PMA, Emerson PM et al. Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia. Lancet. 1987; 2:1050-2. [IDIS 235711] [PubMed 2889964]

109. Shepherd PC, Fooks J, Gray R et al. Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non-cirrhotic portal hypertension. Br J Haematol. 1991; 79:185-92. [PubMed 1958475]

110. McCauley DL. Treatment of adult acute leukemia. Clin Pharm. 1992; 11:767-96. [IDIS 300402] [PubMed 1521402]

111. Arlin Z, Case DC Jr, Moore J et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990; 4:177-83. [PubMed 2179638]

112. Feldman EJ. Acute myelogenous leukemia in the older patient. Semin Oncol. 1995; 22(Suppl 1):21-4. [PubMed 7532322]

113. Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin plus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia. Ann Hematol. 1994; 69:11-5. [PubMed 8061102]

114. Wahlin A, Hornsten P, Hedenus M et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol. 1991; 28:480-3. [PubMed 1934252]

115. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Jul 17.

116. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

b. AHFS drug information 2008. McEvoy GK, ed. Thioguanine. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2008:1232-3.

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