On 4/29/24, FDA alerted healthcare professionals of the rare risk of intrahepatic cholestasis of pregnancy (ICP) associated with the use of thiopurines (azathioprine, 6-mercaptopurine, and 6-thioguanine). Reported cases of ICP occurred among pregnant patients using azathioprine or 6-mercaptopurine primarily to treat inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), or systemic lupus erythematosus (SLE). Thiopurines are not FDA-approved to treat these conditions; however, the American Gastroenterological Association and the American College of Rheumatology have published guidelines indicating that these drugs may be appropriate to continue on an individualized basis for the management of some immunologic conditions during pregnancy. Pregnant patients should stop using thiopurines if they develop ICP. FDA is requiring manufacturers to update labeling to include additional warning information on the risk of ICP associated with thiopurines. For additional information, see [Web] |
Thioguanine, a purine antagonist, is an antimetabolite antineoplastic agent.
Thioguanine is used mainly as a component of various chemotherapeutic regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) in adults and pediatric patients.104, 115, 116 Daunorubicin in conjunction with cytarabine and thioguanine is a common induction regimen that has been used for AML in adults and pediatric patients.104, 115 Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission,110, 115 which generally is defined as less than 5% leukemic blast cells in the bone marrow, normalization of peripheral blood counts (including hemoglobin concentration, hematocrit, granulocyte count, and platelet count), and absence of any evidence of extramedullary disease.110 Optimal postremission therapy has not been established, but current approaches include consolidation chemotherapy with cytarabine-based regimens similar to standard induction regimens, consolidation chemotherapy with high-dose cytarabine-based regimens (for younger adults), high-dose chemotherapy or chemoradiotherapy with autologous bone marrow rescue, or high-dose marrow-ablative therapy with allogeneic bone marrow rescue.115, 116 Although maintenance regimens (with lower doses) previously were administered for prolonged periods (e.g., years) in the treatment of AML, most current treatment regimens in the US no longer employ maintenance therapy since there is no evidence of superior disease-free survival with prolonged maintenance.115 Prolonged therapy with thioguanine is not recommended because of the high risk of hepatotoxicity.103
Although cytarabine and an anthracycline (usually daunorubicin) have been principal components of induction regimens, various regimens have been used in combination therapy and comparative efficacy is continually being evaluated.115 Some clinicians have used thioguanine in addition to intensive therapy with cytarabine and daunorubicin for remission induction;115 complete remissions occurred in 60-85% of patients.
Patients with AML who have complete remission of disease following induction therapy generally receive consolidation chemotherapy.115 The optimal regimen has not been established, but consolidation chemotherapy typically consists of a cytarabine-based regimen similar to that used in induction therapy administered over a short-term period.115 Thioguanine has been used with other antineoplastic agents in regimens of consolidation therapy for AML following induction of a complete remission. Consolidation therapy has ranged in duration from one to 4 or more cycles, but the optimal doses, schedules, and duration of consolidation chemotherapy remain to be established.115
Thioguanine is not effective in the prophylaxis or treatment of meningeal leukemia because therapeutic concentrations of the drug are apparently not attained in the CSF.
Thioguanine is administered orally.
Thioguanine tablets should be stored in a tight container at 15-25°C.
Extemporaneously Compounded Oral Suspension
An oral suspension of thioguanine containing 20 mg/mL has been prepared extemporaneously from the commercially available tablets and a commercially available vehicle.106
Standardized concentrations for an extemporaneously prepared oral suspension of thioguanine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
20 mg/mL |
Dosage of thioguanine must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Testing for thiopurine methytransferase (TPMT) deficiency should be considered prior to initiation of thioguanine therapy; substantial dosage reduction may be required in such patients to avoid severe hematologic toxicity.103
Thioguanine is used as a component of combination chemotherapy for induction and consolidation therapy in acute myeloid leukemia.103, 104, 115 Clinicians should consult currently published protocols for the dosage of thioguanine and other chemotherapeutic agents and the method and sequence of administration.103 The dosage of thioguanine may need to be reduced if the drug is used with other agents whose primary toxicity is myelosuppression.
On occasions when thioguanine monotherapy is appropriate, the usual induction dosage of thioguanine for pediatric patients and adults recommended by the manufacturer is approximately 2 mg/kg daily.103 The total daily dose, calculated to the nearest multiple of 20 mg, may be given at one time. If there is no clinical improvement and no leukocyte or platelet count depression after a period of 4 weeks on the initial dosage recommended by the manufacturer, the dosage may be cautiously increased to 3 mg/kg daily.103
Prolonged therapy with thioguanine is not recommended because of the high risk of hepatotoxicity.103 (See Cautions: Hepatic Effects.)
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Because thioguanine may have a delayed hematologic effect and levels of the formed elements in the peripheral blood may decrease for several days after cessation of treatment, therapy should be discontinued 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 If the leukocyte or platelet count remains at an acceptable level for 2-3 days or increases, thioguanine therapy may be resumed. If the bone marrow status is uncertain, the manufacturer suggests that 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 Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections, and blood product transfusions.
Rapid bone marrow suppression may occur following initiation of thioguanine in patients with inherited deficiency of TPMT.103 Substantial reduction of thioguanine dosage may be required in such patients to avoid the development of life-threatening myelosuppression.103
If any manifestations of hepatotoxicity occur, thioguanine therapy should be discontinued.103 If deterioration of results of liver function tests, jaundice, tender hepatomegaly, or other evidence of toxic hepatitis or biliary stasis occurs, thioguanine should be discontinued until the exact etiology can be determined.103
Dosage in Renal and Hepatic Impairment
Patients with impaired renal or hepatic function should probably receive reduced doses of thioguanine in order to avoid increased accumulation; however, criteria for dosage adjustment have not been clearly defined.
The major adverse effect of thioguanine is hematologic toxicity, which is dose related and manifested by leukopenia, thrombocytopenia, and anemia. The patient's hematologic status must be carefully monitored. (See Cautions: Precautions and Contraindications.) Myelosuppression, which often is initially manifested as leukopenia, usually occurs slowly over 2-4 weeks; however, in some adults with acute leukemia and high leukocyte counts and in some adults with chronic myelogenous leukemia, a fall in the leukocyte count may occur within 1-2 weeks. In many patients with severe depression of the formed elements of the blood caused by thioguanine, the bone marrow appears hypoplastic.
Hepatotoxicity associated with vascular endothelial damage has been reported in a high proportion of pediatric patients, particularly males, who received thioguanine for prolonged periods (e.g., maintenance therapy for acute lymphocytic leukemia).103 Thioguanine-induced hepatotoxicity typically manifests as hepatic veno-occlusive disease, characterized by hyperbilirubinemia, tender hepatomegaly, weight gain caused by fluid retention, and ascites,100, 101, 102, 103 or as signs and symptoms of portal hypertension, such as splenomegaly, thrombocytopenia, and esophageal varices.103 Hepatotoxicity during short-term cyclical therapy with thioguanine typically presents as veno-occlusive disease.103 Early clinical indications of hepatotoxicity include signs associated with portal hypertension, such as thrombocytopenia that is disproportionate to neutropenia and splenomegaly.103 Jaundice and elevated serum concentrations of aminotransferases and alkaline phosphatase also may occur.103 Histologic findings include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.103 Centrilobular hepatic necrosis has been reported in a few patients receiving thioguanine, but a causal relationship has not been established because of confounding factors including use of high doses of thioguanine, concomitant use of other chemotherapeutic agents and oral contraceptives, and chronic alcohol abuse.103 Reversal of the manifestations of hepatotoxicity has occurred in some patients following discontinuance of short-term therapy or long-term continuous therapy with thioguanine.103 (Also see Hepatic Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and see Precautions and Contraindications.)
Jaundice has occurred in some adult and pediatric patients receiving thioguanine for leukemia.103 Elevations of hepatic enzyme concentrations have also occurred in patients receiving combination therapy that included thioguanine.103 Veno-occlusive hepatic disease has been reported in several adult and pediatric patients who were receiving chemotherapy that included thioguanine for acute leukemia; all patients were receiving the drug alone or with other agents when they became symptomatic.100, 101, 102 Esophageal varices and hepatotoxicity have been reported in patients receiving continuous busulfan and thioguanine therapy for chronic myelogenous leukemia.103 (See Drug Interactions.)
Nausea, vomiting, anorexia, stomatitis, and diarrhea may occur in patients receiving thioguanine, particularly with excessive dosage. Nausea and vomiting usually are well tolerated, but stomatitis and severe diarrhea generally necessitate a dosage reduction. Intestinal necrosis and perforation also have occurred in patients receiving chemotherapy that included thioguanine.103
As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia frequently occurs in patients receiving thioguanine and serum uric acid concentrations should be monitored. This effect may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.103 Unlike mercaptopurine and azathioprine, thioguanine therapy may be continued in the usual dosage when allopurinol is administered concurrently.103
Infrequent adverse effects of thioguanine include rash, dermatitis, loss of vibration sensitivity, and an unsteady gait.
Precautions and Contraindications
Thioguanine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by physicians experienced in therapy with cytotoxic agents.
Patients should be informed that the major toxicities of thioguanine are myelosuppression, hepatotoxicity, and GI toxicity.103 Because these complications are potentially fatal, the patient should be instructed to notify their physician if fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia occur.103
Individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) may be unusually sensitive to the myelosuppressive effects of thioguanine and could develop rapid bone marrow suppression.103 Testing for TPMT deficiency is offered by some laboratories and should be considered prior to initiation of thioguanine therapy.103 Because bone marrow suppression may be associated with other factors, testing for TPMT deficiency may not identify all patients at risk for severe hematologic toxicity associated with thioguanine therapy.103
Patients who receive myelosuppressive drugs, such as thioguanine, experience an increased frequency of infections as well as possible hemorrhagic complications. The patient's clinical and hematologic status must be carefully monitored.103 Hemoglobin concentration or hematocrit, leukocyte counts (with differential), and platelet counts should be determined at least once a week during thioguanine therapy; more frequent blood counts may be required in some patients, particularly during remission induction therapy of acute leukemia and when thioguanine is administered with other antineoplastic agents.
Patients receiving thioguanine must be monitored carefully for evidence of hepatotoxicity.103 Serum transaminase, alkaline phosphatase, and bilirubin concentrations should be determined weekly during initiation of therapy and monthly thereafter.103 More frequent testing may be advisable in patients with preexisting liver disease or in those receiving other hepatotoxic drugs.103 Patients should be instructed to discontinue the drug immediately if jaundice occurs.103
Thioguanine should not be used in patients whose disease was resistant to prior therapy with the drug.103
Administration of live vaccines should be avoided in immunocompromised patients.103
Safety and efficacy of thioguanine in geriatric patients have not been studied specifically to date.103 Clinical studies of thioguanine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.103 While other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.103 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.103
Pregnancy, Fertility, and Lactation
Because thioguanine is potentially mutagenic and teratogenic, the drug may cause fetal toxicity when administered to pregnant women.103 Reproduction studies in rats receiving 5 times the human dosage of thioguanine on the fourth and fifth days of gestation revealed that 13% of surviving placentas did not contain fetuses and that 19% of offspring were malformed or stunted.103, 105 Malformations noted in these animals included generalized edema, cranial defects, general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of limbs.103, 105 There are no adequate and controlled studies to date using thioguanine in pregnant women, and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential should be instructed not to become pregnant during thioguanine therapy.103 When thioguanine is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.103
The effects of thioguanine on fertility, in both men and women, are unknown; 2 men reportedly have sired children with congenital abnormalities after discontinuing chemotherapy with multiple agents, including thioguanine.
It is not known whether thioguanine is distributed into milk.103 Because of the carcinogenic potential of thioguanine, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.103
In vitro studies show that aminosalicylate derivatives, such as olsalazine, mesalazine, and sulphasalazine, inhibit the enzyme thiopurine methyltransferase (TPMT).103 Deficiency or inhibition of TMPT can worsen hematologic toxicity associated with thioguanine.103 Concurrent administration of such agents could exacerbate bone marrow suppression in patients receiving thioguanine and caution is advised.103
Hepatotoxicity, esophageal varices, and portal hypertension were reported in some patients receiving long-term therapy of thioguanine and busulfan concomitantly; 107, 109 hepatotoxicity was manifested by elevations of hepatic enzyme concentrations and nodular regenerative hyperplasia of the liver. 107
Hepatic disease also has been reported in patients receiving concomitant administration of thioguanine with other cytotoxic drugs.103
Manifestations of thioguanine overdosage may be immediate (e.g., nausea, vomiting, malaise, hypotension, diaphoresis) or delayed (e.g., myelosuppression, azotemia).103
Toxicity may occur after a single oral dose of as little as thioguanine 2-3 mg/kg.103 A single oral dose of as much as thioguanine 35 mg/kg has been given with reversible myelosuppression.103 For male and female rats, the oral LD50 of thioguanine is about 823 mg/kg and 740 mg/kg, respectively.103
There is no known specific antidote for thioguanine overdosage.103 If unintended toxicity occurs during thioguanine therapy, the drug should be discontinued immediately.103 Supportive treatment for hematologic toxicity may include platelet transfusions for bleeding and granulocyte transfusions and anti-infectives for documented sepsis.103 For acute thioguanine overdosage, induction of emesis may be considered.103 It is not known whether thioguanine may be removed by hemodialysis.103 Because of the rapid intracellular incorporation of thioguanine into active metabolites with long half-lives, hemodialysis is thought to be of marginal benefit.103
Thioguanine is a chemical analog of the physiological purines, guanine and hypoxanthine. Thioguanine, like azathioprine and mercaptopurine, is a purine antagonist antimetabolite
Thioguanine is converted intracellularly to ribonucleotides which have multiple metabolic effects, resulting in a sequential blockade of the synthesis and utilization of purine nucleotides. Thioguanine ribonucleotides are incorporated into DNA and RNA, and the cytotoxic effects of the drug may be related primarily to substitution of the ribonucleotides into DNA. There is usually complete cross-resistance between thioguanine and mercaptopurine. Thioguanine also possesses some immunosuppressive activity.
Absorption of thioguanine from the GI tract is variable and incomplete, averaging approximately 30% of a dose.103 After a single oral dose of thioguanine S 35 in one study, total plasma radioactivity reached a maximum at 8 hours and then declined slowly; unchanged thioguanine represented only a small fraction of the total drug in the plasma.103 Because purine antagonists rapidly enter into anabolic and catabolic pathways of purines, blood concentration measurements actually represent several compounds and the importance of blood concentrations is questionable.103
Thioguanine is incorporated into the DNA and RNA of bone marrow cells. Studies with IV administered radiolabeled thioguanine have shown that incorporation of the drug into DNA is minimal after a single dose, but after 5 daily doses thioguanine replaces 50-100% of guanine in DNA.103 Studies on tissue distribution of thioguanine in animals and the lack of CNS penetration by mercaptopurine suggest that thioguanine does not reach therapeutic concentrations in the CSF.103 The drug apparently crosses the placenta. It is not known if thioguanine or its metabolites are distributed into milk.103
Following IV administration of thioguanine S 35 in a dose of 125 mg/m2 in one study, total plasma radioactivity declined in a biphasic manner with an average half-life of 15 minutes in the initial phase and 11 hours in the terminal phase.
Thioguanine is rapidly and extensively metabolized in the liver and other tissues, largely to the methylated derivative 2-amino-6-methylthiopurine, which has less antitumor activity and toxicity than thioguanine. Inactivation of thioguanine by deamination and subsequent oxidation occurs only to a small extent and is not dependent on the action of xanthine oxidase. Inorganic sulfate is also formed, apparently from metabolism of the methylated derivatives.
Thioguanine is excreted in the urine almost completely as metabolites (e.g., 2-amino-6-methylthiopurine, inorganic sulfate, thiouric acid); only trace quantities of unchanged drug are present in the urine. Because of the rapid intracellular incorporation of thioguanine and formation of active intracellular ribonucleotides with long half-lives, hemodialysis is unlikely to reduce toxicity of the drug.103
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 40 mg | Thioguanine Tabloid® (scored) |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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. [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. [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. [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]
106. Aliabadi HM, Romanick M, Somayaji V et al. Stability of compounded thioguanine oral suspensions. Am J Health Syst Pharm. 2011 May 15;68(10):900-8. doi: 10.2146/ajhp100163. Erratum in: Am J Health Syst Pharm. 2011 Jul 15;68(14):1278. PMID: 21546641.
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. [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. [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.
252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]