Medication Guide App

Thioguanine (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Lanvis; Tabloid.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Accepted

Leukemia, acute nonlymphocytic (treatment)—Thioguanine is indicated for remission induction, remission consolidation, and maintenance therapy of acute nonlymphocytic leukemias {01} {02}.

Note: The response to thioguanine depends upon the age of the patient and whether thioguanine is being used in previously treated or previously untreated patients {01}. Reliance on thioguanine alone is seldom justified for initial remission induction therapy of acute nonlymphocytic leukemias because combination chemotherapy including thioguanine results in more frequent remission induction and longer duration of remission than is achieved with thioguanine alone {01}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    167.2 {02}

Mechanism of action/Effect:

Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP) {01}. This nucleotide reaches high intracellular concentrations at therapeutic doses {01}. TGMP interferes at several points with the synthesis of guanine nucleotides {01}. It inhibits de novo purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis {01}. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase {01}. At one time, TGMP was thought to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have not shown this {01}.

Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides {01}. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of thioguanine {01}.

Thus, thioguanine has multiple metabolic effects and, at present, it is not possible to designate one major site of action {01}. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA {01}. The net consequence of its action is a sequential blockade of the synthesis and utilization of the purine nucleotides {01}.

Absorption:

Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is incomplete and variable, averaging approximately 30% (range 14 to 46%) of the administered dose {01}.

Distribution:

Studies with intravenous S-6–thioguanine in humans have shown that the amount of thioguanine incorporated into nucleic acids is more than 100 times higher after five daily doses than after a single dose {01}. With the five-dose schedule, from one half to virtually all of the guanine in the residual DNA was replaced by thioguanine {01}. In mice, tissue distribution studies of S-6–thioguanine showed only traces of radioactivity in brain after its oral administration {01}.

Biotransformation:

Hepatic (activation and catabolism).

Half-life:

Average, 80 minutes (range, 25 to 240 minutes).

Peak serum concentration:

No measurements have been made of thioguanine concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in animals, together with the lack of central nervous system (CNS) penetration by the closely related compound, mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF {01}.

Elimination:
    Renal, almost totally as metabolites.


Precautions to Consider

Cross-sensitivity and/or related problems

Clinical studies in humans and studies in animals have shown that there is complete cross-resistance between thioguanine and mercaptopurine {01}. Patients who no longer respond to mercaptopurine will not respond to thioguanine, or vice versa {02}.

Carcinogenicity/Mutagenicity

In view of its action on cellular DNA, thioguanine is potentially carcinogenic and mutagenic, and consideration should be given to the theoretical risk of carcinogenesis when thioguanine is administered {01}.

Pregnancy/Reproduction

Pregnancy—
Thioguanine is a potential mutagen and teratogen {01}. Adequate and well-controlled studies have not been done in humans {01}. However, thioguanine may cause fetal harm when administered to a pregnant woman {01}. Therefore, women of childbearing potential undergoing treatment with this agent should be advised to avoid becoming pregnant {01}.

Thioguanine has been shown to be teratogenic in rats when given in doses five times the human dose {01}. In rats given thioguanine on the fourth and fifth days of gestation, 13% of surviving placentas did not contain fetuses, and 19% of the offspring were malformed or stunted {01}. The malformations noted included generalized edema, cranial defects, general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

It is not known whether thioguanine is distributed into breast milk. However, because of the potential for tumorigenicity shown by thioguanine, a decision should be made whether to discontinue nursing or to discontinue treatment with thioguanine, taking into account the importance of thioguanine treatment to the mother {01}.

Pediatrics

Clinical studies in pediatric patients have demonstrated that children with previously untreated acute nonlymphocytic leukemia obtained complete remission with a multiple-drug protocol including thioguanine {01}.


Geriatrics


Clinical studies have demonstrated that the response to thioguanine therapy depends upon the age of the patient {01}. Younger patients usually respond better than elderly patients {01}.


Dental

The bone marrow depressant effects of thioguanine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Thioguanine may also rarely cause stomatitis associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (thioguanine may raise the blood concentration of uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse thioguanine-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of thioguanine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of thioguanine, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by thioguanine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by thioguanine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the thioguanine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Uric acid concentrations in blood and urine    (may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia)


» Hepatic function impairment    (reduced biotransformation; lower dosage is recommended)


» Infection
» Renal function impairment    (reduced elimination; lower dosage is recommended)


Sensitivity to thioguanine{03}
» Caution should be used also in patients who have had cytotoxic drug therapy or radiation therapy within 4 to 6 weeks.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Bilirubin concentrations, serum and
Uric acid concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, and dose, and other agents being used concurrently)


Blood urea nitrogen (BUN) concentrations and
Serum creatinine concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Hematocrit or hemoglobin and
» Platelet count and
» Total and, if appropriate, differential leukocyte count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently. In patients with high total leukocyte counts, a rapid fall in leukocyte count may occur with thioguanine therapy; daily blood counts are recommended in these patients)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Immunosuppression, leukopenia, or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools)—usually asymptomatic

Note: Bone marrow depression usually occurs over 2 to 4 weeks, although a rapid fall in leukocyte count may occur within 1 to 2 weeks.


Incidence less frequent
    
Hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)
    
unsteadiness when walking

Note: Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown, which leads to elevated serum uric acid concentrations.


Incidence rare
    
Gastrointestinal ulceration (black, tarry stools)
    
hepatotoxicity, hepatic fibrosis, or toxic hepatitis (yellow eyes or skin)
    
stomatitis, dose-related (sores in mouth and on lips)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Diarrhea
    
loss of appetite
    
nausea and vomiting
    
skin rash or itching

Note: Loss of appetite or nausea and vomiting occur especially with overdosage.




Those indicating the need for medical attention if they occur after medication is discontinued
    
Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Thioguanine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
  Conditions affecting use, especially:
Sensitivity to thioguanine

Pregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially live virus vaccines, other bone marrow depressants, previous cytotoxic drug therapy or radiation therapy, probenecid, or sulfinpyrazone
Other medical problems, especially bone marrow depression, chickenpox, hepatic function impairment, herpes zoster, infection, renal function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Caution in taking combination chemotherapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

» Possible nausea and vomiting; importance of continuing medication despite stomach upset

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Missed dose: Not taking at all; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problem and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially immunosuppression, leukopenia, infection, thrombocytopenia, hyperuricemia, uric acid nephropathy, unsteadiness when walking, gastrointestinal ulceration, hepatotoxicity, hepatic fibrosis, toxic hepatitis and stomatitis

Physician or nurse can help in dealing with side effects


General Dosing Information
Patients receiving thioguanine should be under supervision of a physician experienced in antimetabolite chemotherapy.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and appearance or severity of toxicity.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated.

Unlike mercaptopurine and azathioprine, thioguanine may be continued in the usual dosage when the patient is receiving allopurinol concurrently to inhibit uric acid formation, because xanthine oxidase is not involved in metabolism of thioguanine.

Patients who have failed to respond to mercaptopurine are unlikely to respond to thioguanine.

Because the actions of thioguanine may be delayed, it is recommended that thioguanine therapy be discontinued promptly at the first sign of leukopenia (particularly granulocytopenia), thrombocytopenia, jaundice, or hemorrhage or bleeding tendencies. Therapy may be resumed at a lower dosage when laboratory values return to satisfactory levels.

In acute nonlymphocytic leukemia, thioguanine may sometimes be administered despite the presence of thrombocytopenia and bleeding; stoppage of bleeding and increase in platelet count have occurred during treatment in some cases and platelet transfusions may be useful in others.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of thioguanine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.


Combination chemotherapy
Thioguanine may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, thioguanine is part of the following chemotherapeutic combination (a commonly used acronym is in parentheses):    —cytarabine and thioguanine (Ara-C + 6-TG).
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.


Oral Dosage Forms

THIOGUANINE TABLETS USP

Usual adult and adolescent dose
Leukemia, acute nonlymphocytic
Induction: Oral, 2 mg per kg of body weight or 75 to 100 mg per square meter of body surface (to the closest 20 mg) a day in a single dose. If there is no clinical improvement and no leukocyte depression after four weeks at this dosage, a cautious increase in dosage to 3 mg per kg of body weight a day may be attempted.

Maintenance: Oral, 2 to 3 mg per kg of body weight or 100 mg per square meter of body surface a day.


Usual pediatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


40 mg (Rx) [Tabloid]

Canada—


40 mg (Rx) [Lanvis]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Store in a tight container.



Revised: 09/26/1997



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Tabloid package insert (GlaxoWellcome—US), Rev 11/96, Rec 3/97.
  1. Lanvis package insert (GlaxoWellcome—Canada), Rev 11/96, Rec 3/97.
  1. General concept per Geriatrics Advisory Panel (1985-1990), 1990 revision.
  1. General precaution per DID policy, 1990 revision.
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