Tioguanine

Tioguanine is a sulfhydryl analogue of guanine that behaves as a purine antimetabolite. It has to be activated inside the cell to its nucleotide, thioguanylic acid. Its cytotoxic effect depends on the phase of the cell cycle, with the S phase most affected.

Mechanism of Action

• Activation: the enzyme hypoxanthine-(guanine) phosphoribosyltransferase turns tioguanine into thioguanosine monophosphate (6-TGMP). Kinases then convert this into the active thioguanine nucleotides (6-TGN), the di- and triphosphates.
• Purine synthesis: the metabolites inhibit de novo purine synthesis and the interconversion of purine nucleotides, so the supply of the nucleotides cells need to build DNA and RNA is cut.
• Nucleic acids: tioguanine is also built into DNA and RNA. Its incorporation into DNA is thought to contribute to the cytotoxicity.
• Cross-resistance: there is generally cross-resistance with mercaptopurine, so a tumour resistant to one is not expected to respond to the other.
• Inactivation: thiopurine S-methyltransferase (TPMT) converts tioguanine and 6-TGMP to inactive methylated products. Xanthine oxidase and aldehyde oxidase also turn tioguanine into inactive metabolites.
• Enzyme-deficient disease: because hypoxanthine-guanine phosphoribosyltransferase is needed for activation, patients lacking it, such as those with Lesch-Nyhan syndrome, may be resistant to the drug.

Pharmacokinetics

• Absorption: variable after an oral dose; on average about 30% of the dose is absorbed (range 14–46%). After 100 mg/m² by mouth, peak plasma levels measured by HPLC occur after 2–4 hours (0.03–0.94 micromolar). Concentrations fall if the dose is taken with food and after vomiting. With radiolabelled drug, total blood radioactivity peaks 8–10 hours after an oral dose and then declines slowly.
• Distribution: human data are limited. Tioguanine enters the cerebrospinal fluid after a constant intravenous infusion of 20 mg/m² per hour over 24 hours in children with acute lymphoblastic leukaemia.
• Metabolism: extensive. Four enzymes are involved: hypoxanthine-(guanine) phosphoribosyltransferase (activation), TPMT (inactive methyl metabolites), and xanthine oxidase and aldehyde oxidase (inactive metabolites). Guanine deaminase first converts tioguanine to 6-thioxanthine, which xanthine oxidase turns into 6-thiouric acid.
• Elimination: after intravenous dosing, plasma concentrations fall in two phases, with initial and terminal half-lives of about 3 and 5.9 hours.
• Genetic variability: the NUDT15 R139C variant (p.Arg139Cys) is believed to lead to loss of enzyme function and is strongly associated with thiopurine toxicity such as leucopenia and alopecia. Its frequency is about 9.8% in East Asians, 3.9% in Hispanic Americans, 0.2% in Europeans and 0.0% in Africans. People carrying variants in both NUDT15 and TPMT tolerate thiopurines significantly less well than those with a risk allele in only one of the two genes.

• Leukaemias: treatment of leukaemias, particularly acute myeloblastic leukaemia and acute lymphoblastic leukaemia.

The exact dose and duration depend on the other cytotoxic medicines given with tioguanine. The SmPC does not recommend tioguanine for maintenance treatment or similar continuous long-term treatment (see Administration and Dosage).

• Hypersensitivity to tioguanine or to any of the excipients (lactose monohydrate, potato starch, gum arabic, stearic acid, magnesium stearate).
• The SmPC adds that, in view of the seriousness of the indications, there are no other absolute contraindications.

Bone marrow failure and liver toxicity are the most important reactions. Liver toxicity linked to damage of the vascular endothelium is classed as very common when tioguanine is used for maintenance or similar continuous long-term treatment, which is not recommended.

Very common (≥1/10): bone marrow failure; liver toxicity, including hepatic veno-occlusive disease (hyperbilirubinaemia, hepatomegaly, weight gain from fluid retention, ascites), portal hypertension (splenomegaly, oesophageal varices, thrombocytopenia), raised liver enzymes, alkaline phosphatase and gamma-glutamyltransferase, jaundice, portal fibrosis, nodular regenerative hyperplasia and peliosis hepatis.

Common (≥1/100 to <1/10): stomatitis, gastrointestinal disorder, hepatic veno-occlusive disease during short-term cyclical treatment, hyperuricaemia, hyperuricosuria and urate nephropathy.

Rare (≥1/10,000 to <1/1,000): necrotising colitis; hepatic necrosis, reported in some patients including those taking combination chemotherapy, oral contraceptives, high doses of tioguanine and alcohol.

Also reported rarely (no frequency category in the SmPC): photosensitivity, electrolyte disturbances, ataxia, rash, tinnitus, cardiovascular disorders, deafness and oculogyric crisis.

Signs and symptoms of the liver toxicity have been reported to reverse after treatment is stopped.

• Live vaccines: not recommended in immunosuppressed patients. A patient in remission should not receive a live vaccine until at least 3 months after chemotherapy has finished.
• Other myelotoxic medicines or radiotherapy: the risk of bone marrow suppression rises.
• Allopurinol: used to block uric acid formation, it does not require a tioguanine dose reduction, unlike mercaptopurine and azathioprine.
• Aminosalicylate derivatives (olsalazine, mesalazine, sulfasalazine): they inhibit TPMT in vitro, so give them with caution to patients taking tioguanine. The effect may add to the marrow-suppressing risk in patients with TPMT deficiency.
• Food: tioguanine may be taken with or without food, but food can lower plasma concentrations (as can vomiting).

Tioguanine is a cytotoxic medicine for use only under the direction of physicians experienced in giving such medicines. The tablets are taken by mouth. The exact dose and duration depend on the nature and dose of the other cytotoxic medicines given with it. Absorption varies, and plasma concentrations can fall after vomiting or food.

Recommended Dose

• Adults: the usual regimen is 60–200 mg/m² of body surface area per day.
• Children: doses similar to those in adults have been used, with correction for body surface area.
• Stage of treatment: it can be used at any stage before maintenance treatment, in short cycles such as induction, consolidation and intensification. It is not recommended for maintenance or similar continuous long-term treatment, because of the high risk of liver toxicity.

Special Populations

• Elderly: no specific dosing recommendation. It has been used in combination regimens in elderly patients with acute leukaemia at doses equal to those in younger patients; see the advice on renal and hepatic impairment.
• Renal or hepatic impairment: consider reducing the dose.
• TPMT deficiency: patients with little or no inherited TPMT activity are at higher risk of severe toxicity at standard doses and generally need a substantial dose reduction; the best starting dose for homozygous deficiency has not been established. Most patients with heterozygous deficiency tolerate the recommended doses, but some need a lower dose. Genotype and phenotype tests are available.
• NUDT15 variant: patients with an inherited NUDT15 variant are at higher risk of severe thiopurine toxicity, such as early leucopenia and alopecia, at standard doses and generally need a substantial dose reduction. People of Asian ethnic origin are particularly at risk. The best starting dose for heterozygous or homozygous deficient patients has not been established. Genotype and phenotype testing of NUDT15 should be considered before starting thiopurine treatment in all patients, including children.

Missed or Vomited Dose

The SmPC gives no rule for a missed or vomited dose; the treating physician decides. It notes that plasma concentrations can fall after vomiting.

Supervision

Tioguanine is an active cytotoxic medicine for use only under the direction of physicians experienced in giving such medicines.

Liver Toxicity

• Tioguanine is not recommended for maintenance or similar continuous long-term treatment because of the high risk of liver toxicity linked to vascular endothelial damage. This toxicity was seen in a large share of children given tioguanine as maintenance for acute lymphoblastic leukaemia, and in other conditions with continuous use. It is particularly frequent in males.
• It usually appears as hepatic veno-occlusive disease (hyperbilirubinaemia, tender hepatomegaly, weight gain from fluid retention, ascites) or as signs of portal hypertension (splenomegaly, thrombocytopenia, oesophageal varices). Liver biopsy findings include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatis and periportal fibrosis.
• Treatment must be stopped in patients with evidence of liver toxicity; reversal has been reported after withdrawal.
• Patients need careful monitoring, including blood counts and weekly liver function tests. The first signs are those of portal hypertension, such as thrombocytopenia out of proportion to neutropenia, and splenomegaly. Liver enzymes may rise but do not always do so.

Bone Marrow Suppression and Infections

• Tioguanine causes bone marrow depression, leading to leucopenia and thrombocytopenia; anaemia is reported less often. The suppression is readily reversible if the drug is stopped early enough.
• It is a very strong myelosuppressant, so full blood counts are needed often during remission induction and patients must be closely supervised. White cell and platelet counts keep falling after treatment is stopped, so at the first sign of an unusually large fall, treatment should be interrupted. During remission induction in acute myeloid leukaemia the patient may have to pass through a period of relative marrow aplasia, so adequate supportive facilities are needed.
• Patients given tioguanine with other immunosuppressive or chemotherapeutic medicines are more susceptible to viral, fungal and bacterial infections, including serious or atypical ones. If infection occurs, appropriate measures, which may include antiviral treatment and supportive care, are needed.

TPMT and NUDT15

Inherited TPMT deficiency can make patients unusually sensitive to the marrow-suppressing effect and prone to rapid depression of the marrow after starting. Tests for TPMT deficiency do not identify every patient at risk, so close monitoring of blood counts is still necessary. Medicines that inhibit TPMT (olsalazine, mesalazine, sulfasalazine) can worsen this. NUDT15 variants carry a further risk of severe toxicity; testing before treatment should be considered.

Uric Acid

During remission induction, particularly when cells break down quickly, take precautions against hyperuricaemia, hyperuricosuria and uric acid nephropathy.

Sunlight

Patients on tioguanine are more sensitive to sun. Exposure to sunlight and ultraviolet light should be limited, and patients should be advised to wear protective clothing and a high-factor sunscreen.

Live Vaccines

Immunisation with a live vaccine can cause infection in immunosuppressed hosts, so live vaccines are not recommended.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: like other cytotoxic agents, tioguanine is potentially teratogenic. It should be avoided during pregnancy, particularly in the first trimester; in each case the possible risk to the foetus must be weighed against the expected benefit to the mother.
• Contraception: adequate contraceptive precautions are needed when either partner is taking tioguanine.
• Breastfeeding: there are no reports on whether tioguanine or its metabolites pass into breast milk; mothers receiving it are advised not to breastfeed.
• Fertility: in isolated cases men given combinations of cytotoxic medicines that included tioguanine fathered children with congenital abnormalities.

Lactose

Each tablet contains 150 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it, and patients with lactose intolerance should be told that it contains a small amount of lactose.

Effect on Driving

There are no data on the effect of tioguanine on driving or using machines. A harmful effect cannot be predicted from its pharmacology.

Do not store above 25 °C. Keep the tablets in the original bottle and carton to protect them from light, and keep the bottle tightly closed to protect them from moisture. Tablets are supplied in amber glass bottles with a child-resistant polypropylene/HDPE closure, 25 tablets per bottle.

5 years.

Prescription only (Rx), for use under the direction of physicians experienced in giving cytotoxic medicines. Tioguanine tablets are taken by the patient as part of a cytotoxic regimen, so they are supplied to the patient or to the treating clinic on prescription. The marketing authorisation holder named in the Spanish SmPC of Lanvis 40 mg tablets is Aspen Pharma Trading Limited.