Mercaptopurine

Mercaptopurine is a purine analogue that acts as a purine antagonist. It is an inactive pro-drug: cells must take it up and convert it, step by step, into thioguanine nucleotides before it becomes cytotoxic. It resembles the natural purine bases adenine and hypoxanthine, and cross-resistance usually exists between mercaptopurine and tioguanine.

Mechanism of Action

• Activation: inside the cell, hypoxanthine-guanine phosphoribosyl transferase converts mercaptopurine into thioinosine monophosphate (TIMP). Later steps, catalysed by inosine monophosphate dehydrogenase and guanine monophosphate synthetase, lead to the thioguanine nucleotides (TGNs).
• Blocking purine synthesis: the metabolites inhibit de novo purine synthesis and the interconversion of purine nucleotides. TIMP and its methylated form both inhibit phosphoribosyl pyrophosphate amidotransferase, an enzyme that is important in de novo purine synthesis.
• Incorporation into nucleic acids: thioguanine nucleotides are built into nucleic acids, which adds to the cytotoxic effect. In experiments with radiolabelled drug, mercaptopurine was recovered from DNA as deoxythioguanosine.
• Cause of cell death: it is not known exactly which of the biochemical effects of mercaptopurine and its metabolites is mainly responsible for killing the cell.
• Inactivation: S-methylation by thiopurine S-methyltransferase (TPMT) gives inactive methylmercaptopurine, and xanthine oxidase converts mercaptopurine to inactive 6-thiouric acid. This is why TPMT activity and xanthine oxidase inhibitors matter for dosing.

Pharmacokinetics

• Absorption: oral bioavailability varies widely between individuals, probably because of first-pass metabolism; in 7 paediatric patients given 75 mg/m² it averaged 16% (range 5–37%). In 60 healthy adults, 50 mg of the oral suspension matched the 50 mg tablet for AUC but not for peak concentration: the mean Cmax with the suspension was 39% higher (90% CI 22–58%), with less variation between subjects. Food may lower exposure slightly, which is unlikely to be clinically significant.
• Distribution: the volume of distribution exceeds total body water, and plasma protein binding is low (about 19% in the concentration range studied). Little mercaptopurine enters the cerebrospinal fluid.
• Metabolism: hepatic. Xanthine oxidase is the main catabolic enzyme and produces inactive 6-thiouric acid, which is excreted in the urine; S-methylation by TPMT is a second route.
• Elimination: half-life of the parent drug 90 ± 30 minutes; the active metabolites last longer (about 5 hours). Apparent body clearance is 4,832 ± 2,562 mL/min/m². Metabolism is the main route of elimination, and about 7% of an oral dose is excreted unchanged within 12 hours.
• Special populations: pharmacokinetics have not been formally studied in renal or hepatic impairment (see Administration and Dosage). Inherited TPMT and NUDT15 variants change sensitivity to the drug (see Special Instructions).

• Oral suspension (Xaluprine, centrally authorised): treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children.
• 50 mg tablets (nationally authorised; Spanish SmPC of Mercaptopurina Aspen): treatment of acute leukaemia in adults, adolescents and children. The SmPC states that it can be used in acute lymphoblastic leukaemia and in acute myeloid leukaemia M3 (acute promyelocytic leukaemia).

The two SmPCs word the indication differently, so the SmPC of the product in use applies.

• Hypersensitivity to mercaptopurine or to any of the excipients.
• Concomitant use with yellow fever vaccine.

The main adverse reaction is bone marrow suppression leading to leucopenia and thrombocytopenia. Both SmPCs note that modern clinical documentation is lacking, so the frequency categories are estimates and can vary with the dose and with other medicines given together. The groups below follow the Xaluprine SmPC.

Very common (≥1/10): bone marrow suppression, leucopenia, thrombocytopenia.

Common (≥1/100 to <1/10): anaemia, anorexia, diarrhoea, vomiting, nausea, biliary stasis, hepatotoxicity; pancreatitis in patients treated for inflammatory bowel disease (an unlicensed use).

Uncommon (≥1/1,000 to <1/100): bacterial and viral infections, infections associated with neutropenia, arthralgia, skin rash, drug fever, oral ulceration, hepatic necrosis.

Rare (≥1/10,000 to <1/1,000): lymphoproliferative disorders and other neoplasms (melanoma and non-melanoma skin cancers, Kaposi’s and non-Kaposi’s sarcomas, uterine cervical cancer in situ), facial oedema, pancreatitis, alopecia, transient oligospermia.

Very rare (<1/10,000): secondary leukaemia and myelodysplasia, intestinal ulceration.

Not known: hepatosplenic T-cell lymphoma (reported in patients with inflammatory bowel disease), hypoglycaemia (in children), pellagra, stomatitis, cheilitis, portal hypertension, nodular regenerative hyperplasia and sinusoidal obstruction syndrome (reported in inflammatory bowel disease), photosensitivity reaction, erythema nodosum, mucosal inflammation, decreased coagulation factors.

Bone marrow suppression can be severe, and blood counts keep falling after treatment stops. Hepatotoxicity is usually reversible if treatment is stopped soon enough, but fatal liver damage has occurred. The SmPC also describes severe or atypical infections and secondary malignancies.

• Yellow fever vaccine: contraindicated, because of the risk of fatal disease in immunocompromised patients. Other live vaccines are not recommended in immunocompromised people.
• Allopurinol, oxipurinol, thiopurinol and other xanthine oxidase inhibitors: they slow the breakdown of mercaptopurine. With allopurinol only a quarter of the usual mercaptopurine dose is given; other xanthine oxidase inhibitors should be avoided.
• TPMT inhibitors (olsalazine, mesalazine, sulfasalazine): can worsen the myelosuppression in patients with TPMT deficiency.
• Other myelosuppressive medicines: the mercaptopurine dose may need to be reduced.
• Warfarin and other oral anticoagulants: inhibition of the anticoagulant effect of warfarin has been reported; the INR should be monitored more closely.
• Antiepileptics: cytotoxic agents may reduce the intestinal absorption of phenytoin, and levels of other antiepileptics may change too. Serum levels should be monitored closely and doses adjusted as necessary.
• Milk and dairy products: they contain xanthine oxidase, which metabolises mercaptopurine and might lower its plasma levels. The suspension should be taken at least 1 hour before or 2 hours after milk or dairy products.
• Food: it may slightly lower exposure, which is unlikely to matter clinically; the medicine may be taken with food or on an empty stomach, but the method should be kept the same from day to day.
• Section 4.5 of the SmPC lists further interactions; consult it before combining mercaptopurine with other medicines.

Treatment should be supervised by a physician (for Xaluprine, or other healthcare professionals) experienced in managing patients with ALL; the tablet SmPC adds acute promyelocytic leukaemia. The dose is governed by carefully monitored haematotoxicity and adjusted to the individual patient according to the treatment protocol.

Oral Suspension (Xaluprine 20 mg/mL)

• Dose: depending on the phase of treatment, starting or target doses generally vary between 25 and 75 mg/m² of body surface area (BSA) per day, but should be lower in patients with reduced or absent TPMT or NUDT15 enzyme activity. The SmPC has tables that convert BSA into the dose in mg and the volume in mL for the 25, 50 and 75 mg/m² levels.
• Giving the dose: shake the bottle vigorously for at least 30 seconds before dosing. A 1 mL and a 5 mL oral syringe are supplied, and the healthcare professional tells the patient or carer which one to use. Water should be taken after each dose.
• Time of day: mercaptopurine shows diurnal variation in pharmacokinetics and efficacy, and evening dosing compared with morning dosing may lower the risk of relapse, so the daily dose is taken in the evening.
• Food and dairy: the dose may be taken with food or on an empty stomach, but the method should be standardised. It should be taken at least 1 hour before or 2 hours after milk or dairy products.

Tablets (50 mg, Mercaptopurina Aspen)

• Dose: for adults and children the usual initial dose is 2.5 mg/kg of body weight per day or 50–75 mg/m² of BSA per day. The dose and duration depend on the nature and dosage of the other cytotoxic medicines given with it, and current treatment recommendations for combination regimens should be consulted. Starting or target doses should be lower in patients with absent or reduced TPMT activity.
• Food and dairy: the tablets may be taken with food or on an empty stomach, but the method should be standardised, and doses should not be taken with milk or other dairy products.

Dose Adjustments and Monitoring

• TPMT deficiency: patients with little or no inherited TPMT activity are at increased risk of severe toxicity from conventional doses and generally need a substantial dose reduction. TPMT genotyping or phenotyping can identify them, but testing cannot replace blood-count monitoring. The best starting dose for homozygous deficient patients has not been established.
• NUDT15 variants: patients with an inherited NUDT15 variant are at increased risk of severe toxicity and generally need a lower dose, particularly homozygotes. Genotype testing for NUDT15 variants may be considered before starting; close monitoring of blood counts is needed in any case.
• Allopurinol: only a quarter of the usual dose is given.
• Other myelosuppressive medicines: a lower mercaptopurine dose may be needed.
• Switching between tablets and suspension: the two forms are not bioequivalent for peak concentration, so blood counts should be monitored more intensively when changing form.

Special Populations

• Elderly: no specific studies. Renal and hepatic function should be monitored, and a lower dose considered if either is impaired.
• Renal impairment: not formally studied, so no specific dose recommendation. Reduced starting doses should be considered, with close monitoring for dose-related adverse reactions.
• Hepatic impairment: not formally studied, so no specific dose recommendation. Reduced starting doses should be considered, with close monitoring for dose-related adverse reactions.
• Children and adolescents: both products are indicated from childhood; doses are calculated per square metre of BSA (tablets also per kilogram) as above.

Bone Marrow Suppression and Blood Monitoring

Mercaptopurine causes bone marrow suppression, leading to leucopenia and thrombocytopenia and, less often, anaemia. Blood counts must be monitored carefully throughout. Leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall the treatment should be interrupted immediately. Suppression is reversible if mercaptopurine is withdrawn early enough. The tablet SmPC adds that, because mercaptopurine is a potent myelosuppressant, full blood counts should be done daily during remission induction.

TPMT and NUDT15 Variants

• TPMT: patients with an inherited TPMT variant causing deficiency or absence of the enzyme are very sensitive to the myelosuppressive effect and prone to rapid bone marrow depression after starting. The problem may be worse with TPMT-inhibiting medicines. Tests do not identify every patient at risk of severe toxicity, so close blood-count monitoring is needed. A possible link between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported with other cytotoxics.
• NUDT15: patients with an inherited NUDT15 variant are at increased risk of severe toxicity, such as early leucopenia and alopecia, from conventional doses. The SmPC gives the frequency of the NUDT15 c.415C>T variant as approximately 10% in East Asians, 4% in Hispanics, 0.2% in Europeans and 0% in Africans.

Liver and Kidney

• Liver: mercaptopurine is hepatotoxic. Liver function tests should be checked weekly during treatment, more often in patients with liver disease or other hepatotoxic therapy, and the patient should stop the medicine immediately if jaundice appears.
• Uric acid: during remission induction, when cells break down quickly, uric acid in blood and urine should be monitored because hyperuricaemia or hyperuricosuria can lead to uric acid nephropathy. Hydration and urine alkalinisation may reduce renal complications.

Infections, Vaccines and Immunosuppression

Live vaccines can cause infection in immunocompromised people and are not recommended; patients in remission should not receive them until they can respond to the vaccine. Treated patients are more susceptible to viral, fungal and bacterial infections, including severe or atypical infection and viral reactivation. Prior exposure to varicella zoster virus should be considered before starting, and hepatitis B serology should be considered. Neutropenic sepsis has been reported in patients with ALL.

Malignancies and Macrophage Activation Syndrome

• Immunosuppression, including with mercaptopurine, increases the risk of lymphoproliferative disorders and other malignancies, notably skin cancers, sarcomas and cervical cancer in situ. The risk relates to the degree and duration of immunosuppression. Regimens with several immunosuppressants should be used with caution, and mercaptopurine is potentially carcinogenic.
• Hepatosplenic T-cell lymphoma, aggressive and usually fatal, has been reported in patients with inflammatory bowel disease (an unlicensed use) treated with azathioprine or mercaptopurine.
• Macrophage activation syndrome is a life-threatening disorder that may develop in autoimmune conditions. If it occurs or is suspected, evaluation and treatment should start early and mercaptopurine should be stopped.

Sun Exposure

Treated patients are more sensitive to the sun. Exposure to sunlight and UV light should be limited, and protective clothing and a high-protection sunscreen are advised.

Pellagra and Hypoglycaemia

• Purine analogues may interfere with the niacin pathway and cause nicotinic acid deficiency (pellagra). It should be considered in patients with a localised pigmented rash, gastroenteritis or neurological deficits including cognitive deterioration; niacin or nicotinamide supplementation is then started.
• Symptomatic hypoglycaemia has been reported in children with ALL, mostly under six years of age or with a low body mass index.

Safe Handling of the Suspension

Parents and carers should avoid contact of the suspension with skin or mucous membranes. If contact occurs, wash immediately and thoroughly with soap and water.

Pregnancy, Breastfeeding and Fertility

• Contraception: the evidence of teratogenicity in humans is equivocal. Sexually active men and women should use effective contraception during treatment and for at least three months (men) or six months (women) after the last dose. Animal studies show embryotoxic and embryolethal effects.
• Pregnancy: it should not be given to pregnant patients or those likely to become pregnant without a careful risk–benefit assessment. Premature birth, low birth weight, congenital abnormalities and spontaneous abortion have been reported after maternal or paternal exposure, while a more recent epidemiological report suggests no increased risk. Newborns of exposed mothers should be monitored for haematological and immune disturbances.
• Breastfeeding: mercaptopurine has been found in the colostrum and breast milk of women taking azathioprine, so women taking Xaluprine should not breastfeed.
• Fertility: transient oligospermia is listed as a rare side effect.

Excipients with Known Effect

• Oral suspension: aspartame (E951) is a source of phenylalanine and may be harmful in phenylketonuria; there are no data on aspartame in infants below 12 weeks. The sodium methyl and ethyl parahydroxybenzoates may cause allergic reactions (possibly delayed). Sucrose is unsuitable for patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency, and long-term use raises the risk of dental caries, so good dental hygiene is needed.
• Tablets: each tablet contains 59 mg of lactose; see the tablet SmPC for the associated warning.

Effect on Driving

No studies have been done. A detrimental effect on driving or using machines cannot be predicted from the pharmacology of the active substance.

Both the oral suspension and the tablets are stored below 25 °C, with the bottle kept tightly closed (the tablet SmPC adds: to protect from humidity). No refrigeration is needed. Xaluprine is supplied as one 100 mL amber glass bottle with a child-resistant closure, a bottle adaptor and two dosing syringes (1 mL and 5 mL).

• Oral suspension: 18 months unopened; use within 56 days of first opening.
• Tablets: 5 years.

Prescription only (Rx). Xaluprine is subject to restricted medical prescription (Annex II B), and treatment is supervised by a physician or other healthcare professional experienced in ALL. The tablets are a nationally authorised prescription medicine, to be used under a physician experienced in treating acute leukaemia. Both forms are taken at home, so they are supplied to the patient or to the treating clinic on prescription; neither needs cold-chain delivery.