Mercaptopurine-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERCAPTOPURINE-VISTA

Composition:

Active substance: 6-mercaptopurine;

One tablet contains mercaptopurine (as mercaptopurine monohydrate) 50 mg;

Excipients: anhydrous lactose, maize starch, maltodextrin, stearic acid, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round tablets with a score line, yellowish in color.

Pharmacotherapeutic group. Antineoplastic agents. Antimetabolites. Purine analogues. Mercaptopurine. ATC code L01B B02.

Pharmacological properties.

Pharmacodynamics.

6-mercaptopurine is a sulfhydryl analogue of the purine base hypoxanthine. It acts as a cytotoxic antimetabolite.

6-mercaptopurine is an inactive prodrug that functions as a purine antagonist, but requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGN) to exert cytotoxicity. TGN and other metabolites (e.g., 6-methylmercaptopurine ribonucleotides) interfere with de novo purine synthesis and interconversion of purine nucleotides. TGN are also incorporated into nucleic acids, contributing to the cytotoxic effects of the drug. The cytotoxic effect of 6-mercaptopurine may be related to the levels of 6-mercaptopurine-derived thioguanine nucleotides in erythrocytes, but not to the plasma concentration of 6-mercaptopurine itself.

Pharmacokinetics.

Absorption. Oral bioavailability of 6-mercaptopurine varies widely among individuals. After administration of a 75 mg/m² body surface dose in 7 children, the mean bioavailability of mercaptopurine was 16% of the administered dose (ranging from 5% to 37%). Variability in bioavailability may be explained by extensive presystemic metabolism of 6-mercaptopurine in the liver. Following oral administration of 6-mercaptopurine at a dose of 75 mg/m² body surface area in 14 children with acute lymphoblastic leukemia, mean Cmax was 0.89 µM (range: 0.29–1.82 µM), and mean Tmax was 2.2 hours (range: 0.5–4 hours). Mean relative bioavailability of 6-mercaptopurine was approximately 26% lower when administered with food and milk compared to administration after overnight fasting. 6-mercaptopurine is unstable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see section "Dosage and administration").

Distribution. Concentrations of 6-mercaptopurine in cerebrospinal fluid (CSF) after intravenous or oral administration are low or negligible (CSF/plasma ratio ranges from 0.05 to 0.27). Higher CSF concentrations are achieved after intrathecal administration.

Biological transformation. 6-mercaptopurine is extensively metabolized into active and inactive metabolites via several multistep pathways. Due to complex metabolism, inhibition of a single enzyme cannot explain all cases of inadequate therapeutic response and/or pronounced myelosuppression. Key enzymes involved in the metabolism of 6-mercaptopurine or its metabolites include: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDH), and hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Additional enzymes involved in the formation of active and inactive metabolites include guanosine monophosphate synthetase (GMPS, which produces TGN) and inosine triphosphate pyrophosphatase (ITPase). Moreover, numerous other inactive metabolites are formed through additional pathways. Evidence suggests that polymorphisms in genes encoding various enzymes involved in 6-mercaptopurine metabolism may predispose to adverse reactions to 6-mercaptopurine therapy. For example, individuals with TPMT deficiency develop very high cytotoxic concentrations of thioguanine nucleotides (see section "Special precautions").

Elimination. In a study involving 22 adult patients, the mean clearance and elimination half-life of 6-mercaptopurine after intravenous infusion were 864 mL/min/m² and 0.9 hours, respectively. Mean renal clearance in 16 of these patients was 191 mL/min/m². After intravenous administration, only about 20% of the administered dose was excreted unchanged in urine. In a study of 7 children, mean clearance and elimination half-life of 6-mercaptopurine after intravenous infusion were 719 (±610) mL/min/m² and 0.9 (±0.3) hours, respectively.

Special patient groups.

Elderly patients. Specific studies on the use of 6-mercaptopurine in elderly patients have not been conducted (see section "Dosage and administration").

Renal impairment. Prodrug studies of 6-mercaptopurine have shown no difference in the pharmacokinetics of 6-mercaptopurine between patients with uremia and those with transplanted kidneys. Because limited information is available on active metabolites of 6-mercaptopurine in renal impairment, reduced doses of 6-mercaptopurine are recommended in patients with impaired renal function (see section "Dosage and administration"). 6-mercaptopurine and its metabolites are removed during hemodialysis: approximately 45% of radioactive metabolites are eliminated within 8 hours of dialysis.

Hepatic impairment. Prodrug studies of 6-mercaptopurine were conducted in three groups of kidney transplant recipients: those without liver disease, those with hepatic dysfunction (but without cirrhosis), and those with hepatic dysfunction and cirrhosis. The study demonstrated that exposure to 6-mercaptopurine was 1.6-fold higher in patients with hepatic dysfunction (but without cirrhosis) and 10-fold higher in patients with hepatic dysfunction and cirrhosis, compared to patients without liver disease (see section "Dosage and administration").

Clinical characteristics.

Indications.

For the treatment of acute leukemia in adults, adolescents, and children with:

• Acute lymphoblastic leukemia (ALL);
• Acute promyelocytic leukemia (APL) / acute myeloid leukemia M3 (AML M3).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Due to the severity of the indications, there are no other absolute contraindications.

Concomitant use with yellow fever vaccine is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Administration of live vaccines to immunocompromised patients is not recommended (see section "Special precautions for use").

Administration of 6-mercaptopurine with food may slightly reduce its systemic exposure. 6-Mercaptopurine may be taken with or without food; however, the patient should standardize the method of administration to prevent significant fluctuations in exposure. The medicinal product should not be taken with milk or dairy products, as they contain xanthine oxidase, an enzyme that metabolizes 6-mercaptopurine, which may lead to reduced plasma concentrations of mercaptopurine.

Effect of concomitant medicinal products on 6-mercaptopurine.

Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), resulting in reduced production of active 6-thioguanine nucleotides. Cases of severe myelosuppression have been reported during concomitant use of 6-mercaptopurine and ribavirin; therefore, concomitant use of ribavirin and 6-mercaptopurine is not recommended (see sections "Special precautions for use" and "Pharmacokinetics").

Myelosuppressive medicinal products. Concomitant use of 6-mercaptopurine with other myelosuppressive agents should be performed with caution; dosage adjustments should be considered based on hematological monitoring (see section "Special precautions for use").

Allopurinol/oxypurinol/thiopurinol and other xanthine oxidase inhibitors. Allopurinol, oxypurinol, and thiopurinol inhibit xanthine oxidase activity, leading to suppression of the conversion of biologically active 6-thioinosinic acid into biologically inactive 6-thiouric acid. When used concomitantly with allopurinol, oxypurinol, and/or thiopurinol, only 25% of the usual dose of 6-mercaptopurine should be administered (see section "Dosage and administration"), as allopurinol reduces the metabolism of mercaptopurine monohydrate by xanthine oxidase.

Other xanthine oxidase inhibitors, such as febuxostat, may delay the metabolism of 6-mercaptopurine. Concomitant use of these medicinal products is not recommended, as insufficient data are available to establish an appropriate dose reduction regimen for 6-mercaptopurine.

Aminosalicylates. In vitro and in vivo data show that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulfasalazine) inhibit the TPMT enzyme; therefore, when used concomitantly with aminosalicylate derivatives, dose reduction of 6-mercaptopurine should be considered (see section "Special precautions for use").

Methotrexate. Oral methotrexate at a dose of 20 mg/m² increased the AUC of 6-mercaptopurine by approximately 31%, while intravenous doses of 2 or 5 g/m² increased the AUC of 6-mercaptopurine by 69% and 93%, respectively. Therefore, if 6-mercaptopurine is administered concomitantly with high-dose methotrexate, the dose of the medicinal product should be adjusted to maintain a normal white blood cell count.

Infliximab. An interaction has been observed between azathioprine, a prodrug of 6-mercaptopurine, and infliximab. In patients receiving long-term azathioprine, transient increases in 6-TGN (6-thioguanine nucleotide, the active metabolite of azathioprine) levels and decreases in mean white blood cell count were observed during the first weeks after infliximab infusion. Parameters returned to baseline levels within 3 months. Therefore, careful hematological monitoring is recommended when the medicinal product is used concomitantly with infliximab.

Effect of 6-mercaptopurine on other medicinal products.

Anticoagulants. Reduced anticoagulant effect of warfarin and acenocoumarol has been reported during concomitant use with 6-mercaptopurine, potentially requiring higher anticoagulant doses. Close monitoring of coagulation parameters is recommended when anticoagulants are used concomitantly with 6-mercaptopurine.

Antiepileptic agents.

Cytotoxic agents may reduce intestinal absorption of phenytoin. Careful monitoring of serum phenytoin levels is recommended. Changes in serum levels of other antiepileptic agents are also possible. Serum levels of antiepileptic agents should be closely monitored during treatment with mercaptopurine monohydrate. Dose adjustments should be made as necessary.

Special precautions for use.

6-Mercaptopurine is an active cytostatic medicinal product and therefore should only be used under the supervision of a physician experienced in the administration of such agents. Vaccination with live vaccines may lead to infection in immunocompromised patients. Therefore, live vaccines should not be administered to patients with CLL or CML. In any case, live vaccines may be given to patients in remission only after the patient is considered capable of responding to vaccination. The interval between the end of chemotherapy and recovery of the patient's ability to respond to vaccination depends on the intensity and type of medicinal products causing immunosuppression, the underlying disease, and other factors.

Concomitant use of ribavirin and 6-mercaptopurine is not recommended. Ribavirin may reduce the efficacy and enhance the toxic effects of 6-mercaptopurine (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring.

Since 6-mercaptopurine exerts a strong myelosuppressive effect, a complete blood count should be performed daily during induction of remission. Close monitoring of the patient is required throughout treatment.

Suppression of bone marrow.

Treatment with 6-mercaptopurine causes suppression of bone marrow, leading to leukopenia and thrombocytopenia, and less frequently to anemia. Complete blood counts should be performed frequently during induction of remission. Hematological parameters, including platelet levels, should be monitored regularly during maintenance therapy and more frequently if high doses are used or in patients with severe renal and/or hepatic impairment. Enhanced hematological monitoring is recommended when switching between different formulations of mercaptopurine. Leukocyte and platelet counts may continue to decrease even after discontinuation of treatment; therefore, treatment should be stopped immediately at the first signs of excessive reduction in leukocyte or platelet counts. With timely discontinuation of 6-mercaptopurine, bone marrow suppression is reversible. During induction of remission in acute myeloid leukemia, it is essential to ensure the availability of frequent supportive care during the period of possible treatment-related bone marrow aplasia, and appropriate equipment must be available. The dose of 6-mercaptopurine may need to be reduced when co-administered with medicinal products whose primary or secondary toxicity manifests as myelosuppression (see section "Interaction with other medicinal products and other forms of interaction").

Hepatotoxicity.

6-Mercaptopurine is hepatotoxic; therefore, liver function tests should be monitored weekly throughout treatment. Plasma levels of gamma-glutamyl transferase (GGT) are the most important prognostic factor for discontinuation of the medicinal product due to hepatotoxicity. This monitoring should be performed more frequently in patients with liver disease or those receiving other potentially hepatotoxic medicinal products. Patients should be warned to discontinue 6-mercaptopurine immediately if jaundice occurs.

Tumour lysis syndrome.

During induction of remission, when rapid cell lysis occurs, serum and urinary uric acid levels should be monitored, as there is a risk of hyperuricemia and/or hyperuricosuria, with a potential risk of uric acid nephropathy.

TPMT deficiency.

Some individuals have an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT). These patients may be extremely sensitive to the myelosuppressive effects of 6-mercaptopurine, resulting in rapid development of bone marrow suppression after initiation of 6-mercaptopurine therapy. This problem may be further complicated by concomitant administration of drugs that inhibit thiopurine methyltransferase, such as olsalazine, mesalazine, or sulfasalazine. In addition, a possible association has been reported between reduced TPMT activity and the development of secondary leukemias and myelodysplasia in patients receiving 6-mercaptopurine in combination with other cytotoxic medicinal products (see section "Undesirable effects"). Approximately 0.3% (1:300) of patients have low or absent activity of this enzyme. Approximately 10% of patients have low or intermediate TPMT activity, and 90% have normal TPMT activity. There is also a group of about 2% with high TPMT activity. Some laboratories perform testing for TPMT deficiency, although such tests do not always identify all patients at risk of severe toxicity. Therefore, hematological parameters should be carefully monitored.

Patients with NUDT15 variant.

Patients with an inherited mutation in the NUDT15 gene have an increased risk of developing severe toxic effects of 6-mercaptopurine treatment, such as early leukopenia and alopecia, at standard thiopurine therapy doses. Such patients usually require reduced doses, especially homozygous patients with the NUDT15 variant (see section "Posology and method of administration"). The frequency of the NUDT15 c.415C>T variant varies ethnically: approximately 10% in East Asian populations, 4% in Latin American populations, 0.2% in European populations, and 0% in African populations. In any case, hematological parameters should be carefully monitored.

Cross-resistance.

Cross-resistance between 6-mercaptopurine and 6-thioguanine is usually observed.

Hypersensitivity.

Administration of azathioprine, the prodrug of 6-mercaptopurine, is not recommended in patients with a suspected history of hypersensitivity reactions to 6-mercaptopurine, except in cases where allergy testing has confirmed hypersensitivity to 6-mercaptopurine but yielded a negative result for azathioprine. Since azathioprine is a prodrug of 6-mercaptopurine, patients with a history of hypersensitivity to azathioprine should undergo hypersensitivity testing for 6-mercaptopurine prior to initiation of treatment.

Impairment of liver and/or kidney function.

Caution is advised when administering 6-mercaptopurine to patients with impaired renal and/or hepatic function. Reduced doses are recommended for such patients, and hematological response should be closely monitored (see sections "Posology and method of administration" and "Pharmacokinetics").

Mutagenicity and carcinogenicity.

An increased number of chromosomal aberrations has been observed in peripheral lymphocytes of patients with leukemia, in a patient with hypernephroma who received an unknown dose of 6-mercaptopurine, and in patients with chronic kidney disease receiving doses of 0.4–1.0 mg/kg body weight per day.

Two cases of acute non-lymphocytic leukemia have been reported in patients receiving 6-mercaptopurine in combination with other medicinal products for benign conditions. One case involved a patient treated with 6-mercaptopurine for pyoderma gangrenosum who later developed acute non-lymphocytic leukemia; however, it remains unclear whether this was due to the natural course of the disease or to 6-mercaptopurine treatment. A patient with Hodgkin's disease developed acute myeloid leukemia while receiving 6-mercaptopurine and multiple other cytostatics.

Twelve and a half years after treatment with 6-mercaptopurine for myasthenia gravis, a patient developed chronic myeloid leukemia.

Cases of hepatosplenic T-cell lymphoma have been reported in patients with inflammatory bowel disease (IBD) (an unapproved indication) who received 6-mercaptopurine in combination with tumour necrosis factor (TNF) inhibitors (see section "Undesirable effects").

Patients receiving immunosuppressive therapy, including mercaptopurine, have an increased risk of developing lymphoproliferative disorders and other malignancies, particularly skin cancer (melanoma and non-melanoma types), sarcomas (Kaposi's sarcoma and others), and cervical intraepithelial neoplasia. The increased risk is likely related to the degree and duration of immunosuppression. Discontinuation of immunosuppressive medicinal products has been reported to lead to partial regression of lymphoproliferative disorders. Therefore, treatment regimens containing multiple immunosuppressive agents (including thiopurines) should be used with caution, as they may lead to lymphoproliferative disorders, including fatal outcomes. The combination of multiple immunosuppressive agents used simultaneously increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

Macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a known life-threatening disorder that may develop in patients with autoimmune conditions, particularly inflammatory bowel disease (IBD) (an unapproved indication), who may potentially have increased sensitivity to mercaptopurine. If MAS develops or is suspected, appropriate treatment should be initiated as early as possible, and mercaptopurine should be discontinued. Physicians should be vigilant for infections such as EBV or cytomegalovirus (CMV), as they are known triggers of MAS.

Metabolism and nutrition disorders.

Administration of purine analogs—azathioprine and mercaptopurine—may interfere with niacin metabolism, potentially leading to niacin deficiency (pellagra). Several such cases have been reported with azathioprine and mercaptopurine, particularly in patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis). Pellagra should be considered in patients presenting with localized pigmented rash (dermatitis), gastroenteritis (diarrhea), or neurological disturbances, including cognitive decline (dementia). Appropriate treatment with niacin/nicotinamide supplementation should be initiated, and consideration should be given to reducing the dose or discontinuing azathioprine.

Children.

Symptomatic hypoglycemia has been observed in children with ALL receiving 6-mercaptopurine therapy (see section "Undesirable effects"). These cases mostly involved children under 6 years of age or with low body mass index.

Metabolic and nutritional disorders.

Purine analogs (azathioprine and mercaptopurine) may affect the niacin pathway, potentially leading to niacin deficiency (pellagra). Cases of pellagra have been reported with purine analogs, particularly in patients with chronic inflammatory bowel disease. The diagnosis of pellagra should be considered in patients with localized pigmented rash (dermatitis), gastroenteritis, or neurological deficits, including cognitive impairment. Appropriate medical management with niacin/nicotinamide supplementation should be initiated.

Infections.

Increased susceptibility to viral, fungal, and bacterial infections, including severe or atypical infections, as well as reactivation of viral infections, has been observed in patients receiving 6-mercaptopurine alone or in combination with other immunosuppressive agents, including corticosteroids. Infections and their complications may be more severe in these patients than in those not receiving treatment. Prior exposure or infection with varicella-zoster virus should be considered before initiating treatment. If necessary, local recommendations should be followed, including prophylactic treatment. Serological testing for hepatitis B virus should be considered before starting treatment. If serological tests are positive, local recommendations should be followed, including prophylactic treatment. Cases of neutropenic sepsis have been observed in patients receiving 6-mercaptopurine for ALL. If an infection occurs during treatment, appropriate measures should be taken, which may include antiviral therapy and supportive care.

Lesch-Nyhan syndrome.

Limited data indicate that neither 6-mercaptopurine nor its prodrug azathioprine is effective in patients with the rare inherited condition of complete hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). 6-Mercaptopurine or azathioprine should not be administered to such patients.

Ultraviolet radiation.

Patients receiving 6-mercaptopurine are more sensitive to sunlight. Exposure to sunlight and ultraviolet radiation should be limited. Patients should be advised to wear protective clothing and use cosmetic products with high UV protection factor.

Xanthine oxidase inhibitors.

When used concomitantly with xanthine oxidase inhibitors such as allopurinol, oxypurinol, or thiopurinol, patients should receive only 25% of the usual dose of 6-mercaptopurine, as allopurinol reduces the catabolism rate of 6-mercaptopurine (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Anticoagulants.

Reduced anticoagulant effect of warfarin and acenocoumarol has been reported with concomitant use of 6-mercaptopurine; therefore, higher doses of anticoagulants may be required (see section "Interaction with other medicinal products and other forms of interaction").

Safe handling of 6-mercaptopurine tablets.

When handling 6-mercaptopurine tablets, it is recommended to follow applicable local guidelines and/or regulations for handling and disposal of cytotoxic medicinal products.

Disposal of unused medicinal product or expired product. Environmental contamination should be minimized. The medicinal product should not be disposed of in wastewater or household waste. A "take-back" system should be used if available. Any unused medicinal products or waste should be disposed of in accordance with local requirements.

Important information on excipients.

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Patients with known sugar intolerance should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Contraception in men and women

Evidence of teratogenicity of mercaptopurine monohydrate in humans is inconclusive. Sexually active men and women should use effective contraception during treatment and for at least three months after the last dose. Animal studies have demonstrated embryotoxic and embryolethal effects.

Reproductive function. The effect of 6-mercaptopurine therapy on human fertility is unknown.

There are reports of healthy children born to parents/mothers who were treated in childhood or adolescence.

Cases of transient oligospermia after 6-mercaptopurine treatment have been reported.

Pregnancy. Significant transfer of 6-mercaptopurine and its metabolites from mother to fetus through the placenta and amniotic fluid has been demonstrated.

Use of 6-mercaptopurine during pregnancy, especially in the first trimester, should be avoided if possible. In each individual case, the potential risk to the fetus should be weighed against the expected benefit to the mother.

Cholestasis during pregnancy has occasionally been reported with azathioprine therapy (prodrug of 6-mercaptopurine). The benefit to the mother and the effect on the fetus should be carefully evaluated if cholestasis of pregnancy is confirmed.

As with other forms of cytotoxic chemotherapy, if either partner is receiving 6-mercaptopurine tablets, patients should be advised to use adequate contraception during treatment and for at least 3 months after the last dose.

Animal studies with 6-mercaptopurine indicate reproductive toxicity of the medicinal product. The potential risk to humans has not been fully established.

Effect of maternal treatment. Healthy children have been born to women after 6-mercaptopurine monotherapy, particularly when treatment was administered before conception or after the first trimester.

Cases of spontaneous abortions and preterm births have been reported in women receiving the medicinal product. Cases of children born with multiple congenital anomalies have been reported after use of 6-mercaptopurine in combination with other chemotherapeutic agents in pregnant women.

Effect of paternal treatment. Cases of spontaneous abortions and congenital anomalies in children have been reported after paternal exposure to 6-mercaptopurine.

Breastfeeding. 6-Mercaptopurine has been detected in breast milk of patients after kidney transplantation who received immunosuppressive therapy with azathioprine (prodrug of 6-mercaptopurine). Therefore, women receiving 6-mercaptopurine should not breastfeed.

Ability to affect reaction speed when driving or operating machinery.

There are no data on the effect of 6-mercaptopurine on the ability to drive or operate machinery. Given the pharmacological properties of the medicinal product, its effect on these activities cannot be predicted.

Method of Administration and Dosage

Treatment with 6-mercaptopurine should be conducted only under the supervision of a physician or other healthcare professional experienced in managing patients with CLL or AML (AML M3). 6-Mercaptopurine may be taken with or without food, but the patient should standardize the method of administration. The medicinal product should not be taken with milk or dairy products (see section "Interaction with other medicinal products and other forms of interaction"). 6-Mercaptopurine should be taken at least 1 hour before or 2 hours after consuming milk or dairy products.

For adults and children, the usual dose is 2.5 mg/kg body weight per day, or 50–75 mg/m² body surface area per day. However, the dose and duration of treatment depend on the type and dosage of other cytostatic agents used concomitantly with 6-mercaptopurine. Doses should be individualized according to the patient's specific characteristics. 6-Mercaptopurine has been used in various combination regimens for the treatment of acute leukemia. Studies in children with acute lymphoblastic leukemia suggest that evening administration of 6-mercaptopurine reduces the risk of disease relapse compared to morning administration.

Elderly Patients

In elderly patients, renal and hepatic function should be monitored, and the dose of 6-mercaptopurine should be reduced in case of impairment.

Renal Impairment

Since the pharmacokinetics of mercaptopurine monohydrate have not been formally studied in patients with impaired renal function, specific dosage recommendations cannot be provided. As renal impairment may lead to slower elimination of mercaptopurine monohydrate and its metabolites, resulting in greater cumulative effects, consideration should be given to reducing the initial dose in patients with renal dysfunction. Patients should be closely monitored for the development of dose-dependent adverse reactions.

Hepatic Impairment

Since the pharmacokinetics of mercaptopurine monohydrate have not been formally studied in patients with impaired hepatic function, specific dosage recommendations cannot be provided. As there is a potential for delayed elimination of mercaptopurine monohydrate, consideration should be given to reducing the initial dose in patients with hepatic dysfunction. Patients should be closely monitored for dose-dependent adverse reactions (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Drug Interactions

When co-administered with xanthine oxidase inhibitors such as allopurinol, oxypurinol, or thiopurinol, only 25% of the usual dose of 6-mercaptopurine should be administered, as these medicinal products reduce the catabolism rate of 6-mercaptopurine. Concomitant use with other xanthine oxidase inhibitors such as febuxostat should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Patients with TPMT Deficiency

Patients with inherited low or completely absent thiopurine S-methyltransferase (TPMT) activity are at increased risk of developing severe toxicities from 6-mercaptopurine treatment when administered at usual doses, typically requiring substantial dose reduction. The optimal initial dose for homozygous patients with deficiency of this enzyme has not been established. Most heterozygous TPMT-deficient patients can tolerate the recommended doses of 6-mercaptopurine, although some may require dose reductions (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Genotyping or phenotyping for TPMT may be used to identify patients with absent or reduced TPMT activity. TPMT testing cannot replace hematological monitoring in patients receiving mercaptopurine monohydrate (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Patients with NUDT15 Variant

Patients with inherited NUDT15 gene mutations are at increased risk of developing severe toxicities from 6-mercaptopurine treatment (see section "Special Warnings and Precautions for Use"). Such patients usually require reduced doses, particularly homozygous patients with the NUDT15 variant (see section "Special Warnings and Precautions for Use"). Genotypic testing for NUDT15 variants is recommended prior to initiating 6-mercaptopurine therapy. In all cases, careful hematological monitoring is required.

Children

The medicinal product is used in pediatric practice.

Overdose

Symptoms. Gastrointestinal symptoms including nausea, vomiting, diarrhea, and anorexia may be early signs of overdose. The principal toxic effect is bone marrow suppression leading to myelosuppression. Hematological toxicity is more pronounced in chronic overdose than after a single large dose. Hepatic and gastrointestinal tract dysfunction may also occur. The risk of overdose is increased when allopurinol is co-administered with 6-mercaptopurine (see section "Interaction with other medicinal products and other forms of interaction").

Treatment. As no specific antidote is known, blood parameters should be closely monitored and appropriate supportive therapy provided, including blood transfusions if necessary. Active methods (such as activated charcoal) may be effective in cases of 6-mercaptopurine overdose only within 60 minutes after drug ingestion. Further management of overdose should be based on clinical judgment or recommendations from a national toxicology center (if available).

Adverse reactions

Currently, there is a lack of modern clinical data on mercaptopurine for accurately determining the frequency of adverse effects. The frequency category has been estimated for the adverse reactions listed below; for most reactions, frequency calculation is not possible. Adverse effects may vary in frequency depending on the administered dose and when used in combination with other medicinal products. The main adverse effect of mercaptopurine is bone marrow suppression, leading to leukopenia and thrombocytopenia.

The following frequency categories are used to classify the occurrence of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

System organ class	Frequency	Adverse reactions
Infections and infestations	Uncommon	Bacterial and viral infections; infections associated with neutropenia
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Very rare	Secondary leukemia and myelodysplasia (see section "Special precautions"); hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease (IBD) (unauthorized indication) when used in combination with anti-tumor necrosis factor (TNF) agents (see section "Special precautions")
	Rare	Neoplasms including lymphoproliferative disorders, skin cancer (melanoma and non-melanoma), sarcomas (Kaposi's sarcoma and other types of sarcoma), and cervical carcinoma in situ (see section "Special precautions")
Blood and lymphatic system disorders	Very common	Bone marrow suppression; leukopenia and thrombocytopenia
	Common	Anemia
Immune system disorders	Rare	Hypersensitivity reactions presenting as arthralgia, skin rash, drug fever
	Very rare	Hypersensitivity reactions presenting as facial swelling
Gastrointestinal disorders	Common	Nausea; vomiting; pancreatitis in patients with IBD (unauthorized indication)
	Rare	Oral ulcers; pancreatitis (in approved indications)
	Very rare	Intestinal ulceration
	Not known	Stomatitis, cheilitis
General disorders	Not known	Mucosal inflammation.
Hepatobiliary disorders	Common	Cholestasis; hepatotoxicity
	Rare	Hepatocellular necrosis
Skin and subcutaneous tissue disorders	Rare	Alopecia
	Not known	Photosensitivity
Metabolism and nutrition disorders	Uncommon	Anorexia
	Not known	Hypoglycemia#, pellagra (see section "Special precautions").
Reproductive system and breast disorders	Very rare	Transient oligospermia
Investigations	Not known	Reduced blood coagulation factors

#In children.

Description of individual adverse reactions.

Disorders of the hepatobiliary system.

6-mercaptopurine is hepatotoxic in both animals and humans. Histological findings in humans have shown necrosis of liver cells and biliary stasis. Cases of hepatotoxicity vary widely and may develop with the use of any dose, but they occur more frequently when the recommended doses of 2.5 mg/kg body weight or 75 mg/m² body surface area per day are exceeded.

Monitoring of liver function parameters allows early detection of the drug's toxic effects. Plasma levels of gamma-glutamyl transferase (GGT) are the most important prognostic factor for discontinuation of the drug due to hepatotoxicity. If 6-mercaptopurine is discontinued promptly, hepatotoxic effects are reversible; however, there have been reports of fatal liver damage.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions following drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of using this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life.

3 years.

Storage conditions.

The medicinal product does not require special storage conditions. Keep out of reach of children.

Packaging.

25 tablets in a bottle, 1 bottle in a carton.

Prescription status.

Prescription only.

Manufacturer.

Ardena Pamplona S.L.

Manufacturer's address and place of business.

Polígono Mocholí, C/ Noain, No. 1, Noain, 31110 Navarra, Spain