Mercaptopurine

Package leaflet (information for patients)

Tradename
Mercaptopurine

Dosage form
Tablets 50 mg.

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredient: Mercaptopurine 50 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Antineoplastic agents. Antimetabolites.

Pharmacological properties
Mercaptopurine has antitumor and immunosuppressive effects. As a result of its action, the growth of malignant neoplasms is inhibited and a cytotoxic effect is manifested.

Indications for use
Acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia (induction of remission and supportive therapy).

Method of administration and dosage
Inside. Mercaptopurine can be used both as monotherapy and in combination with other cytostatics in different doses depending on the therapy regimen. The dose and duration of treatment is determined depending on which cytotoxic agents and in what doses are prescribed simultaneously with mercaptopurine. When choosing an individual dose, one should be guided by the data of special literature. Usually for adults and children, the dose is 50-75 mg / m2 or 2.5 mg / kg; in the future, the daily dose of mercaptopurine is adjusted depending on the effect and the state of bone marrow hematopoiesis. The daily dose is usually administered once. In elderly patients, it is recommended to monitor liver and kidney function. If signs of hepatic or renal failure are detected, the dose should be reduced. At the first signs of severe leukopenia, it is recommended to interrupt the drug intake for 2-3 days. If during this time leukopenia does not worsen, the treatment is resumed. When combined with allopurinol, the dose of mercaptopurine is reduced by 25% of the standard dose, since allopurinol reduces the metabolic rate of mercaptopurine.

Side effects
From the side of hematopoiesis: anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, pancytopenia. On the part of the digestive system: anorexia, nausea, vomiting, diarrhea, hepatonecrosis, intrahepatic cholestasis (hepatotoxicity has a toxic-allergic genesis and often occurs when the recommended dose is exceeded at 2.5 mg / kg / day or 75 mg / m2 / day); ulceration of the oral mucosa; less often - ulceration of the intestinal mucosa, pancreatitis. From the immune system: arthralgia, skin rash, drug fever, facial edema. On the part of the skin and cutaneous appendages: alopecia. Reproductive system: transient oligospermia. Benign and malignant neoplasms (including cysts and polyps), including lymphoproliferative diseases, various types of cancer, including hemoblastosis, skin cancer (melanoma, etc.), sarcoma (Kaloshi's sarcoma, etc.), cervical cancer in situ (see. (See Precautions section). Others: hypersensitivity reactions, decreased immunity, accession of secondary infections, skin hyperpigmentation; hyperuricemia and nephropathy due to tumor lysis; the development of secondary leukemia and myelodysplasia. Potentially possible mutagenicity, carcinogenicity. In case of adverse reactions, including those not listed in this instruction, you should consult a doctor.

Contraindication
- hypersensitivity to mercaptopurine or to any component of the drug;
- a history of previous resistance to mercaptopurine and thioguanine ;
- simultaneous use with yellow fever vaccine.
Given the seriousness of the indications for the use of mercaptopurine, there are no absolute contraindications to its appointment.
The rest of the information is placed in the appropriate sections and subsections: "Precautions", "Use during pregnancy and lactation."

Overdose
Symptoms: when prescribing high doses of the drug (higher than 60 mg / kg / day), undesirable effects may increase, incl. with severe dysfunction of the bone marrow.
Treatment: symptomatic, prophylactic anti-infectious therapy, transfusion of blood components according to indications. The specific antidote is unknown.

Precautions
To avoid complications, mercaptopurine should be used only under the supervision of physicians experienced in the use of cytostatics. Detailed blood tests should be performed daily during treatment. Early detection of hepatotoxicity is ensured by regular "liver" tests (every week - at the beginning of therapy, every month - during maintenance therapy): "hepatic" transaminases ; alkaline phosphatase, bilirubin. In patients with a history of liver disease or other potentially hepatotoxic drugs, these tests should be done more frequently. Patients should be warned about the need to immediately stop treatment if jaundice appears. These violations are usually reversible with timely discontinuation of mercaptopurine. During the induction of remission, when rapid cell lysis occurs, the concentration of uric acid in the blood and urine should be monitored to avoid hyperuricemia and / or hyperuricosuria and the risk of developing uric acid nephrourolithiasis. To prevent hyperuricemia, it is recommended to drink plenty of fluids, if necessary - allopurino L and alkalinization of urine.
Myelosuppression is reversible if the drug is discontinued in a timely manner. After completion of treatment, the number of leukocytes and platelets may continue to decline (delayed action), therefore, at the first signs of an excessively large decrease in their number, treatment should be temporarily stopped.
Patients with congenital deficiency of the enzyme thiopurine methyltransferase (TPMT) are more susceptible to the rapid development of myelosuppression after administration of mercaptopurine, therefore, if possible, it is necessary to carry out genetic and phenotypic analysis of the activity of the enzyme thiopurine methyltransferase (TPMT).
Due to the fact that there is no antidote, it is necessary to carefully monitor the blood picture and, if necessary, carry out supportive therapy and blood transfusion.
During the treatment period of any of the sexual partners, it is recommended to use reliable methods of contraception.
Mercaptopurine is used with caution in patients with a history of gout or nephrourolithiasis who have previously received antitumor or radiation therapy. In patients with impaired liver and / or kidney function, dosage adjustment is required. In patients with suppression of bone marrow hematopoiesis, with acute viral (including chickenpox, shingles), fungal and bacterial diseases, with sucrase / isomaltase deficiency, with fructose intolerance, mercaptopurine is used with caution.
The drug contains lactose. In this regard, it is not recommended for patients with congenital galactosemia, lack of lactase Lappa and ma labsorbtsiey galactose / glucose.
Use mercaptopurine with caution in children under 2 years of age.
Care is advised when handling the tablets (for example, dividing them in half) to avoid contamination of the hands or inhalation of the drug.
In patients with congenital deficiency of the enzyme thiopurine methyltransferase (TPMT), taking mercaptopurine can lead to the development of severe myelosuppression. With the simultaneous administration of drugs that inhibit TPMT (for example, olsalazine, mesalazine, sulfalazine), severe myelosuppression may increase. There is a possible relationship between reduced TPMT enzyme activity and secondary leukemia and myelodysplasia in individuals receiving mercaptopurine in combination with other cytotoxic drugs.
If possible, before using mercaptopurine, it is necessary to monitor the activity of the TPMT enzyme. Some laboratories have the appropriate equipment to monitor TPMT enzyme activity, but this test is optional to identify patients at increased risk of developing toxicity with mercaptopurine treatment.
During the period of treatment with mercaptopurine, it is not recommended to carry out immunization with vaccines containing live microorganisms. Contact with people who have received the "polio vaccine, with patients with bacterial infections should be avoided. Vaccines containing live microorganisms should not be used in patients with leukemia in remission for at least 3 months after the last course of chemotherapy. Immunization with oral vaccine against poliomyelitis in people in close contact with such a patient, especially family members, should be delayed.
If you are receiving immunosuppressive therapy while taking mercaptopurine, you have an increased risk of developing:
- tumors, including skin cancer. When using mercaptopurine, avoid overexposure to sunlight, wear closed clothing, and use a high SPF sunscreen.
- lymphoproliferative diseases:
• A treatment regimen that includes several immunosuppressive drugs (including mercaptopurine) can lead to lymphoproliferative diseases, sometimes fatal.
• the simultaneous administration of several immunosuppressive drugs increases the risk of developing lymphoproliferative diseases associated with the Epstein- Barr virus.
- hemophagocytic syndrome (over-activation of macrophages (white blood cells) associated with inflammation), which usually occurs in people with certain types of arthritis.
Experimental studies have shown that mercaptopurine has a carcinogenic and mutagenic effect.
An increase in the number of chromosomal aberrations in peripheral blood lymphocytes was observed in patients with leukemia, in a patient with hypernephroma who took an unspecified dose of mercaptopurine, and in patients with chronic kidney disease who took mercaptopurine at a dose of 0.4-1.0 mg / kg / day.
Two cases of acute myeloid leukemia have been described in patients taking mercaptopurine in combination with other drugs for non-neoplastic diseases. A case is described when a patient was treated for pyoderma gangrenous with mercaptopurine, and then acute myeloid leukemia developed, but it is not known whether mercaptopurine is the cause of the disease.
There was a case of the development of acute myeloid leukemia in a patient with Hodgkin's disease who took mercaptopurine in combination with many other cytotoxic drugs.
A case of a patient of chronic myeloid leukemia after 12.5 years after therapy measurement ptopurinom about myasthenia gravis.
Cases of hepato - splenic T-cell lymphoma in patients with inflammatory bowel disease (IBD) can be obtained when mercaptopurine is given in combination with anti-TNF drugs.
Mercaptopurine also has a mutagenic effect: it causes chromosomal aberrations in animal and human cells and causes dominantly lethal mutations in male rats. Mercaptopurine is embryotoxic. In rat embryos, the drug causes pathological changes. The effect of mercaptopurine on fertility in humans is not well understood for both men and women.

Interaction with other medicinal products
When used together with drugs that block tubular secretion (especially with uricosuric anti - gout drugs - probenecid, sulfinpyrazone, colchicine), the risk of developing nephropathy increases. Vincristine and methotrexate increase (reciprocally) activity and toxicity.
With the combined use of allopurinol and mercaptopurine, the dose of mercaptopurine is reduced by 4 times, since allopurinol reduces the metabolic rate of 6-mercaptopurine through the action of the enzyme xanthine oxidase. Other xanthine oxidase inhibitors, such as febuxostat, azathioprine, can also decrease the metabolic rate of mercaptopurine, so their combined use is not recommended due to the lack of sufficient data to adequately adjust the dose of mercaptopurine.
When used together with indirect anticoagulants, mercapturin can increase anticoagulant activity and / or the risk of bleeding as a result of a decrease in the synthesis of coagulation factors in the liver and impaired platelet formation, or reduce anticoagulant activity by increasing the synthesis or activation of prothrombin.
There is evidence of inhibition of the anticoagulant effect of warfarin when taken together with mercaptopurine. Monitoring of INR is recommended when taking mercaptopurine and oral anticoagulants together.
Drugs that suppress bone marrow hematopoiesis (incl. Ko -trimoxazole), cytotoxic agents and radiation therapy increase the severity s leukopenia and thrombocytopenia.
Cytostatics can lead to a decrease in the absorption of phenytoin in the intestine. Regular monitoring of serum phenytoin levels is recommended. A change in the content in serum and other antiepileptic drugs is possible, therefore, their content in serum should be monitored, adjusting the dose of mercaptopurine as necessary.
With simultaneous use with glucocorticosteroids, azathioprine, chlorambucil, corticotropin, cyclophosphamide and cyclosporine, the risk of developing infection and secondary tumors increases (increased immunosuppressive action).
Concomitant administration with doxorubicin significantly increases the risk of developing hepatotoxicity.
Marked cross-resistance to cell merkaptopur Inu and derivatives thioguanine.
With simultaneous use with derivatives of aminosalicylate (for example, with olsalazine, mesalazine, sulfasalazine) that inhibit thiopurine methyltransferase (TPMT), the risk of myelosuppression increases. Concomitant administration of yellow fever vaccine with mercaptopurine is contraindicated due to the risk of fatal disease in immunocompromised patients. The combination of mercaptopurine with the administration of other live vaccines is not recommended in immunocompromised patients. In combination with live viral vaccines, it can intensify the replication of the vaccine virus. It is possible to increase the side effects of the vaccine and reduce the production of antibodies in response to the administration of both live and inactivated vaccines.
The combined use of mercaptopurine with food may slightly reduce the systemic exposure of the drug, which is probably not of clinical significance. Therefore, mercaptopurine can be taken with food or on an empty stomach, but patients should be standardized on how they are taken. This drug should not be taken with milk and dairy products, as they contain xanthine oxidase, an enzyme that metabolizes 6-mercaptopurine, which can lead to a decrease in plasma mercaptopurine concentration.

Special instructions
Mercaptopurine should only be used under the supervision of physicians experienced in the use of cytostatics. Treatment should be carried out under the close supervision of a complete complete blood count, as well as "liver" tests (every week - at the beginning of therapy, every month - during the maintenance therapy) and serum uric acid levels. With the use of mercaptopurine, a delayed myelotoxic effect may be observed. To prevent hyperuricemia, it is recommended to drink plenty of fluids, if necessary, allopurinol and alkalinize the urine. With a decrease in the number of leukocytes and platelets below the permissible value, a tendency to bleeding or the appearance of jaundice, mercaptopurine should be canceled. During the treatment period of any of the sexual partners, it is recommended to use reliable methods of contraception. The drug may increase the risk of secondary malignant neoplasms and nephropathy (due to increased production of uric acid). During treatment, and for at least 3 months after, immunization should be abandoned and contact with people who have received oral polio vaccine should be avoided. Precautions - inhibition of bone marrow hematopoiesis, acute viral (in divided into chickenpox, herpes zoster.) Fungal and bacterial diseases, renal and / or liver failure, hyperuricemia, gout or urate nephrolithiasis deficit sucrase / isomaltase, fructose intolerance, glucose - galactose malabsorption, age up to 2 years.

Pregnancy and elbowing
The use of the drug during pregnancy is possible only for health reasons. Mercaptopurine is teratogenic. If possible, avoid prescribing the drug during pregnancy, especially in the first trimester. In each case, it is necessary to assess the expected benefits of therapy for the mother and the potential risk to the fetus. As with any cytotoxic drug treatment, any partner should take steps to prevent pregnancy and use reliable contraception when taking mercaptopurine. Experimental studies have shown that mercaptopurine has a toxic effect on the fetus in animals. The effect of the drug on the fetus in humans has not been studied enough. Healthy babies were born in pregnant women who took mercaptopurine as monotherapy throughout their pregnancy. At the same time, cases of spontaneous abortions, premature births and various fetal disorders are described. Multiple congenital anomalies have been reported following treatment with mercaptopurine in combination with other antineoplastic agents. The effect of mercaptopurine on fertility in humans is not well understood, but there are reports of the birth of children in men and women who took mercaptopurine in childhood or adolescence. Transient severe oligospermia was observed in a young man taking mercaptopurine at a dose of 150 mg / day in combination with prednisolone at a dose of 80 mg / day for acute leukemia. 2 years after the termination of chemotherapy, the patient's spermogram returned to normal, and he became the father of a normal child. Women taking mercaptopurine are not advised to breastfeed their baby. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
Mercaptopurine 50 mg Tablets. There are 25 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.