Mechanism of action
Mercaptopurine is a sulfhydryl analog of the purine bases of adenine and hypoxanthine. It acts as a cytotoxic antimetabolite.
Mercaptopurine are inactive prodrugs that act as a purine antagonist, but for the manifestation of cytotoxicity, cells and intracellular steroids need to be uptake to the nucleotides of thioguanine (NTG). NTG and other metabolites (for example, ribonucleotides to Methylmethotptopurine) disrupt purine nucleotide purine purine synthesis and interconversion. NTG is also embedded in nucleic acids, plays a role in the cytotoxic effects of the drug.
The cytotoxic effect of Mercaptopurine may be related to the level of derivatives of Mercaptopurine in the nucleotides of thioguanine in erythrocytes, but not with the concentration of Mercaptopurine in the blood plasma.
Pharmacokinetics of absorption
Bioavailability of Mercaptopurine in oral administration is very different in different people. After taking the drug at a dose of 75 mg / m 2 body surface in children . 16% of the dose taken (with fluctuations ranging from 5% to 37%). The bioavailability fluctuations, perhaps, explains the metabolism of part of the Mercaptopurine part during the pre-systemic metabolism in the liver.
After oral administration of Mercaptopurine at a dose of 75 mg / m 2 of the body surface in children with acute lymphoblastic leukemia, the mean C max value was 0.89 μM (range 0.29-1.82 μM), the T max reading was 2.2 hours in the range from 0.5 to 4:00).
The average relative bioavailability of Mercaptopurine was approximately 26% lower after ingestion with food and milk compared with administration after fasting overnight. Mercaptopurine is unstable in milk due to the presence of xanthine oxidase (decay 30% for 30 minutes). Mercaptopurine should be administered at least 1:00 before or 3:00 after ingestion of food or milk.
The average (± CO) apparent volume of distribution of Mercaptopurine is 0.9 (± 0.8) l / kg, although this figure may be underestimated, as clearance of Mercaptopurine occurs throughout the body (and not only in the liver).
The concentration of Mercaptopurine in the cerebrospinal fluid (CMP) after intravenous or oral administration is low or generally insignificant (the ratio of CMP: blood plasma is from 0.05 to 0.27). Concentrations in CMP after intrathecal administration are higher.
Mercaptopurine is extensively metabolized in active and inactive metabolites involving several multistage pathways, with no enzyme dominating in this process. Because of the complex metabolism of the blocking of a single enzyme, it can not explain all cases of ineffective treatment and / or severe myelosuppression. The dominant enzymes that are responsible for the metabolism of Mercaptopurine or its metabolites are the polymorphic enzyme thiopurin S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDG) and hypoxanthine-guanine phosphoribosyltransferase (HGF). In addition, such enzymes are involved in the formation of active and inactive metabolites: guanosine monophosphate synthetase (ITPase). In addition, other pathways form many more other inactive metabolites.
Mercaptopurine, may contribute to the development of adverse reactions to treatment with Mercaptopurine.
Thiopurin S-methyltransferase (TPMT)
The activity of TPMT is inversely proportional to the concentration in the erythrocytes of the Mercaptopurine derivatives of thioguanine nucleotides, high concentrations of thioguanine nucleotides lead to a more pronounced decrease in the number of leukocytes and neutrophils. Persons with TMP deficiency tend to develop very high cytotoxic concentrations of thioguanine nucleotides.
The analysis for genotyping allows to determine the allelic profile of the patient. As of today, it is known that 3 alleles - TPMT * 2, TPMT * 3A and TPMT * 3C - are responsible for approximately 95% of all cases of decreased activity of TPMT. Approximately 0.3% (1: 300) of patients show two non-functioning alleles (homozygotes deficient) of the TPMT gene and, as a result, a small activity of this enzyme or one that is not detected at all. Approximately 10% of patients have one non-functioning allele of the TPMT gene (heterozygotes), which manifests itself in low or intermediate activity of TPMT, whereas 90% of people show normal activity of TPMT with two instituting alleles. In addition, there may be a group with 2% of patients who have very high TSTM activity. Phenotyping determines the nucleotide level of thiopurin or the activity of TPMT in erythrocytes, so this analysis can also be informative.
It was found that the average clearance of Mercaptopurine and half-life after infusion is 864 ml / min / m 2 and 0.9 hours, respectively. The average renal clearance in most patients was 191 ml / min / m 2. After administration, only about 20% of the dose was excreted unchanged in the urine.
Primary skin reticulosis - tumor proliferation of reticular cells that occurs initially in the skin, then assumes a systemic character and is characterized by variable malignancy.
Special patient groups
Special studies of the use of Mercaptopurine in elderly patients have not been conducted.
Children with overweight
Children who are overweight may require doses of Mercaptopurine at the upper end of the dosing range, and therefore, careful monitoring of the therapeutic response to treatment in such patients is recommended.
Impaired renal function
The study of the prodrug Mercaptopurine did not reveal a difference in the pharmacokinetics of Mercaptopurine in patients with uremia compared to patients with a transplanted kidney. Since there is little known about active metabolites of Mercaptopurine in renal dysfunction, it is recommended to administer reduced doses of Mercaptopurine to patients with impaired renal function.
Mercaptopurine and / or its metabolites are excreted during hemodialysis: approximately 45% of radioactive metabolites are excreted within 8:00 during dialysis.
Impaired liver function
Exposure to Mercaptopurine was 1.6 times higher in patients with impaired liver function (but without cirrhosis) and 10 times higher in patients with impaired liver function and cirrhosis compared with patients without liver disease. Given this, it is recommended that reduced doses of Mercaptopurine be administered to patients with hepatic impairment
Treatment of acute leukemia. The drug is used to induce remission and, in particular, is prescribed for maintenance therapy with:
Acute lymphoblastic leukemia (ALL)
acute myelogenous leukemia (AML).
Hypersensitivity to Mercaptopurine or any of the components of the drug.
Given the severity of the testimony, there are no other absolute contraindications.
Interaction with other drugs and other interactions
It is not recommended to vaccinate live vaccines with immunosupplementation to patients.
The effect of the use of concomitant medications on the action of Mercaptopurine
Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDG), which leads to a decrease in the production of active nucleotides 6-thioguanine. It has been reported about the development of severe myelosuppression against the background of the concomitant use of the prodrug Mercaptopurine and ribavirin in connection with this simultaneous use of ribavirin and Mercaptopurine is not recommended.
It should be used with caution combination of Mercaptopurine with other mielosupressivnyh drugs on the results of hematological monitoring, they decide whether it is advisable to reduce the dose of the drug.
Allopurinol / oxypurinol / thiopurinol and other xanthine oxidase inhibitors
Allopurinol, oxypurinol and thiopurinol block the activity of xanthine oxidase, which leads to inhibition of the conversion of biologically active 6-thioinosinic acid into biologically inactive 6-thiosocyanic acid. When used simultaneously with allopurinol, oxypurinol and thiopurinol, the dose of Mercaptopurine should be reduced 4-fold compared with the usual dose.
Other xanthine oxidase inhibitors, for example, fequusostat, can delay the metabolism of Mercaptopurine. The simultaneous use of these drugs is not recommended, since there is insufficient data to establish an adequate dose-reduction regimen for Mercaptopurine.
Obtained in vitro and in vivo data that show that aminosalicylate derivatives (eg, olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, so when combined with aminosalicylate derivatives it is advisable to consider reducing the dose of Mercaptopurine.
Methotrexate at a dose of 20 mg / m 2 inwards led to an increase in AUC of Mercaptopurine by about 31%, while doses of 2 or 5 g / 2 intravenously increased AUC Mercaptopurine by 69% and 93%, respectively. Given this, if Mercaptopurine is administered simultaneously with high doses of methotrexate, the dose of the drug must be adjusted to maintain a normal white blood cell count.
Interaction reactions between azathioprine (prodrug Mercaptopurine) and infliximab were observed. In patients who continued to receive azathioprine, transient increases in 6-THN (nucleotide 6-thioguanine, the active metabolite of azathioprine) and a decrease in the average leukocyte counts during the first weeks after infusion of infliximab were observed. These indicators returned to normal after 3 months.
Effect of Mercaptopurine on other drugs
There was reported oppression of the anticoagulant effect of warfarin and acenocoumarol with simultaneous use with Mercaptopurine, which may require higher doses of anticoagulant. It is recommended to closely monitor coagulation samples with simultaneous use of anticoagulants and Mercaptopurine.
Mercaptopurine is an active cytotoxic drug, therefore it can be used only under the supervision of a doctor who has experience in prescribing such drugs.
When immunized with live vaccines, patients with immunodeficiency may develop an infection. Given this, immunization with live vaccines to patients with ALL or AML is not recommended. In any case, patients in the stage of remission to administer live vaccines are allowed not earlier than 3 months after the completion of chemotherapy.
It is not recommended to simultaneously use ribavirin and Mercaptopurine. Ribavirin may reduce the effectiveness and enhance toxic effects of Mercaptopurine.
Since Mercaptopurine has a strong myelosuppressive effect, an in-depth blood test must be performed daily during the induction of remission. During the entire course of treatment, you need to carefully monitor the patient.
Treatment with Mercaptopurine causes bone marrow suppression and leads to leukopenia, thrombocytopenia, and less often to anemia. During the induction of remission, it is necessary to perform a detailed blood test every day. During maintenance therapy, hematologic indices, including platelets, should be monitored weekly or more often if high doses are used or severe kidney and / or liver diseases are present.
When changing the dosage forms of the drug, hematological control of the patient is recommended.
The number of leukocytes and platelets continues to decrease after the cessation of treatment, therefore, at the very first signs of excessive reduction in the number of white blood cells or platelets, treatment should be stopped immediately.
With the timely abolition of Mercaptopurine oppression of the bone marrow is reversible.
During the induction of remission with acute myelogenous leukemia, appropriate supportive therapy should be provided for the period of possible development of bone marrow related aplasia associated with treatment.
Mercaptopurine is hepatotoxic, therefore it is necessary to monitor liver function indices every week. In patients with existing liver diseases or patients receiving other potentially hepatotoxic drugs, it is recommended to conduct this control more often. Patients should be advised to immediately cancel Mercaptopurine in the event of jaundice.
During the induction of remission, when there is a rapid lysis of the cells, it is necessary to control the level of uric acid in the blood and urine, since there is a danger of developing hyperuricemia and / or hyperuricosuria with a risk of developing urinary nephropathy.
Some people have congenital deficiency of thiopurin methyltransferase (TPMT) enzyme. These patients can manifest themselves extremely sensitive to myelosuppressive effects of Mercaptopurine, which results in a very rapid development of bone marrow suppression after the initiation of treatment with Mercaptopurine. This problem can be further complicated by the simultaneous administration of drugs that suppress thiopurin methyltransferases, like olsalazine, mesalazine or sulfasalazine. In addition, a possible association was reported between decreased TMP activity and development of secondary leukemia and myelodysplasia in patients receiving Mercaptopurine in combination with other cytotoxic drugs. In some laboratories, an analysis is performed to identify a TPMT deficiency, although such tests did not always show all patients who were at risk of severe toxic treatment. Given this, it is necessary to carefully monitor hematologic indices.
There is cross-resistance between Mercaptopurine and 6-thioguanine.
The dose of Mercaptopurine may need to be reduced with simultaneous administration of drugs in which primary or secondary toxicity manifests itself in the form of myelosuppression.
Patients who are suspected of developing hypersensitivity reactions to Mercaptopurine in the past are not recommended to use its precursor, azathioprine, unless allergic tests in the patient have confirmed the sensitivity to Mercaptopurine, but have a negative effect on azathioprine. Since azathioprine is a prodrug of Mercaptopurine, patients with a history of azathioprine hypersensitivity must be tested for sensitivity to Mercaptopurine before treatment.
Impaired liver and / or kidney function
When prescribing Mercaptopurine, patients with impaired renal and / or liver function should be cautious. It is recommended to prescribe reduced doses of Mercaptopurine to such patients and carefully monitor the hematologic response.
Mutagenicity and carcinogenicity
There was an increase in the number of chromosomal aberrations in peripheral lymphocytes in patients with leukemia, in a patient with hypernephroma who received an unidentified dose of Mercaptopurine, and in patients with chronic kidney disease receiving doses of 0.4-1.0 mg / kg of body weight per day .
Two cases of development of acute non-lymphocytic leukemia in patients who received Mercaptopurine in combination with other drugs for non-malignant diseases were recorded. One case was described when the patient received Mercaptopurine for the treatment of gangrenous pyoderma and subsequently developed acute non-lymphocytic leukemia, but it remains unclear whether this was due to the natural course of the disease or the reason for this was the use of Mercaptopurine.
In a patient with Hodgkin's disease, on the background of treatment with Mercaptopurine and many other cytostatics, acute myelogenous leukemia developed.
12.5 years after the treatment with Mercaptopurine myasthenia gravis, the patient developed chronic myeloid leukemia.
Received a report on the development of hepatic-splenic T-cell lymphoma in patients with IBD who received Mercaptopurine in combination with anti-TNF drugs.
In patients treated with Mercaptopurine alone or in combination with other immunosuppressive drugs, including corticosteroids, they noted increased sensitivity to viral, fungal and bacterial infections, including severe or atypical infections, as well as the reactivation of viral infections. The course of infection and complications in these patients may be more severe than those who did not receive treatment.
Before starting treatment, consider the appointment of serological tests for the varicella-zoster virus and hepatitis B. If serological tests are positive, local recommendations should be followed, including preventive treatment. If the patient develops an infection during treatment, appropriate measures must be taken, which may include antiviral therapy and maintenance treatment.
General recommendations should include - a healthy lifestyle, a balanced diet, physical activity, good rest and sleep, and a reduction in stress levels.
Some evidence suggests that neither Mercaptopurine nor its precursor, azathioprine, is effective in patients with deficiency of hypoxanthine-guanine phosphoribosyltransferase (Lesch-Nichan syndrome). Such patients are not recommended to use Mercaptopurine or azathioprine.
Patients receiving Mercaptopurine are more sensitive to the sun. Limit exposure to sunlight and ultraviolet radiation, patients should be advised to wear protective clothing and use cosmetics with a high UV protection factor.
The composition of the drug includes lactose, so patients with rare hereditary problems of galactose intolerance, lactase deficiency Lappa, or malabsorption of glucose-galactose use of the drug is not indicated.
Use during pregnancy or lactation.
A study of Mercaptopurine in animals indicates a reproductive toxicity of the drug. The potential risk to a person is not fully understood.
The effect of Mercaptopurine therapy on human fertility is unknown.
Received reports on the birth of healthy children from parents / mothers who were treated in childhood or adolescence.
Cases of transient oligospermia after treatment with Mercaptopurine have been reported.
An important transfer of Mercaptopurine and its metabolites from pregnant to the fetus via the placenta and amniotic fluid was demonstrated.
If possible, avoid the use of Mercaptopurine during pregnancy, especially in the first trimester. In each specific case, the potential hazard to the fetus and the expected benefit for the pregnant woman should be weighed.
As with other types of cytotoxic chemotherapy, if one of the partners receives Mercaptopurine tablets, patients should be advised to apply adequate contraceptive methods during the treatment period and at least three months after the last dose.
Exposition in the mother
After treatment with Mercaptopurine in the form of one-component chemotherapy, healthy children were born in women, especially when treatment was performed for fertilization or after the first trimester.
Cases of spontaneous miscarriages and premature births in women who received the drug are described. After the use of Mercaptopurine in combination with other chemotherapeutic drugs, pregnant women were informed of the birth of children with multiple congenital malformations.
Exposition in the father
Reported cases of spontaneous abortions and congenital malformations in children after exposure to the father of Mercaptopurine.
Mercaptopurine was shown in breast milk of patients after kidney transplantation receiving immunosuppressive therapy with azathioprine (prodrug Mercaptopurine). Therefore, women who receive Mercaptopurine should not breast-feed.
The ability to influence the reaction rate when driving vehicles or other mechanisms.
There is no evidence of the effect of Mercaptopurine on the ability to drive vehicles and work with other mechanisms. Based on the pharmacological properties of the drug, it should not be possible to influence the speed of psychomotor reactions of this drug.
Dosing and Administration
Mercaptopurine is administered at least 1:00 before or 3:00 after ingestion of food or milk.
For adults and children, the usual dose is 2.5 mg / kg body weight per day, or 50-75 mg / m 2 body area per day, but the dose and duration of treatment depend on the type and dose of other cytotoxic drugs used together with 6 - mercaptopurine.
Doses should be selected depending on the individual characteristics of the patient.
Mercaptopurine was used in various schemes of combined treatment of acute leukemia.
A study involving children with acute lymphoblastic leukemia indicates that the appointment of Mercaptopurine in the evening reduces the risk of relapse of the disease as compared with the morning.
Children with overweight may require a dose of the upper limit of the dosing range, and therefore it is recommended that careful monitoring of the therapeutic response to treatment in such patients is recommended.
In elderly patients, it is recommended that kidney and liver function be monitored and, when they are disrupted, the dose of Mercaptopurine should be reduced.
Impaired renal function
It is recommended to administer reduced doses of Mercaptopurine in cases of impaired renal function.
Impaired liver function
It is recommended to prescribe reduced doses of Mercaptopurine for violations of liver function.
Interactions with drugs
When used simultaneously with xanthine oxidase inhibitors, for example with allopurinol, the dose of Mercaptopurine should be reduced 4-fold, as allopurinol reduces the catabolism rate of Mercaptopurine.
Patients with a shortage of TMP
In patients with inherited little or no activity of S-methyltransferase (TPMT), there is an increased risk of developing severe toxic effects of Mercaptopurine treatment when used in normal doses, usually requiring a significant reduction in the dose of the drug. The optimal initial dose for homozygous patients with a deficiency of this enzyme is not established.
The majority of heterozygous patients with TMP deficiency can tolerate recommended doses of Mercaptopurine, but some patients sometimes have to reduce doses. In clinical practice, available tests for genotyping and phenotyping TPMT.
The drug is used in pediatric practice.
Symptoms and signs
Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and anorexia, may be early signs of an overdose. The main toxic effect is the effect on the bone marrow, which leads to myelosuppression. Hematological toxicity is more pronounced in chronic overdose than with a single dose of a large dose of the drug. Also, there are violations of the liver and gastrointestinal tract.
The risk of overdose rises if allopurinol is used together with Mercaptopurine.
Since the antidote for the drug is not known, blood parameters should be carefully monitored and appropriate maintenance therapy should be carried out, if necessary, blood transfusion. Active methods (such as the use of activated carbon) in case of an overdose of Mercaptopurine can be effective only within 60 minutes after taking the drug.
Further treatment of cases of overdose should be based on clinical indications or recommendations of the State Toxicology Center (if available).
Active ingredient: 6 mercaptopurine;
1 tablet contains Mercaptopurine 50 mg
Excipients: lactose, corn starch, oxidized starch, magnesium stearate, stearic acid.
Basic physical and chemical properties: round, biconvex tablets of pale yellow color, on one side with a notch and an engraving "GX" above it and "EX2" under it, on the other hand are smooth.
Antineoplastic agents. Antimetabolites. Structural analogues of purine. ATX code L01B B02.
Store in the original packaging at a temperature not higher than 25 ° C in a place inaccessible to children.
For 30,60,90 tablets in a vial.