MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

Drug package leaflet of

(information for patients)

MERCAPTOPURINE

Trade name: Mercaptopurine

International nonproprietary name: Mercaptopurine

Appearance: light yellow flat round beveled tablets. Roughness and inclusions are acceptable on the surface of tablets.

Composition: each tablet contains: active ingredient: mercaptopurine – 50 mg; excipients: lactose monohydrate, sodium starch glycolate type A, calcium stearate, potato starch.

Pharmaceutical form: tablets.

Pharmacotherapeutic group: Antitumor agents. Antimatabolites.

ATC-code: Lo1BB02

 

Pharmacological action

Mercaptopurine has an antitumor and immunodepressive action. As a result of its action growth of malignancies is inhibited and cytotoxic effect exhibits.

Indications for administration

Acute lymphatic leukemia, acute myeloleukemia (remission induction and supporting therapy).

Official instructions on proper treatment of the above diseases should be taken into account.

Mode of administration and dosage

The drug product I taken orally. Mercaptopurine may be taken with meal or on an empty stomach but the patients should standardize the mode of administration. The drug product should not be taken with milk and dairy products. Mercaptopurine should be taken at least 1 hour prior to and 2 hours after consumption of milk and dairy products. Evening administration of the drug product decreases the risk of recurrence as compared to morning administration of the drug product. Therefore, daily dose of the drug product should be taken in the evening with small amount of water.

For adults and children initial dose is 2.5 mg/kg or 50-75 mg/m2 per day during 4 weeks; subsequently, the dose is adjusted depending on the effect and state of bone-marrow hemopoiesis, nature and dosages of other cytostatics prescribed in the combination with mercaptopurine according to the treatment protocol. In case of good tolerance during 4 weeks and inadequate effect intensity, the dose may be increased up to 5 mg/kg per day but not more. Supporting dose: 1.5-2.5 mg/kg or 75 mg/m2 per day.

Children: 2.5 mg/kg or 50-75 mg/m2 per day. Daily dose is prescribed on a single occasion or in several administrations.

In case of initial symptoms of leucopenia, administration of the drug product is recommended to suspend for 2-3 days. If leucopenia does not exacerbate, treatment is restarted.

Allopurinol and other inhibitors of xanthine oxidase decreases the rate of catabolism of 6-mercaptopurine. In case of concomitant administration with allopurinol, dose of mercaptopurine should be decreased up to ¼ of the usual does. Administration of other inhibitors of xanthine oxidase should be avoided.

Dosage regimen in patients with congenital deficiency of thiopurine methyltransferase (TPMT):

Patients with low/intermittent activity or TPMT deficiency are in the group of higher risk of mercaptopurine toxicity development following standard doses, and, as a rule, require significant dose reduction. Initial dose for such patients are not established.

Dosage regimen in elderly patients:

Special studies on elderly patients have not been carried out. Nevertheless, it is recommended to monitor laboratory parameters of kidney and liver function in such patients, and, in case of serious changes, decrease in the dose of the drug product should be considered.

Dosage regimen in patients with kidney/liver failure:

For patients with kidney failure it is reasonable to start treatment with lower doses due to slow elimination of mercaptopurine and its metabolites and high cumulative effect. Dose decrease in patients with impaired liver function should be considered.

Side effects

Blood-forming organs: anemia, leucopenia, neutropenia, agranulocytosis, thromcocytopenia, pancytopenia.

Digestive system : anorexy, nausea, vomiting, diarrhea, hepatorenal syndrome, intrahepatic cholestasis (hepatotoxicity has toxic allergic genesis and more often occurs in case of exceeding the recommended dose of 2.5 mg/kg or 50-75 mg/m2 daily); mouth mucosa ulceration; rarely – intestinal mucosa ulceration, pancreatitis.

Immune system: arthralgia, skin rash, drug fever, face edema.

Skin and appendages of skin: alopecia.

Reproductive system: transient oligospermia.

Other: hypersensitivity, decrease in immunity, secondary infections, dermatomelasma; hyperuricemia and nephropathy due to tumor lysis; very rare – secondary leucosis and myelodysplasia.

Mutagenicity and carcinogenicity are potential.

Contraindications

-          Hypersensitivity to mercaptopurine or any component of the drug product;

-          Resistance to mercaptopurine and thioguanin in the past medical history;

-          Concomitant administration with vaccine against yellow fever;

Taking into account indications for use for mercaptopurine, there are no absolute contraindications to its prescription.

The remaining information is given in the relevant sections and subsections – “Precautions”, “Pregnancy and lactation”.

Overdosage

Symptoms: immediate – nausea, vomiting, anorexy, diarrhea; delayed – myelosuppression, liver function abnomality, gastroenteritis.

Treatment: symptomatic (text is illegible – translator’s note; hemodialysis is virtually ineffective). For the first 60 minutes after overdosage, vomiting may be induced and gastric lavage is carried out.

Precautions

To avoid complications, mercaptopurine should be administered under medical supervision only. Physicians should be experienced in using cytostatics. During treatment, complete blood count should be daily carried out. Early detection of hepatotoxicity is provided by regular “liver” tests (weekly – at the beginning of therapy, monthly – during supporting period): “liver” transaminases, alkaline phosphatase, bilirubin. In patients who earlier had liver diseases or who receive other potentially hepatotoxic drug products, such analyses should be carried out more often. Patients should be warned of immediate treatment cessation if jaundice occurs. During remission induction, when rapid cell lysis occurs, concentration of uric acid in the blood and urine should be monitored to avoid hyperuricemia and/or hyperuricosuria and risk of uric nephrourolithiasis. To prevent hyperuricemia, abundant drinking is recommended, if required – allopurinol and urine alkalization.

Myelosuppression is reversible in case of concomitant cessation of the drug product. Upon completion of treatment, number of leucocytes and thrombocytes may continue to decrease (delayed effect) therefore, in case of early symptoms of too rapid decrease in their quantity, treatment should be suspended.

Patients with congenital deficiency of thiopurine methyltransferase (TPMT) are to a greater extent subject to rapid development of myelosuppression after mercaptopurine prescription. Therefore, if possible, genetic and phenotypic analysis of thiopurine methyltransferase (TPMT) activity should be performed.

Due to the fact that there is no any antidote, close monitoring of blood picture is recommended and, if required, supporting therapy and blood transfusion.

During treatment of any sexual partner, it is recommended to use reliable contraceptive methods.

With care, mercaptopurine should be administered in patients with gout or nephrourolithiasis in past medical history who received antitumor or radiation treatment. In patients with decreased kidney/liver function, it is required to adjust a dosage regimen. In patients with inhibited bone-marrow hemopoiesis, acute virus (including chicken pox, herpes zoster), fungal and bacterial diseases, sucrose/isomaltose deficiency, fructose intolerance, mercaptopurine should be administered with care.

The drug product contains lactose. Due to this, it is not recommended for patients with congenital galactosemia, Lapp lactase deficiency and galactose/glucose malabsorption.

With care, mercaptopurine is administered in children under 2 years of age.

Care is recommended in manipulations with tablets (e.g. dividing into two parts) to avoid hand contamination and drug product inhalation.

In patients with congenital deficiency of thiopurine methyltransferase (TPMT), administration of mercaptopurine may result in severe myelosuppression. In concomitant administration of drug products inhibiting TPMT (e.g. olsalazine, mesalazine, sulphasalazine), severe myelosuppresion may exacerbate. Interrelation of decreased TPMT activity, secondary leukemia and myelodysplasia in patients receiving mercaptopurine in the combination with other cytotoxic drug products is potential.

If possible, prior to treatment with mercaptopurine, it is required to monitore TPMT activity . Some laboratories have the relevant equipment to monitor TPMT activity. Nevertheless, this test is optional in determination of patients with higher risk of toxicity during treatment with mercaptopurine.

During treatment with mercaptopurine, immunization with vaccines containing live microorganisms is not recommended. Contact with persons vaccinated against poliomyelitis and patients with bacterial infections should be avoided. Administration of vaccines containing live microorganisms in patients with leucosis at the stage of remission is not recommended at least during 3 months after the last course of chemotherapy. Immunization with oral vaccine against poliomyelitis of people in close contact to such patients, especially members of the family, should be delayed.

According to experimental studies, mercaptopurine has carcinogenic and mutagenic effects.

Increase in chromosome aberrations in lymphocytes of the peripheral blood was evident in patients with leucosis, and in a patient with hypernephroma received mercaptopurine in an unspecified dose, and in patients with chronic kidney diseases received mercaptopurine in the dose of 0.4-1.0 mg/kg/per day.

Two cases of acute myeloleucosis in patients received mercaptopurine in the combination with other drug products for non-tumor diseases were described. A single case where the patient was treated with mercaptopurine for pyoderma gangrenosum and acute myeloleucosis occurred but it is not known if mercaptopurine was a reason for the disease.

A case of acute myeloleucosis in a patient with Hodgkin’s disease received mercaptopurine in the combination with many other cytotoxic drugs was evident.

A case of chronic myeloleucosis in a patient 12.5 years after treatment with mercaptopurine for myasthenia was described.

Cases of hepatosplenic T-cell lymphoma in patients with intestine inflammatory disease may be obtained in case of administration of mercaptopurine in the combination with anti-TNF drugs.

Mercaptopurine has a mutagenic effect as well, causes chromosomal aberrations in the cells of animals and humans and causes DML in rat males. Mercaptopurine has embryo toxic effect. In rat embryos, the drug product causes pathological changes. Effect of mercaptopurine on human fertility both for men and women has been studied inadequately.

Use across pregnancy and lactation. Administration of the drug product across pregnancy is possible for life saving only. Mercaptopurine has a teratogenic effect. Administration of the drug product across pregnancy should be avoided, especially in I trimester. In each individual case, expected benefit of the treatment for mother and potential risk for fetus should be assessed. As in case of treatment with any cytotoxic drugs, during administration of mercaptopurine, any sexual partner should take measures on birth control and use reliable contraceptives. According to experimental studies, mercaptopurine has a toxic effect on fetus of animals. Effect of the drug product on human fetus has been studied inadequately. In pregnant women received mercaptopurine as monotherapy across the whole pregnancy, healthy babies were born. At the same time, cases of spontaneous abortions, premature labor and various disorders in fetus were described. Numerous congenital abnormalities were registered after treatment with mercaptopurine in the combination with other antitumor agents. Effect of mercaptopurine on human fertility has been studied inadequately but there are reports on birth of babies in men and women receiving mercaptopurine in childhood or adolescence. Transient pronounced oligospermia was evident in a young men receiving mercaptopurine in the dose of 150 mg/per day in the combination with prednisolone in the dose of 80 mg/per day for acute leucosis. 2 years after chemotherapy, spermogram of the patient normalized, and he became father of a normal baby. Women receiving mercaptopurine should refrain from breastfeeding. In case of necessity for administration of the drug product during lactation, breastfeeding should be stopped.

Effect on ability to drive and be involved in other potentially hazardous activities: not studies.

Interactions with other drug products

In concomitant administration with drug products blocking tubular secretion (especially with uricosuric anti-gout drug products – probenecid, sulfinpyrazone, colchicines), risk of nephropathy is increased. Vincristine and methotrexat increase (mutually) activity and toxicity.

In concomitant administration of allopurinol and mercaptopurine, dose of mercaptopurine is decreased 4-fold, as allopurinol decreases metabolism rate of 6-mercaptopurine by effect of xanthine oxidase. Other inhibitors of xanthine oxidase such as febuzostat, azathioprine may also decrease the rate of mercaptopurine metabolism. Therefore, their concomitant administration is not recommended due to the absence of adequate data for adequate adjustment of mercaptopurine dose.

In case of concomitant administration with indirect anticoagulants, mercaptopurine may increase anticoagulant activity and/or risk of bleeding following decreased liver synthesis of blood-coagulation factors and impaired formation of thrombocytes, or decrease anticoagulant activity by potentiation of prothrombin synthesis or activation.

There is data on inhibition of anticoagulant effect of warfarin in concomitant administration with mercaptopurine. INR monitoring in concomitant administration of mercaptopurine with oral anticoagulants is recommended.

Drug products inhibiting bone-marrow hemopoeisis (including co-trimoxazole), cytostatics as well as radiation therapy increase intensity of leucopenia and thrombocytopenia.

Cytostatics may lead to decreased absorption of phenytoin in the intestine. Regular monitoring of phenytoin concentration in the blood serum is recommended. Changes in concentration of other antiepileptic drugs in the blood serum may occur. Therefore, their concentration in the blood serum adjusting the dose of mercaptopurine if required is recommended.

In concomitant administration with glucocorticosteroids, azathioprine, chlorambucil, cortico tropin, cyclophophamide and cyclosporine, risk of infections and secondary tumors (potentiation of immunodepressive effect) is increased.

Concomitant administration with doxorubicin significantly increases the risk of hepatotoxicity.

Cross stability of cells to mercaptopurine and thioguanin is evident.

In concomitant administration with amyl salicylate derivatives (e.g. with olsalazine, mesalazine, sulphasalazine) inhibiting thiopurine methyltransferase (TPMT), risk of myelosuppression is increased. Concomitant administration of mercaptopurine and vaccine against yellow fever is contraindicated due to the risk of lethal disease in patients with compromised immunity. Combination of mercaptopurine with administration of other live vaccines is not recommended in patients with compromised immunity. Combination with live virus vaccines may cause intensification of vaccine virus replication. Intensification of side effect of the vaccine and decreased antibody production in response to administration of both live and inactivated vaccines are possible.

Concomitant administration of mercaptopurine with food may insignificantly decrease systemic effect of the drug product which is likely not of clinical significance. Therefore, mercaptopurine may be administered both with meal or on an empty stomach but the patients should standardize the mode of administration. The drug product should not be taken with milk and dairy products as they contain xanthine oxidase enzyme which metabolizes 6-mercaptipurine which may result in decreased concentration of mercaptopurine in the blood plasma.

Storage conditions

Keep in a place protected from light and humidity at a temperature not above 25°C.

Keep out of reach of children.

Shelf life

5 years.

Do not use after the expiration date specified on the package.

Package

10 tablets in a blister, 50 tablets in a vial, 1 or 5 blisters or 1 vial with instruction for use in a carton package. Package for in-patient hospitals: 100 blisters or 40 vials with the relevant number of instructions for use in a carton package.

Pharmacy purchasing terms

On prescription.

Manufacturer:

Belmedpreparaty RUE

30 Fabritsiusa St., 220007 Minsk, Republic of Belarus

Tel./Fax: (+375 17) 220 37 16

e-mail: medic@belmedpreparaty.com