Puri-Nethol (Tablets) Instructions for Use

Marketing Authorization Holder

Aspen Pharma Trading, Limited (Ireland)

Manufactured By

Excella, GmbH & Co. KG (Germany)

ATC Code

L01BB02 (Mercaptopurine)

Active Substance

Mercaptopurine (Rec.INN registered by WHO)

Dosage Form

Puri-Nethol

Tablets 50 mg: 25 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, light yellow in color, with a break line on one side of the tablet; the inscription “GX” is embossed above the break line, and the inscription “EX2” is embossed below the break line.

Excipients: lactose monohydrate – 59 mg, corn starch – 10.3 mg, oxidized starch – 4 mg, magnesium stearate – 0.75 mg, stearic acid – 0.15 mg.

25 pcs. – dark glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Puri-Nethol has an antitumor and immunosuppressive effect. It is a competitive antagonist of purine bases. It competes with hypoxanthine and guanine for hypoxanthine-guanine phosphoribosyltransferase.

It is transformed into mercaptopurine phosphoribosyl, which, under the influence of thiopurine methyltransferase, turns into methylmercaptopurine. Both of them inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase – the first enzyme in the synthesis of purine ribonucleotides.

As a result, the mitotic cycle (S-phase) is disrupted, especially in rapidly proliferating cells of the bone marrow and tumors, the growth of malignant neoplasms is inhibited, and a cytotoxic effect is manifested.

Pharmacokinetics

Absorption after oral administration is variable, averaging about 50%, which is associated with the first-pass metabolism through the liver of a significant portion of the ingested mercaptopurine.

The C_max of mercaptopurine in plasma is noted on average after 2.2 hours (0.5-4 hours).

It poorly penetrates the blood-brain barrier and is found in the cerebrospinal fluid in insignificant amounts. Plasma protein binding is about 20%.

The T_1/2 of mercaptopurine is approximately 90-130 minutes. The pharmacological effect is largely due to metabolites, which are excreted by the kidneys through tubular secretion and glomerular filtration.

Metabolites are detected in the urine as early as 2 hours after administration, 46% of the drug is excreted during the first day. Metabolites continue to be detected in the urine for several weeks after cessation of treatment; the metabolites are pharmacologically active and have a longer half-life than Mercaptopurine itself.

After oral administration, the following are detected in the urine: the unchanged drug, 6-thiouric acid (formed as a result of direct oxidation involving xanthine oxidase) and several methylated thiopurines.

Increased toxicity when co-administered with allopurinol is associated with the latter’s blockade of xanthine oxidase and, accordingly, the accumulation of pharmacologically active substances.

Indications

• Acute lymphoblastic leukemia;
• Acute myeloid leukemia;
• Chronic myeloid leukemia (remission induction and maintenance therapy).

ICD codes

Dosage Regimen

Orally.

Puri-Nethol can be used both as monotherapy and in combination with other cytostatics in various doses depending on the treatment regimen. When individually selecting the dose, one should be guided by data from specialized literature.

Usually for adults and children, the dose is 50-75 mg/m² or 2.5 mg/kg/day; subsequently, the daily dose of Puri-Nethol is adjusted depending on the effect and the state of bone marrow hematopoiesis.

At the first signs of severe leukopenia, it is recommended to interrupt administration for 2-3 days. If leukopenia does not worsen during this time, treatment is resumed.

In elderly patients, it is recommended to monitor liver and kidney function. If signs of renal or hepatic insufficiency are detected, the dose should be reduced.

In patients with hepatic and/or renal insufficiency, the dose must be reduced.

When used concomitantly with allopurinol, the dose of mercaptopurine should be reduced to 25% of the standard dose, since allopurinol reduces the rate of metabolism of mercaptopurine.

Adverse Reactions

By frequency, adverse effects were divided into the following categories: very common ≥ 1/10; common ≥ 1/100 and <1/10; uncommon ≥ 1/1000 and <1/100; rare ≥ 1/10,000 and < 1/1000; very rare <1/10,000.

From the hematopoietic organs: very common – leukopenia, thrombocytopenia, anemia.

From the immune system: hypersensitivity reactions: rare – arthralgia, skin rash, drug fever; very rare – facial edema.

From the digestive system: common – nausea, vomiting, anorexia, intrahepatic cholestasis, hepatotoxicity (hepatotoxicity has a toxic-allergic genesis and more often occurs when the recommended dose of 2.5 mg/kg/day or 75 mg/m²/day is exceeded); rare – ulceration of the oral mucosa, diarrhea, pancreatitis, hepatonecrosis; very rare – ulceration of the intestinal mucosa.

From the skin and skin appendages: rare – alopecia.

From the reproductive system: very rare – transient oligospermia.

Other: decreased immunity, addition of secondary infections, skin hyperpigmentation; hyperuricemia and nephropathy due to tumor lysis; very rare – development of secondary leukemias, myelodysplasia and hepatosplenic T-cell lymphoma when used in combination with tumor necrosis factor antagonists (anti-TNF therapy).

Contraindications

• Pregnancy;
• Breastfeeding period.
• Hypersensitivity to mercaptopurine or other components included in the drug.

With caution – suppression of bone marrow hematopoiesis, acute viral (including chickenpox, herpes zoster) fungal and bacterial diseases, renal and/or hepatic insufficiency, hyperuricemia, gout or urate nephrolithiasis, age under 2 years.

Use in Pregnancy and Lactation

Contraindication: pregnancy, breastfeeding period.

Use in Hepatic Impairment

In patients with hepatic insufficiency, the dose must be reduced.

Use in Renal Impairment

In patients with renal insufficiency, the dose must be reduced.

Pediatric Use

With caution – age under 2 years. Usually for children, the dose is 50-75 mg/m² or 2.5 mg/kg/day; subsequently, the daily dose of Puri-Nethol is adjusted depending on the effect and the state of bone marrow hematopoiesis.

Geriatric Use

In elderly patients, it is recommended to monitor liver and kidney function. If signs of renal or hepatic insufficiency are detected, the dose should be reduced.

Special Precautions

Puri-Nethol should be used only under the supervision of physicians experienced in the use of cytostatics.

Treatment should be carried out under careful monitoring of a complete blood count (daily monitoring is recommended during remission induction), as well as liver function tests (weekly at the beginning of therapy, monthly during maintenance therapy) and serum uric acid levels.

Delayed myelotoxic effects may be observed with the use of the drug.

If the number of leukocytes and platelets decreases below the permissible level, if there is a tendency to bleed, or if jaundice or other signs of hepatotoxicity appear, Puri-Nethol should be discontinued. If Puri-Nethol is discontinued in a timely manner, myelosuppression and hepatotoxicity are reversible.

During the induction of remission of acute myeloid leukemia, patients often experience a period of relative bone marrow aplasia, which requires appropriate supportive therapy.

To prevent hyperuricemia, plenty of fluids are recommended, if necessary allopurinol and urine alkalinization.

The drug may increase the risk of secondary malignant neoplasms, as well as nephropathy due to increased uric acid formation.

In rare cases, some people have a congenital deficiency of the enzyme thiopurine methyltransferase (TPMT). Patients with TPMT deficiency may be more susceptible to rapid development of myelosuppression after administration of Puri-Nethol.

A possible association between reduced thiopurine methyltransferase activity and secondary leukemia and myelodysplasia in individuals receiving Puri-Nethol in combination with other cytotoxic drugs has also been reported.

During treatment of either sexual partner, reliable methods of contraception are recommended.

Care must be taken when handling Puri-Nethol tablets to avoid hand contamination or inhalation of the drug.

During treatment and for at least 3 months after, vaccination with live vaccines should be avoided and contact with people immunized with live vaccines should be avoided.

Overdose

Symptoms: immediate – nausea, vomiting, anorexia, diarrhea; delayed – myelosuppression, impaired liver function, gastroenteritis.

The risk of overdose increases with simultaneous use of allopurinol.

Treatment: symptomatic (no effective antagonist, hemodialysis is practically ineffective). Within the first 60 minutes after an overdose, activated charcoal can be taken orally.

Treatment should be based on the clinical picture or according to the recommendations of the national toxicology center.

Drug Interactions

When used concomitantly with drugs that block tubular secretion (especially uricosuric anti-gout drugs – probenecid, sulfinpyrazone, colchicine), the risk of nephropathy increases.

Vincristine and methotrexate increase (mutually) activity and toxicity.

Allopurinol and azathioprine reduce the intensity of mercaptopurine metabolism by blocking xanthine oxidase.

It enhances the effect of indirect anticoagulants, thereby increasing the risk of bleeding.

Drugs that suppress bone marrow hematopoiesis (including co-trimoxazole), cytostatics, as well as radiation therapy increase the severity of leukopenia and thrombocytopenia.

When used concomitantly with glucocorticosteroids, azathioprine, chlorambucil, corticotropin, cyclophosphamide and cyclosporine, the risk of infection and secondary tumors increases (enhancement of immunosuppressive effect).

Concomitant use with doxorubicin significantly increases the risk of hepatotoxicity.

Cross-resistance of cells to mercaptopurine and thioguanine derivatives has been noted.

When drugs that inhibit thiopurine methyltransferase (for example, olsalazine, mesalazine, sulfasalazine) are prescribed simultaneously – more rapid development of myelosuppression.

In combination with live viral vaccines, it can cause intensification of the replication process of the vaccine virus. It is possible to enhance the side effects of the vaccine and reduce the production of antibodies in response to the administration of both live and inactivated vaccines.

Storage Conditions

List A. At a temperature not exceeding 25°C (77°F) in a dry place, protected from light and out of reach of children.

Shelf Life

Shelf life – 5 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.