Ispolat^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Laboratorio Tuteur S.A.C.I.F.I.A. (Argentina)

Manufactured By

Laboratorio Ima S.A.I.C. (Argentina)

Packaging and Quality Control Release

Laboratorio TUTEUR S.A.C.I.F.I.A. (Argentina)

ATC Code

L01BA04 (Pemetrexed)

Active Substance

Pemetrexed (Rec.INN registered by WHO)

Dosage Form

Ispolat®

Lyophilizate for preparation of solution for infusion 500 mg: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for infusion in the form of a lyophilized powder from almost white to yellowish color; reconstituted solution: a clear or slightly opalescent, colorless or from light yellow to greenish-yellow solution.

Excipients: mannitol – 500 mg.

Colorless glass vials with a capacity of 50 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor agent, antimetabolite. It is an antifolate, inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) – key folate-dependent enzymes in the biosynthesis of thymidine and purine nucleotides. Pemetrexed enters cells via the reduced folate carrier and folate-binding protein transport systems. Upon entering the cell, Pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthase. Polyglutamate forms are retained in cells and are more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. The polyglutamated metabolites have an increased T_1/2, thereby increasing the duration of the drug’s action on tumor cells.

When Pemetrexed and cisplatin were used in combination, a synergistic antitumor effect was observed in in vitro studies.

Pharmacokinetics

At steady state, the V_d of Pemetrexed is 16.1 L. Plasma protein binding is approximately 81%.

Pemetrexed undergoes limited metabolism in the liver.

Within the first 24 hours after administration, 70-90% is excreted by the kidneys unchanged. The total plasma clearance of Pemetrexed is 92 ml/min, T_1/2 from plasma is 3.5 hours in patients with normal renal function.

In severe renal impairment, plasma protein binding does not change.

Indications

Locally advanced or metastatic non-squamous, non-small cell lung cancer – in combination with cisplatin as first-line therapy.

Locally advanced or metastatic non-squamous, non-small cell lung cancer without disease progression after four cycles of first-line platinum-based chemotherapy – for maintenance therapy.

Locally advanced or metastatic, non-squamous, non-small cell lung cancer – as monotherapy for second-line therapy.

Treatment of malignant pleural mesothelioma in patients who have not received prior chemotherapy, with inoperable tumor or in the presence of contraindications to surgery.

ICD codes

Dosage Regimen

Administer as an intravenous infusion over 10 minutes. Calculate the dose using ideal body weight for patients with obesity. The recommended dosage is 500 mg/m² of body surface area.

Administer in combination with cisplatin on day 1 of a 21-day cycle. Infuse pemetrexed first, followed by cisplatin hydration and infusion at a dose of 75 mg/m² approximately 30 minutes after the end of the pemetrexed infusion.

For monotherapy, administer 500 mg/m² on day 1 of a 21-day cycle.

Premedicate with a corticosteroid to reduce the risk and severity of skin rash. Administer dexamethasone 4 mg orally twice daily the day before, the day of, and the day after pemetrexed administration.

Initiate vitamin supplementation to reduce toxicity. Administer folic acid (350-1000 mcg) orally daily, beginning 1-2 weeks before the first dose and continuing until 21 days after the last dose. Administer one intramuscular injection of vitamin B12 (1000 mcg) 1-2 weeks before the first dose and every 3 cycles thereafter.

Assess complete blood count before each cycle. Adjust dosage based on nadir neutrophil count, platelet count, and non-hematologic toxicity from the previous cycle.

For nadir absolute neutrophil count (ANC) <500/µL and platelet count ≥50,000/µL, or for non-hematologic grade 3 toxicity (excluding neurotoxicity), reduce the dose to 75% of the previous dose.

For nadir platelet count <50,000/µL without bleeding, regardless of ANC, or for non-hematologic grade 4 toxicity (excluding neurotoxicity), reduce the dose to 50% of the previous dose.

Discontinue therapy for any hematologic toxicity requiring a dose reduction after two previous dose reductions, or for grade 3 or 4 neurotoxicity.

Adjust dosage for renal impairment. Omit the dose if creatinine clearance (CrCl) is <45 mL/min. For CrCl from 45 to 79 mL/min, no adjustment is required for the initial dose; adjust subsequent doses based on tolerance.

Adverse Reactions

From the hematopoietic system: very often – leukopenia, neutropenia, anemia; often – thrombocytopenia.

From the digestive system: very often – nausea, vomiting, anorexia, stomatitis/pharyngitis, diarrhea, increased ALT and AST levels; often – constipation, abdominal pain.

Dermatological reactions: very often – rash/desquamation; often – skin itching, alopecia; rarely – erythema multiforme.

From the peripheral nervous system: often – sensory or motor neuropathy.

From the urinary system: often – increased creatinine levels.

From the cardiovascular system: rarely – supraventricular tachycardia.

Other: very often – increased fatigue; often – fever, febrile neutropenia, allergic reactions, and secondary infections without neutropenia.

Contraindications

Pregnancy, lactation, hypersensitivity to Pemetrexed.

Pemetrexed is not intended for the treatment of patients with squamous non-small cell lung cancer.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

To assess liver function, periodic biochemical blood tests are necessary.

Use in Renal Impairment

To assess renal function, periodic biochemical blood tests are necessary.

Pediatric Use

Pemetrexed is not recommended for use in pediatrics, as safety and efficacy in children have not been established.

Special Precautions

Before each administration of Pemetrexed, a complete blood count with differential leukocyte count and platelet count must be performed.

To assess renal and liver function, periodic biochemical blood tests are necessary.

Before starting use, the absolute neutrophil count should be ≥1500/µL, platelets ≥100,000/µL.

Prescription of folic acid and vitamin B₁₂ reduces the toxicity of Pemetrexed and the need for dose reduction due to hematological and non-hematological toxicity of grade 3-4, including neutropenia, febrile neutropenia, and infection with grade 3-4 neutropenia.

Patients with clinical manifestations of ascites and pleurisy require drainage of the effusion before starting Pemetrexed, as the influence of these conditions on the action of Pemetrexed is unknown.

Pemetrexed is not recommended for use in pediatrics, as safety and efficacy in children have not been established.

Drug Interactions

Concomitant use with nephrotoxic drugs and/or substances excreted by the kidneys may reduce the clearance of Pemetrexed.

Results of in vitro studies indicate that Pemetrexed minimally interacts with drugs metabolized by CYP3A, CYP2D6, CYP2C9, CYP1A2.

The pharmacokinetics of Pemetrexed do not change with oral folic acid, intramuscular vitamin B₁₂, or when used in combination with cisplatin. The total clearance of platinum is not impaired with the use of Pemetrexed.

Pemetrexed can be used concomitantly with ibuprofen (400 mg four times/day) in patients with normal renal function (CrCl≥80 ml/min). Caution should be exercised when prescribing ibuprofen together with Pemetrexed in patients with mild or moderate renal impairment (CrCl 45-79 ml/min).

In patients with mild to moderate renal impairment, the use of NSAIDs with a short T_1/2 is not recommended for 2 days before Pemetrexed administration, on the day of administration, and for 2 days after administration.

Due to the lack of data on possible interaction between Pemetrexed and NSAIDs with a long T_1/2, all patients taking NSAIDs should discontinue them at least 5 days before Pemetrexed administration, on the day of administration, and for 2 days after administration. If concomitant administration of NSAIDs is required, patients require strict monitoring for toxicity, especially myelosuppression and gastrointestinal toxicity.

Pemetrexed is incompatible with Ringer’s lactate solution and Ringer’s solution.

Concomitant use of Pemetrexed with other drugs and solutions has not been studied and is therefore not recommended.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.