Verotrexed^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Veropharm, LLC (Russia)

ATC Code

L01BA04 (Pemetrexed)

Active Substance

Pemetrexed (Rec.INN registered by WHO)

Dosage Forms

	Verotrexed®	Lyophilisate for preparation of solution for infusion 100 mg: vial.
		Lyophilisate for preparation of solution for infusion 500 mg: vial.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion from white to yellowish or yellowish-green in color.

Excipients: mannitol – 100 mg, hydrochloric acid or sodium hydroxide* – to adjust pH to 6.6-7.8.

* Used if necessary for pH adjustment during the manufacturing process.

Colorless glass vials (type I) (1) – cardboard packs.
Colorless glass vials (type I) (50) – cardboard boxes (for hospitals).
Colorless glass vials (type I) (100) – cardboard boxes (for hospitals).

Lyophilisate for preparation of solution for infusion from white to yellowish or yellowish-green in color.

Excipients: mannitol – 500 mg, hydrochloric acid or sodium hydroxide* – to adjust pH to 6.6-7.8.

* Used if necessary for pH adjustment during the manufacturing process.

500 mg – Colorless glass vials (type I) (1) – cardboard packs.
500 mg – Colorless glass vials (type I) (50) – cardboard boxes (for hospitals).
500 mg – Colorless glass vials (type I) (100) – cardboard boxes (for hospitals).

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor agent, antimetabolite. It is an antifolate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and 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 membrane 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.

Polyglutamated metabolites have an increased half-life, thereby increasing the duration of the drug’s action on tumor cells.

Synergistic antitumor action was observed in vitro studies with the combined use of pemetrexed and cisplatin.

Pharmacokinetics

At steady state, the volume of distribution (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, and the plasma half-life 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 based on body surface area. The recommended dose is 500 mg/m².

Administer prior to cisplatin. Repeat the cycle every 21 days.

For combination therapy with cisplatin, administer pemetrexed first, followed 30 minutes later by cisplatin.

Premedicate with corticosteroids 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 infusion.

Initiate vitamin supplementation to reduce toxicity. Administer folic acid 400-1000 mcg orally daily, beginning 7 days before the first dose and continuing until 21 days after the last dose.

Administer vitamin B12 1000 mcg intramuscularly once during the week before the first dose and then every 3 cycles.

Obtain a complete blood count before each dose. Do not administer if the absolute neutrophil count is below 1500 cells/mm³ or platelets are below 100,000 cells/mm³.

Assess renal function before each cycle. Do not administer if creatinine clearance is below 45 mL/min.

For toxicity, modify the dose based on nadir counts and non-hematologic toxicity from the previous cycle.

Reconstitute the 100 mg vial with 4.2 mL and the 500 mg vial with 20 mL of 0.9% Sodium Chloride Injection. Resulting concentration is 25 mg/mL.

Gently swirl until powder is dissolved. The solution should be clear and colorless to yellow or green-yellow.

Further dilute the calculated dose in 100 mL of 0.9% Sodium Chloride Injection. Use immediately. The diluted solution is stable for 24 hours at 2°C to 8°C or at room temperature for 24 hours without light protection.

Do not use with Ringer’s Lactate solution for reconstitution or dilution. Administer via a free-flowing IV line. Flush the line with 0.9% Sodium Chloride Injection before and after administration.

Adverse Reactions

Hematologic system: very common – leukopenia, neutropenia, anemia; common – thrombocytopenia.

Digestive system: very common – nausea, vomiting, anorexia, stomatitis/pharyngitis, diarrhea, increased ALT and AST levels; common – constipation, abdominal pain.

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

Peripheral nervous system: common – sensory or motor neuropathy.

Urinary system: common – increased creatinine levels.

Cardiovascular system: rare – supraventricular tachycardia.

Other: very common – increased fatigue; common – 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

Biochemical blood tests should be performed periodically to assess liver function.

Use in Renal Impairment

Biochemical blood tests should be performed periodically to assess renal function.

Pediatric Use

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

Special Precautions

A complete blood count with differential leukocyte count and platelet count should be performed before each administration of pemetrexed.

Biochemical blood tests should be performed periodically to assess renal and liver function.

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

Administration 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 effect 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.

In vitro study results indicate that Pemetrexed minimally interacts with drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

The pharmacokinetics of pemetrexed are not altered by oral folic acid, intramuscular vitamin B₁₂, or combined use with cisplatin. The total clearance of platinum is not impaired by pemetrexed administration.

Pemetrexed can be used concomitantly with ibuprofen (400 mg four times daily) in patients with normal renal function (CrCl ≥80 ml/min). Caution is advised when prescribing ibuprofen together with pemetrexed in patients with mild to moderate renal impairment (CrCl 45-79 ml/min).

In patients with mild to moderate renal impairment, the use of short half-life NSAIDs 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 long half-life NSAIDs, 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 NSAID use is required, patients should be strictly monitored 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 25°C (77°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.