Alimta^® (Lyophilisate) Instructions for Use

ATC Code

L01BA04 (Pemetrexed)

Active Substance

Pemetrexed (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; antimetabolites; folic acid analogues

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 protein folate-binding 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 T_1/2, thereby increasing the duration of the drug’s action on tumor cells.

In studies in vitro, a synergy of antitumor action was observed with the combined use of pemetrexed and cisplatin.

Pharmacokinetics

At steady state, the V_d of pemetrexed is 16.1 L. Binding to plasma proteins is approximately 81%.

Pemetrexed is limitedly metabolized 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, binding to plasma proteins 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 intravenously as an infusion over 10 minutes.

Calculate the dose based on body surface area (BSA).

The recommended dose for most indications is 500 mg/m².

Administer pemetrexed prior to cisplatin when used in combination.

Repeat the infusion every 21 days.

Perform complete blood count (CBC) before each dose.

Do not administer if the absolute neutrophil count (ANC) is less than 1500 cells/mm³.

Do not administer if the platelet count is less than 100,000 cells/mm³.

Initiate vitamin supplementation to reduce toxicity.

Administer folic acid (350-1000 mcg) orally daily, beginning 7 days before the first dose.

Continue folic acid daily throughout therapy and for 21 days after the last dose.

Administer vitamin B12 (1000 mcg) intramuscularly, 1 week before the first dose.

Repeat vitamin B12 injections every 3 cycles thereafter.

Administer dexamethasone (4 mg) orally twice daily.

Give dexamethasone the day before, the day of, and the day after pemetrexed administration to reduce the risk of skin rash.

Adjust dosage for renal impairment based on creatinine clearance (CrCl).

For CrCl 45-79 mL/min, reduce dose to 75% of the standard dose.

Do not administer for CrCl less than 45 mL/min.

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

For nadir ANC < 500/mm³ and platelets ≥ 50,000/mm³, reduce dose to 75% of the previous dose.

For nadir platelets < 50,000/mm³ without bleeding, regardless of ANC, reduce dose to 75% of the previous dose.

For nadir platelets < 50,000/mm³ with bleeding, regardless of ANC, reduce dose to 50% of the previous dose.

For grade 3 or 4 non-hematologic toxicity (excluding nausea/vomiting), reduce dose to 75% of the previous dose.

Discontinue therapy for any grade 3 or 4 toxicity occurring after two dose reductions, or for persistent grade 3 or 4 non-hematologic toxicity.

Reconstitute the 500 mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative-free).

This yields a solution containing 25 mg/mL of pemetrexed.

Gently swirl the vial until the powder is fully dissolved.

The resulting solution is clear and ranges from colorless to yellow or green-yellow.

Further dilute the calculated dose in 100 mL of 0.9% Sodium Chloride Injection (preservative-free).

Use the reconstituted and diluted solution immediately.

Administer the infusion using a non-PVC lined administration set.

Do not administer as a bolus or rapid intravenous push.

Do not mix with other medications or diluents containing calcium.

Do not co-administer with other drugs through the same intravenous line.

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

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

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 for grade 3-4 hematological and non-hematological toxicity, 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, and with combined use 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). When prescribing ibuprofen together with pemetrexed in patients with mild or moderate renal impairment (CrCl 45-79 ml/min), caution is necessary.

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 15°C (59°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.