Pemjem^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

L01BA04 (Pemetrexed)

Active Substance

Pemetrexed (Rec.INN registered by WHO)

Dosage Form

Pemjem®

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

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for infusion as a mixture of powder and porous mass from white to light yellow or greenish-yellow in color.

Excipients: mannitol – 500 mg, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% – q.s.

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

Antineoplastic 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.

Polyglutamated metabolites have an increased T_1/2, thereby increasing the duration of the drug’s action on tumor cells.

In combined use of pemetrexed and cisplatin, 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 not previously treated with 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 pemetrexed dose based on body surface area. The recommended dose for most indications is 500 mg/m².

Administer pemetrexed prior to cisplatin when used in combination. Initiate cisplatin infusion approximately 30 minutes after the end of the pemetrexed infusion. Prehydrate the patient as per the cisplatin prescribing information.

Repeat the administration cycle every 21 days. Perform complete blood count monitoring prior to each dose. Absolute neutrophil count must be ≥1500 cells/mm³ and platelet count must be ≥100,000 cells/mm³ prior to therapy.

Initiate folic acid supplementation at a dose of 400-1000 mcg daily. Begin supplementation 7 days before the first pemetrexed dose and continue daily throughout therapy and for 21 days after the last dose.

Administer vitamin B12 as a 1000 mcg intramuscular injection. Give the first injection 7 days before the first pemetrexed dose and repeat every 3 cycles thereafter.

Administer dexamethasone (or equivalent) at a dose of 4 mg twice daily. Start the day before pemetrexed administration and continue on the day of and the day after to reduce the risk and severity of skin rash.

For preparation, reconstitute the 500 mg vial with 4.8 ml of 0.9% Sodium Chloride Injection, resulting in a solution containing 25 mg/ml pemetrexed. Gently swirl until the powder is fully dissolved. The resulting solution is clear and ranges from colorless to yellow or green-yellow.

Further dilute the reconstituted solution in 100 ml of 0.9% Sodium Chloride Injection. Use the solution immediately. The chemical and physical stability of the diluted solution has been demonstrated for up to 24 hours when stored refrigerated at 2°C to 8°C (36°F to 46°F). Do not refrigerate if administered without delay.

Do not use Ringer’s Lactate solution or other solutions containing calcium for dilution. Administer the infusion using a non-PVC lined administration set with a 0.22 micrometer in-line filter. Do not administer as a bolus or rapid intravenous push.

Adjust the dose based on hematologic and non-hematologic toxicity from the previous cycle. For nadir ANC <500/µL and platelets ≥50,000/µL, or for platelets <50,000/µL without bleeding, administer 75% of the previous dose. For platelets <50,000/µL with bleeding, administer 50% of the previous dose.

For non-hematologic toxicity (excluding neurotoxicity), administer 75% of the previous dose for any Grade 3 toxicity (except mucositis) and 50% for any Grade 4 toxicity (except mucositis). For Grade 3 or 4 mucositis, administer 50% of the previous dose. Discontinue therapy for any Grade 3 or 4 neurotoxicity.

Adjust the dose in patients with renal impairment. For CrCl ≥45 mL/min, administer the full dose (500 mg/m²). For CrCl <45 mL/min, do not administer pemetrexed. No dose adjustment is recommended for patients with mild to moderate hepatic impairment based on clinical studies. Use in patients with severe hepatic impairment is not recommended.

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 during lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

To assess liver function, periodic biochemical blood tests should be performed.

Use in Renal Impairment

To assess renal function, periodic biochemical blood tests should be performed.

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 should be performed.

To assess renal and liver function, periodic biochemical blood tests should be performed.

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 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.

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 administration of folic acid, intramuscular administration of vitamin B₁₂, or 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 4 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 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.