Antifol

Pemetrexed is a folate metabolic inhibitor belonging to the class of antifolate antineoplastic agents.

It disrupts folate-dependent metabolic processes essential for cell replication by inhibiting multiple folate-dependent enzymes involved in the biosynthesis of thymidine and purine nucleotides.

Pemetrexed is available as a sterile lyophilized powder for intravenous infusion.

Strengths available

• 100 mg
• 500 mg

Pemetrexed is indicated for

• Nonsquamous Non-Small Cell Lung Cancer (NSCLC)

• Malignant Pleural Mesothelioma

It is used

• In combination with Cisplatin for the treatment of malignant pleural mesothelioma

• In combination therapy for nonsquamous NSCLC

• As maintenance therapy following first-line treatment

• As second-line therapy in eligible patients

Pemetrexed has demonstrated efficacy in patients with nonsquamous non-small cell lung cancer and malignant pleural mesothelioma.

It is widely used as a folate antimetabolite that inhibits tumor cell replication by disrupting DNA and RNA synthesis pathways.

Clinical studies have demonstrated its utility both as a maintenance therapy and as part of combination regimens with Cisplatin.

Patients receiving Pemetrexed should undergo regular monitoring of

• Complete blood counts
• Platelet counts
• Renal function
• Hepatic function

Vitamin supplementation with

• Folic Acid
• Vitamin B12

is required to reduce treatment-related toxicity.

Patients should not begin a new treatment cycle unless:

• ANC is ≥ 1500 cells/mm³
• Platelet count is ≥ 100,000 cells/mm³
• Creatinine clearance is ≥ 45 mL/min

Combination Use with Cisplatin for Nonsqamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma

The recommended dose of Pemetrexed is 500 mg/m² infused over 2 hours beginning approximately 30 minutes after the end of the cycle.

The recommended dose of cisplatin is 75 mg/m² infused over 2 hours beginning approximately 30 minutes after the end of Pemetrexed administration.

Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy

The recommended dose of Pemetrexed is 500 mg/m² administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

Premedication Regimen and Concurrent Medications

Vitamin Supplementation

Folic acid 400 mcg to 1000 mcg orally to be initiated once daily, beginning 7 days before the first dose of Pemetrexed.

Continue folic acid during the full course of therapy and for 21 days after the last dose of Pemetrexed.

Vitamin B12 1 mg intramuscularly 1 week prior to the first dose of Pemetrexed and every 3 cycles thereafter to be administered.

Subsequent vitamin B12 injections may be given the same day as treatment with Pemetrexed.

Corticosteroids

Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after Pemetrexed administration.

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations

Monitoring

Complete blood cell counts, including platelet counts, should be performed on all patients receiving Pemetrexed.

Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle.

Patients should not begin a new cycle of treatment unless:

• ANC is ≥ 1500 cells/mm³
• Platelet count is ≥ 100,000 cells/mm³
• Creatinine clearance is ≥ 45 mL/min

Periodic chemistry tests should be performed to evaluate renal and hepatic function.

Dose Reduction Recommendations

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated according to the following guidelines:

Hematologic Toxicities

• Nadir ANC < 500/mm³ and nadir platelets ≥ 50,000/mm³:
• 75% of previous dose (Pemetrexed and Cisplatin)

• Nadir platelets < 50,000/mm³ without bleeding regardless of nadir ANC:
• 75% of previous dose (Pemetrexed and Cisplatin)

• Nadir platelets < 50,000/mm³ with bleeding regardless of nadir ANC:
• 50% of previous dose (Pemetrexed and Cisplatin)

Nonhematologic Toxicities

• Any Grade 3 or 4 toxicities except mucositis:
• 75% of previous dose of Pemetrexed
• 75% of previous dose of Cisplatin

• Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea:
• 75% of previous dose of Pemetrexed
• 75% of previous dose of Cisplatin

• Grade 3 or 4 mucositis:
• 50% of previous dose of Pemetrexed
• 100% of previous dose of Cisplatin

Neurotoxicity

CTC Grade 0-1

• 100% of previous dose of Pemetrexed
• 100% of previous dose of Cisplatin

CTC Grade 2

• 100% of previous dose of Pemetrexed
• 50% of previous dose of Cisplatin

Discontinuation Recommendation

Pemetrexed therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renal Impaired Patients

In clinical studies, patients with creatinine clearance ≥ 45 mL/min required no dose adjustments other than those recommended for all patients.

Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients.

Therefore, Pemetrexed should not be administered to patients whose creatinine clearance is < 45 mL/min using the standard Cockcroft and Gault formula or GFR measured by Tc99m-DTPA serum clearance method.

(weight in kg) × (140-age)

Males

(72) × serum creatinine (mg/100 ml)

Females

Estimated creatinine clearance for males × 0.85

Caution should be exercised when administering Pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is < 80 mL/min.