Pemexen IV Infusion

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, Pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of of TS and GARFT.

Recommended Dosage for Non-Squamous NSCLC: The recommended dose of Pemetrexed when administered with Pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered after Pembrolizumab and prior to Carboplatin or Cisplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, treatment with Pemetrexed with or without Pembrolizumab is administered until disease progression or unacceptable toxicity.

The recommended dose of Pemetrexed when administered with Cisplatin: for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered prior to Cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.

The recommended dose of Pemetrexed for maintenance treatment of non-squamous NSCLC: in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy.

The recommended dose of Pemetrexed for treatment of recurrent non-squamous NSCLC: in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Recommended Dosage for Mesothelioma: The recommended dose of Pemetrexed when administered with Cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Pemetrexed is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Calculate the dose of Pemetrexed and determine the number of vials needed.

Reconstitute Pemetrexed to achieve a concentration of 25mg/m2L as follows:

• Reconstitute each 100-mg vial with 4.2mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
• Reconstitute each 500-mg vial with 20mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
• Do not use Calcium-containing solutions for reconstitution.

Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in
color from.

Store reconstituted, preservative-free product under refrigerated conditions (2°-8°C) for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours.

Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If
particulate matter is observed, discard vial.

Withdraw the calculated dose of Pemetrexed from the vial(s) and discard vial with any unused portion.

Further dilute Pemetrexed with 0.9% Sodium Chloride Injection (preservative-free) to achieve a total volume of 100mL for intravenous infusion.

Store diluted, reconstituted product under refrigerated conditions (2°-8°C) for no more than 24 hours from the time of reconstitution. Discard after 24 hours.

• Ibuprofen increases exposure (AUC) of Pemexen. In patients with creatinine clearance between 45mL/min and 79mL/min
• Avoid administration of Ibuprofen for 2 days before, the day of, and 2 days following administration of Pemexen.
• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of Ibuprofen cannot be avoided.

Pemetrexed is contraindicated in patients with a history of severe hypersensitivity reaction to Pemetrexed.

• Myelosuppression
• Renal failure
• Bullous and exfoliative skin toxicity
• Interstitial
• pneumonitis
• Radiation recall

Can cause fetal harm when administered to a pregnant woman. There are no available data on Pemetrexed use in pregnant women. Pregnant women should be advised of the potential risk to a fetus. There is no information regarding the presence of Pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Pemetrexed, advise women not to breastfeed during treatment with Pemetrexed and for one week after last dose.

Myelosuppression and Increased Risk of Myelosuppression without Vitamin: Supplementation: Pemexen can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. Supplementation with oral folic acid and intramuscular vitamin B12 should be initiated prior to the first dose of Pemexen; vitamin supplementation should be continued during treatment and for 21 days after the last dose of Pemexen to reduce the severity of hematologic and gastrointestinal toxicity of Pemexen.

Renal Failure: Pemexen can cause severe, and sometimes fatal, renal toxicity. The incidence of renal failure in clinical studies in which patients received Pemexen as a single agent ranged from 0.4% to 0.6%. Creatinine clearance should be determined before each dose and periodically monitored renal function during treatment with Pemexen. It should be withheld in patients with a creatinine clearance of less than 45mL/minute.

Bullous and Exfoliative Skin Toxicity: Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with Pemexen. It should be permanently discontinued for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

Interstitial Pneumonitis: Serious interstitial pneumonitis, including fatal cases, can occur with Pemexen
treatment. Pemexen should be withheld for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, Pemexen should be permanently discontinued.

Radiation Recall: Radiation recall can occur with Pemexen in patients who have received radiation weeks to years previously. Patients should be monitored for inflammation or blistering in areas of previous radiation treatment. Pemexen should be permanently discontinued for signs of radiation recall.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Exposure to Pemexen is increased in patients with mild to moderate renal impairment who take concomitant Ibuprofen, increasing the risks of adverse reactions of Pemexen. In patients with Creatinine clearances between 45mL/min and 79mL/min, Ibuprofen administration should be avoided for 2 days before, the day of, and 2 days following administration of Pemexen. If concomitant Ibuprofen use cannot be avoided, patients should be monitored more frequently for Pemexen adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

No drugs are approved for the treatment of Pemexen overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of Pemexen overdosage. It is not known whether Pemexen is dialyzable.

Cytotoxic Chemotherapy

Store below 30°C in a cool and dry place, away from sunlight. Keep out of the reach of children.