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PEMETREXED injection

Pemetrexed Injection is a folate analog metabolic inhibitor. The drug substance, Pemetrexed disodium hemipentahydrate, has the chemical name N-{4-[2-(2-amino-4oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl] carbonyl}-L-glutamic acid disodium, hemipentahydrate, with a molecular formula of C₂₀H₁₉N₅Na₂O₆•2.5H₂O and a molecular weight of 516.41.

Pemetrexed Injection, 100 mg/4 mL, 500 mg/20 mL, 850 mg/34 mL and 1000 mg/40 mL are supplied as a sterile clear, colorless to pale yellow solution for intravenous infusion available in single-dose vials. Each mL contains 25 mg pemetrexed equivalent to 27.5 mg pemetrexed disodium, 15 mg of citric acid anhydrous, 0.5 mg of L-methionine, 4.4 mg of monothioglycerol and Water for injection (quantity enough to 1 mL). Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

INDICATIONS AND USAGE

Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Pemetrexed Injection is indicated:

in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, NSCLC.
as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.

Mesothelioma: Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Mechanism of Action

Pemetrexed Injection 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 TS and GARFT.

DOSAGE AND ADMINISTRATION

Recommended Dosage for Non-Squamous NSCLC

The recommended dose of Pemetrexed Injection 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/m²as 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 Injection with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.

The recommended dose of Pemetrexed Injection 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/m²as 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 Injection 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/m²as 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 Injection 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/m²as 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 Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m²as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Renal Impairment

Pemetrexed Injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min.

Premedication and Concomitant Medications to Mitigate Toxicity

Vitamin Supplementation

Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of Pemetrexed Injection and continuing until 21 days after the last dose of Pemetrexed Injection.
Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles thereafter. Subsequent vitamin B12 Injections may be given the same day as treatment with Pemetrexed Injection. Do not substitute oral vitamin B12 for intramuscular vitamin B12.

Corticosteroids

Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration.

Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment

Receiving Pemetrexed Injection

In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows:

Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection.
Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

Preparation for Administration

Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures.¹
Calculate the dose of Pemetrexed Injection and determine the number of vials needed.
Inspect Pemetrexed Injection vials visually for particulate matter and discoloration prior to use. If particulate matter is observed, discard vial.
Withdraw the calculated dose of Pemetrexed Injection from the vial(s) and discard vial with any unused portion.
Dilute required dose of Pemetrexed Injection, 25 mg/mL with 0.9% Sodium Chloride Injection, USP (preservative-free) to achieve a total volume of 100 mL for intravenous infusion.
If not used immediately, store diluted product under refrigerated conditions [2°C to 8°C (36°F to 46°F)] for no more than 24 hours from the time of dilution. The diluted solution should be protected from light. Discard after 24 hours.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation: Pemetrexed 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.

Renal Failure: Pemetrexed can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with Pemetrexed Injection Withhold Pemetrexed Injection in patients with a creatinine clearance of less than 45 mL/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 pemetrexed. Permanently discontinue Pemetrexed Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

Interstitial Pneumonitis: Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Withhold Pemetrexed Injection for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue Pemetrexed Injection.

Radiation Recall: Radiation recall can occur with pemetrexed in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue Pemetrexed Injection for signs of radiation recall.

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

Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m². Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose.

DRUG INTERACTIONS

Effects of Ibuprofen on Pemetrexed: Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79mL/min

Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of pemetrexed.
Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a pregnant woman. There are no available data on Pemetrexed Injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m^2.Advise pregnant women of the potential risk to a fetus.

Lactation: 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 Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after the last dose.

Patients with Renal Impairment: Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.

OVERDOSAGE

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

PEMETREXED injection

PEMETREXED injection