PEMETREXED

PEMETREXED- pemetrexed disodium injection, solution, concentrate
Hospira, Inc.

1 INDICATIONS AND USAGE

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

Pemetrexed Injection is indicated:

• In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (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 [see Clinical Studies 14.1].

1.2 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Non-Squamous NSCLC

• 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/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 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/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 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/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.2 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/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.3 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 [see Dosage and Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)].

2.4 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 [see Warnings and Precautions (5.1)].
• 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 [see Warnings and Precautions (5.1)]. 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.

2.5 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 [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]:

• 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.

2.6 Dosage Modifications for Adverse Reactions

Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer Pemetrexed Injection if the creatinine clearance is less than 45 mL/min.

Delay initiation of the next cycle of Pemetrexed Injection until:

• Recovery of non-hematologic toxicity to Grade 0–2,
• Absolute neutrophil count (ANC) is 1500 cells/mm³ or higher, and
• Platelet count is 100,000 cells/mm³ or higher.

Upon recovery, modify the dosage of Pemetrexed Injection in the next cycle as specified in Table 1.

For dosing modifications for cisplatin, refer to the prescribing information for cisplatin.

Table 1: Recommended Dosage Modifications for Adverse Reactions *

Toxicity in Most Recent Treatment Cycle	Pemetrexed Injection Dose Modification for Next Cycle
* National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2)
Myelosuppressive toxicity [see Warnings and Precautions (5.1)]
ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3 ORPlatelet count less than 50,000/mm3 without bleeding	75% of previous dose
Platelet count less than 50,000/mm3 with bleeding	50% of previous dose
Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions	Discontinue
Non-hematologic toxicity
Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity or diarrhea requiring hospitalization	75% of previous dose
Grade 3 or 4 mucositis	50% of previous dose
Renal toxicity [see Warnings and Precautions (5.2)]	Withhold until creatinine clearance is 45 mL/min or greater
Grade 3 or 4 neurologic toxicity	Permanently discontinue
Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions	Permanently discontinue
Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)]	Permanently discontinue
Interstitial Pneumonitis [see Warnings and Precautions (5.4)]	Permanently discontinue