Pemetrexed: Package Insert and Label Information

PEMETREXED- pemetrexed disodium hemipentahydrate injection, powder, lyophilized, for solution
Athenex Pharmaceutical Division, LLC.

1 INDICATIONS AND USAGE

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

Pemetrexed for Injection is indicated:

  • in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

  • in combination with cisplatin for 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 for 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 for 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 for 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/m 2 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 for 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 for 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/m 2 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 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/m 2 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 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/m 2 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 for 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/m 2 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 for 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 for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection [see Warnings and Precautions ( 5.1 )] .
  • Administer vitamin B 12, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pemetrexed for Injection [see Warnings and Precautions ( 5.1 )] . Do not substitute oral vitamin B 12 for intramuscular vitamin B 12 .

Corticosteroids

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

2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed for 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 for 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 for Injection if the creatinine clearance is less than 45 mL/min.

Delay initiation of the next cycle of Pemetrexed for Injection until:

  • recovery of non-hematologic toxicity to Grade 0-2,
  • absolute neutrophil count (ANC) is 1500 cells/mm 3 or higher, and
  • platelet count is 100,000 cells/mm 3 or higher.

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

For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information.

Table 1: Recommended Dosage Modifications for Adverse ReactionsÂȘ
Toxicity in Most Recent Treatment Cycle Pemetrexed for Injection Dose Modification for Next Cycle

a 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/mm 3 and platelets greater than or equal to 50,000/mm 3

OR

Platelet count less than 50,000/mm 3 without bleeding.

75% of previous dose

Platelet count less than 50,000/mm 3 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

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