Pemetrexed

PEMETREXED- pemetrexed monohydrate solution, concentrate
Teva Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

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

Pemetrexed Injection is indicated:

  • 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Non-Squamous NSCLC

  • 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 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)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)].

2.3 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.

2.4 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.

2.5 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.

Table 1: Recommended Dosage Modifications for Adverse Reactionsa

Toxicity in Most Recent Treatment Cycle

Pemetrexed Injection Dose Modification for Next Cycle

Myelosuppressive toxicity [see Warnings and Precautions (5.1)]

ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3

OR

Platelet 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

a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2).

2.6 Preparation for Administration

  • Pemetrexed Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
  • Calculate the dose of Pemetrexed Injection and determine the number of vials needed.
  • Withdraw the calculated dose of Pemetrexed Injection from the vial(s) and discard vial with any unused portion.
  • Dilute Pemetrexed Injection with 5% Dextrose Injection, USP to achieve a total volume of 100 mL for intravenous infusion.
  • Administer diluted solution via an 0.2 µm in-line filter.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.

Store diluted solution under refrigerated conditions [2° to 8°C (36° to 46°F)] for no more than 14 days from the time of dilution and at room temperature for not more than 8 hours from the time of dilution.

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