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In combination with cisplatin: The recommended dose of Pexitaz is 500 mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle. The recommended dose of cisplatin is 75 mg/m2 BSA infused over 2 hours beginning approximately 30 minutes after the end of Pexitaz administration on Day 1 of each 21 day cycle. Patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving cisplatin.
As a single agent: In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pexitaz is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.
Premedication Regimen: Corticosteroid: Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after Pexitaz administration.
Vitamin Supplementation: To reduce toxicity, patients treated with Pexitaz must be instructed to take a low dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7 day period preceding the first dose of Pexitaz; and dosing should continue during the full course of therapy and for 21 days after the last dose of Pexitaz. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of Pexitaz and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as Pexitaz. In clinical trials, the dose of folic acid studied ranged from 350 to 1,000 mcg, and the dose of vitamin B12 was 1,000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg.
Laboratory Monitoring and Dose Reduction Recommendations: Complete blood cell counts, including platelet counts, should be performed on all patients receiving Pexitaz. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1,500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
Dose Reduction Recommendations: Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using Pexitaz as a single agent or in combination with cisplatin. (See Table 1.)
Click on icon to see table/diagram/imageIf patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3 (except Grade 3 transaminase elevations), Pexitaz should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to guidelines in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageIn the event of neurotoxicity, the recommended dose adjustments for Pexitaz and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. (See Table 3.)
Click on icon to see table/diagram/imagePexitaz therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed.
Elderly Patients: No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. Hence, no dose reductions other than those recommended for all patients are necessary for patients ≥65 years of age.
Pediatric use: Pexitaz is not recommended for use in children, as safety and efficacy have not been established in children.
Hepatic impairment: Pemetrexed is not extensively metabolized by the liver. There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. There is limited clinical experience in patients with hepatic impairment. Patients with bilirubin >1.5 times the upper limit of normal were excluded from clinical trials of pemetrexed. Patients with transaminase >3.0 times the upper limit of normal were routinely excluded from clinical trials if they had no evidence of hepatic metastases. Patients with transaminase from 3 to 5 times the upper limit of normal were included in the clinical trial of pemetrexed if they had hepatic metastases. Dose adjustments based on hepatic impairment experienced during treatment with Pexitaz are provided in Table 2.
Renal impairment: Pemetrexed is known to be primarily excreted by the kidney. Decreased renal function will result in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. Cisplatin coadministration with pemetrexed has not been studied in patients with moderate renal impairment. In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, Pexitaz should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DPTAserum clearance method: See equation.
Click on icon to see table/diagram/imageCaution should be exercised when administering Pexitaz concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min.
Preparation and Administration Precautions: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of Pexitaz. The use of gloves is recommended. If a solution of Pexitaz contacts the skin, wash the skin immediately and thoroughly with soap and water. If Pexitaz contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available. Pexitaz is not a vesicant.
There is no specific antidote for extravasation of pemetrexed. To date, there have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Pexitaz extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
Preparation for Intravenous Infusion Administration: 1. Use aseptic technique during the reconstitution and further dilution of Pexitaz for intravenous infusion administration.
2. Calculate the dose of Pexitaz and determine the number of vials needed. Vials contain either 100 mg or 500 mg of Pexitaz. The vials contain an excess of Pexitaz to facilitate delivery of label amount.
3. Reconstitute each 100 mg vial with 4.2 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitute 500 mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL Pexitaz. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green yellow without adversely affecting product quality. The pH of the reconstituted Pexitaz solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is observed, do not administer.
5. An appropriate quantity of the reconstituted Pexitaz solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 mL. Pexitaz is administered as an intravenous infusion over 10 minutes.
6. Chemical and physical stability of reconstituted and infusion solutions of Pexitaz were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature and lighting. When prepared as directed, reconstitution and infusion solutions of Pexitaz contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). Pexitaz is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection and therefore these should not be used.
Coadministration of pemetrexed for injection with other drugs and diluents has not been studied, and therefore is not recommended.
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