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

Non-Small Cell Lung Cancer: ALIMTA as a single-agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.

The effectiveness of ALIMTA in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms.

ALIMTA is for Intravenous Infusion Only

Combination Use With Cisplatin

Malignant Pleural Mesothelioma —The recommended dose of ALIMTA is 500 mg/m² 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 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin. See cisplatin package insert for more information.

Single-Agent Use

Non-Small Cell Lung Cancer—The recommended dose of ALIMTA is 500 mg/m² 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 ALIMTA administration.

Vitamin Supplementation— To reduce toxicity, patients treated with ALIMTA 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 ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B₁₂ during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B₁₂ injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 µg, and the dose of vitamin B₁₂ was 1000 µg. The most commonly used dose of oral folic acid in clinical trials was 400 µg (see WARNINGS).

Laboratory Monitoring and Dose Reduction Recommendations

Monitoring— Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. 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 ≥1500 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 8-10, which are suitable for using ALIMTA as a single agent or in combination with cisplatin.

Table 8: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3 (except Grade 3 transaminase elevations), ALIMTA 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 9.

Table 9: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicities^a,b

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 10. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 10: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity

ALIMTA 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 dose reductions other than those recommended for all patients are necessary for patients ≥65 years of age.

Children —ALIMTA is not recommended for use in children, as safety and efficacy have not been established in children.

Renally Impaired Patients — 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, ALIMTA 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-DPTA serum clearance method:

Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min (see DRUG INTERACTIONS under PRECAUTIONS).

Hepatically Impaired Patients — ALIMTA is not extensively metabolized by the liver. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 9 (see Patients with Hepatic Impairment under PRECAUTIONS).

Preparation and Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.^1-4 ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA 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 ALIMTA for intravenous infusion administration.
2. Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount.
3. Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride
4. 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 ALIMTA. 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 ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
5. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is observed, do not administer.
6. An appropriate quantity of the reconstituted ALIMTA 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. ALIMTA is administered as an intravenous infusion over 10 minutes.
7. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature [see USP Controlled Room Temperature] and lighting. When prepared as directed, reconstitution and infusion solutions of ALIMTA 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). ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended.

ALIMTA® vials

100 mg lyophilized powder in a 10-mL size sterile single-use vial with flip-off cap individually packaged in a carton. NDC 0002-7640-01 (VL7640)

500 mg lyophilized powder in a 50-mL size sterile single use vial with flip off cap individually packaged in a carton. NDC 0002-7623-01 (VL7623)

Storage

ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When prepared as directed, reconstituted and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard unused portion.

ALIMTA is not light sensitive.

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society

Literature revised September 2007 Eli Lilly and Company Indianapolis, IN 46285, USA www.ALIMTA.com. FDA Rev date: 9/7/2007

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