Pemetrexed

Pemetrexed
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

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Overview

Pemetrexed is a antineoplastic agent that is FDA approved for the treatment of non-squamous non-small cell lung cancer, mesothelioma. Common adverse reactions include itching, peeling of skin, constipation, diarrhea, loss of appetite, nausea, pharyngitis, stomatitis, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma

The recommended dose of pemetrexed 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 pemetrexed administration. See cisplatin package insert for more information.

Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy

The recommended dose of pemetrexed is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

Premedication Regimen and Concurrent Medications

Vitamin Supplementation

Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of pemetrexed. Continue folic acid during the full course of therapy and for 21 days after the last dose of pemetrexed.
Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed.

Corticosteroids

Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after pemetrexed administration.

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations

Monitoring

Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. 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 1-3, which are suitable for using pemetrexed as a single-agent or in combination with cisplatin.

This image is provided by the National Library of Medicine.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment 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.

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

Discontinuation Recommendation

ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

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, pemetrexed 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-DTPA serum clearance method:

Caution should be exercised when administering pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

Preparation and Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of pemetrexed. The use of gloves is recommended. If a solution of pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

pemetrexed 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. Pemetrexed extravasation should be managed with local standard practice for extravasation as with other non-vesicants.

Preparation for Intravenous Infusion Administration

Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.
Calculate the dose of pemetrexed and determine the number of vials needed. Vials contain either 100 mg or 500 mg of pemetrexed. The vials contain an excess of pemetrexed to facilitate delivery of label amount.
Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each 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 pemetrexed. 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 pemetrexed solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
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.
An appropriate quantity of the reconstituted pemetrexed 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. pemetrexed is administered as an intravenous infusion over 10 minutes.
Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions of pemetrexed 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). pemetrexed 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 pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended. Pemetrexed is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.

Off-Label Use and Dosage (Adult)

Non–Guideline-Supported Use

Condition 1

Dosing Information

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Condition 2

Dosing Information

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Condition 3

Dosing Information

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Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Pemetrexed FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

Pemetrexed is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings

Requirement for Premedication and Concomitant Medication to Reduce Toxicity

Vitamin Supplementation

Prior to treatment with pemetrxed, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrxed. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrxed treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

Corticosteroids

Administer dexamethasone the day before, the day of, and the day after pemetrxed administration.

Bone Marrow Suppression

Pemetrxed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle.

Decreased Renal Function

Pemetrxed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, pemetrxed should not be administered to patients whose creatinine clearance is <45 mL/min.

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of pemetrxed alone.

Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency

Caution should be used when administering NSAIDs concurrently with pemetrxed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

Required Laboratory Monitoring

Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a 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.

Pregnancy Category D

Based on its mechanism of action, pemetrxed can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If pemetrxed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with pemetrxed.