Pronunciation (pem e TREKS ed)

U.S. Brand Names Alimta

Synonyms L4231514; MTA; Multitargeted Antifolate; NSC-698037

Therapeutic Category
Antineoplastic Agent, Antimetabolite
Use Treatment of malignant pleural mesothelioma in combination with cisplatin

Pregnancy Risk Factor D

Pregnancy Implications In animal studies, was associated with fetotoxicity and teratogenicity when given on gestation days 6-15. Embryotoxicity also occurred. There are no adequate or well-controlled studies in pregnant women. Patients should avoid becoming pregnant while using this drug. If used during pregnancy or if patient becomes pregnant during therapy, patient should be educated about the potential hazards to the fetus.

Contraindications Hypersensitivity to pemetrexed or any component of the formulation; Clcr<45 mL/minutes

Warnings/Precautions Prophylactic folic acid and vitamin B12 supplements are necessary to reduce hematologic and gastrointestinal toxicity. Folic acid and vitamin B12 should be started 1 week before the first dose of pemetrexed. Pretreatment with corticosteroids reduces the incidence and severity of cutaneous reactions. Use caution in patients with renal dysfunction, hepatic dysfunction not due to metastases, and patients receiving concurrent nephrotoxins. Use caution when administering NSAIDs to patients with Clcr<80 mL/minutes. Patient should have an ANC 1500 cells/mm3, platelets 100,000 cells/mm3, and Clcr >45 mL/minutes before a dose is given. Safety and efficacy have not been established in pediatric patients.

Adverse Reactions
>10%:Cardiovascular: Chest pain (40%)
Central nervous system: Fatigue (80%), fever (17%), depression (14%)
Dermatologic: Rash (22%)
Gastrointestinal: Nausea (84%), vomiting (58%), constipation (44%), anorexia (35%), stomatitis/pharyngitis (28%), diarrhea (26%)
Hematologic: Neutropenia (58%), leukopenia (55%), anemia (33%), thrombocytopenia (27%)
Nadir: 8-10 days
Recovery: 12-17 days
Neuromuscular & skeletal: Neuropathy (17%)
Renal: Creatinine increased (16%)
Respiratory: Dyspnea (66%)
Miscellaneous: Infection (17%)

1% to 10%:Cardiovascular: Thrombosis (7%)
Endocrine & metabolic: Dehydration (7%)
Gastrointestinal: Dysphagia/esophagitis/odynophagia (6%)
Renal: Renal failure (2%)
Miscellaneous: Allergic reaction (2%)

Overdose/Toxicology Toxicities include neutropenia, anemia, thrombocytopenia, mucositis, rash, infection, and diarrhea. Treatment is supportive and symptom-directed. Leucovorin may help reverse bone marrow suppression. The intravenous leucovorin doses used in clinical trials were 100 mg/m2 once, followed by 50 mg/m2 every 6 hours for 8 days. It is unknown if pemetrexed is removed by hemodialysis.

Drug Interactions

NSAIDs: NSAIDs may reduce the clearance of pemetrexed. Patients with Clcr 45-79 mL/minute should avoid NSAIDs with short elimination half-lives (eg, ibuprofen, indomethacin, ketoprofen, ketorolac) for 2 days before, the day of, and 2 days following a dose of pemetrexed. All patients should avoid NSAIDs with long half-lives (eg, nabumetone, naproxen, oxaprozin, piroxicam) for 5 days before, the day of, and 2 days following a dose of pemetrexed.

Food Interactions Lower ANC nadirs occur in patients with elevated baseline cystathionine or homocysteine concentrations. Levels of these substances can be reduced by folic acid and vitamin B12 supplementation.

Add 20 mL of 0.9% preservative free sodium chloride injection to make a 25 mg/mL solution. Gently swirl. Solution may be colorless to green-yellow. Reconstituted and infusion solutions are stable for 24 hours when refrigerated or stored at room temperature. Further dilute in 100 mL of 0.9% sodium chloride for administration. Discard unused portion.

Mechanism of Action Disrupts folate-dependent metabolic processes essential for cell replication.

Pharmacodynamics/Kinetics

Duration: Vdss: 16.1 L

Protein binding: ~81%

Metabolism: Minimal

Half-life elimination: Normal renal function: 3.5 hours

Excretion: Urine (70% to 90% as unchanged drug)

Usual Dosage I.V.: Adults: Malignant pleural mesothelioma: 500 mg/m2 on day 1 of each 21-day cycle in combination with cisplatin

Note: Start vitamin supplements 1 week before initial dose of pemetrexed. Folic acid 350-1000 mcg/day orally and vitamin B12 1000 mcg I.M. every 9 weeks. Dexamethasone 4 mg twice daily can be started the day before therapy, and continued the day of and the day after to minimize cutaneous reactions.

Dosage adjustments for toxicities:Toxicity: Discontinue if patient has any grade 3 or 4 toxicity after two dose reductions (except grade 3 transaminase elevations) or immediately if grade 3 or 4 neurotoxicity develops
Hematologic toxicity: Upon recovery, reinitiate therapy
Nadir ANC <500/mm3 and nadir platelets 50,000/mm3: Reduce dose to 75% of previous dose of pemetrexed and cisplatin
Nadir platelets <50,000/mm3: Reduce dose to 50% of previous dose of pemetrexed and cisplatin
Nonhematologic toxicity (excluding neurotoxicity or?grade 3 transaminase elevations): Upon recovery, reinitiate therapy
Grade 3 or 4 toxicity (excluding mucositis or transaminase elevations): Reduce dose to 75% of previous dose of pemetrexed and cisplatin
Diarrhea requiring hospitalization: Reduce dose to 75% of previous dose of pemetrexed and cisplatin
Grade 3 or 4 mucositis: Reduce dose to 50% of previous dose of pemetrexed; continue cisplatin at 100% of previous dose
Neurotoxicity:
Common Toxicity Criteria (CTC) Grade 0-1: Continue at previous dose of pemetrexed and cisplatin.
CTC Grade 2: Continue at previous dose of pemetrexed; Reduce dose to 50% of previous dose of cisplatin.

Dosage adjustment in renal impairment:Clcr<45 mL/minute: Do not use.
Clcr 45 mL/minute: No dosage adjustment required.

Dosage adjustment in hepatic impairment: No dosage adjustment required.

Dietary Considerations Initiate folic acid supplementation 1 week before first dose of pemetrexed, continue for full course of therapy, and for 21 days after last dose. Institute vitamin B12 1 week before the first dose; administer every 9 weeks thereafter.

Administration I.V.: Infuse over 10 minutes.

Monitoring Parameters CBC (before each dose, on days 8 and 15 of each cycle), chemistry tests

Dosage Forms Injection, powder for reconstitution, as disodium: 500 mg