Pemetrexed Disodium

Trade Names:Alimta- Injection, lyophilized powder for solution 100 mg- Injection, lyophilized powder for solution 500 mg

Pharmacology

Disrupts folate-dependent metabolic processes that are essential for cell replication.

Pharmacokinetics

Distribution

Vd is about 16.1 L. Protein binding is approximately 81%.

Metabolism

Not appreciably metabolized.

Elimination

Primarily eliminated in the urine. Elimination half-life is 3.5 h.

Special Populations

Cl decreases and AUC increases as renal function decreases.

Studies have not been conducted. However, elevated ALT, AST, or total bilirubin did not alter the pharmacokinetics.

Pharmacokinetics not affected by age.

Pharmacokinetics not affected by gender.

Pharmacokinetics similar in white and black patients. No data are available for other ethnic groups.

Indications and Usage

In combination with cisplatin for the treatment of malignant pleural mesothelioma in patients whose disease is unresectable or who are otherwise not candidates for curative surgery; as a single agent for the initial treatment of locally advanced or metastatic non–small cell lung cancer after prior chemotherapy; in combination with cisplatin for the treatment of locally advanced or metastatic nonsquamous non–small cell lung cancer; for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non–small cell lung cancer whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.

Contraindications

Standard considerations.

Dosage and Administration

IV Recommended dose is 500 mg/m ² infused over 10 min on day 1 of each 21-day cycle.

IV Reduce the dose of pemetrexed to 75% of previous dose in patients with nadir absolute neutrophil count (ANC) less than 500/mm ³ and nadir platelets of at least 50,000/mm ³ , nadir platelets less than 50,000/mm ³ without bleeding regardless of nadir ANC, any grade 3 or 4 toxicities (except mucositis), or any diarrhea requiring hospitalization or grade 3 or 4 diarrhea. Reduce the dose to 50% of previous dose in patients with nadir platelets less than 50,000/mm ³ with bleeding regardless of nadir ANC or grade 3 or 4 mucositis. Discontinue immediately if grade 3 or 4 neurotoxicity occurs or if a patient experiences any hematologic or nonhematologic grade 3 or 4 toxicity after 2 dose reductions.

General Advice

• For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
• Administer corticosteroid (eg, dexamethasone on day before, day of, and day after infusion) as prescribed to reduce incidence and severity of cutaneous reactions.
• Follow institutional procedures for handling, administration, and disposal of anticancer drugs.
• Reconstitute each 100 mg vial with 4.2 mL and each 500 mg vial with 20 mL of preservative-free sodium chloride 0.9% injection. Gently swirl until completely dissolved. Reconstituted solution contains pemetrexed 25 mg/mL. Further dilute prescribed amount of reconstituted solution so that the total volume of solution is 100 mL with preservative-free sodium chloride injection; administer as IV infusion over 10 min.
• Do not administer if particulate matter or cloudiness is noted. A slight yellow or green-yellow coloration is normal and of no concern.
• Discard unused portions of vial. Do not save any unused portions for future use.
• Do not mix with any other medications or diluents. Physically incompatible with diluents containing calcium (eg, Ringer's lactate injection).
• If pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed contacts mucous membranes, flush thoroughly with water.
• To reduce toxicity, patients must take a low-dose folic acid preparation or multivitamin containing 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 pemetrexed dose, and daily dosing should continue for 21 days after the last dose. One IM vitamin B ₁₂ injection must be given during the week preceding the first pemetrexed dose and every 3 cycles thereafter. Subsequent vitamin B ₁₂ injections may be given the same day as pemetrexed.

Storage/Stability

Store unopened vials at 59° to 86°F. Reconstituted solution should be used immediately or within 24 h if stored in refrigerator (36° to 46°F) or at controlled room temperature. Discard solution if not used within 24 h.

Drug Interactions

May delay Cl of pemetrexed.

Patients should interrupt NSAID dosing for at least 5 days before (2 days for NSAIDs with short elimination half-lives in patients with mild to moderate renal insufficiency), the day of, and 2 days following pemetrexed administration. If coadministration of an NSAID is necessary, closely monitor for toxicity, especially myelosuppression and renal and GI toxicity.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Supraventricular arrhythmia (less than 1%).

CNS

Fatigue (34%); sensory neuropathy (9%); motor neuropathy (1% to 5%).

Dermatologic

Rash/desquamation (14%); pruritus (7%); alopecia (6%); erythema multiforme (1% to 5%).

EENT

Increased lacrimation, ocular surface disease including conjunctivitis (1% to 5%).

GI

Nausea (31%); anorexia (22%); vomiting (16%); stomatitis/pharyngitis (15%); diarrhea (13%); mucositis/stomatitis (7%); constipation (6%); abdominal pain (1% to 5%); colitis (postmarketing).

Genitourinary

CrCl decreased, creatinine increased, glomerular filtration rate decreased (1% to 5%); renal failure (less than 1%).

Hematologic-Lymphatic

Anemia (19%); leukopenia (12%); neutropenia (11%); thrombocytopenia (8%); febrile neutropenia (1% to 5%).

Hepatic

Increased ALT (10%); increased AST (8%).

Hypersensitivity

Allergic reactions/hypersensitivity (1% to 5%).

Respiratory

Interstitial pneumonitis (postmarketing).

Miscellaneous

Fever (8%); infection (5%); edema (1% to 5%); radiation recall (postmarketing).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution because of the increased likelihood of decreased renal function.

Renal Function

Do not administer to patients with CrCl less than 45 mL/min.

Bone marrow suppression

Suppression of bone marrow function, manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia), may occur.

Cutaneous reactions

Pretreat with corticosteroids (eg, dexamethasone) to reduce incidence and severity of cutaneous reactions.

Hematologic and GI toxicity

Folic acid and vitamin B ₁₂ supplementation should be taken to reduce treatment-related hematologic and GI toxicity. Ensure patient is taking low-dose folic acid supplement or multivitamin containing folic acid daily, starting 7 days before first dose of pemetrexed, during treatment, and for 21 days following last dose of pemetrexed. Ensure patient receives 1 IM injection of vitamin B ₁₂ during the week preceding the first dose of pemetrexed and then every 3 cycles thereafter. Subsequent doses may be administered the same day as pemetrexed.

NSAIDs

Coadminister NSAIDs with caution to patients with mild to moderate renal insufficiency.

Third-space fluid

Consider draining third-space fluid (eg, pleural effusion and ascites) prior to administering pemetrexed.

Overdosage

Symptoms

Anemia, diarrhea, infection (with or without fever), mucositis, neutropenia, rash, thrombocytopenia.

Patient Information

• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Review dosing schedule with patient, family, or caregiver.
• Instruct patient to carefully follow premedication orders for folic acid, vitamin B ₁₂ supplementation, and corticosteroid to reduce toxic effects of chemotherapy.
• Caution patient with mild renal insufficiency (CrCl 45 to 79 mL/min) to avoid taking short-acting NSAIDs (eg, ibuprofen) for a period of 2 days before, the day of, and for 2 days following administration of pemetrexed.
• Caution patient with mild renal insufficiency (CrCl 45 to 79 mL/min) to avoid taking long-acting NSAIDs (eg, piroxicam) for a period of 5 days before, the day of, and for 2 days following administration of pemetrexed.
• Advise patient, family, or caregiver to immediately report any of the following to health care provider: bleeding or unusual bruising; fever, chills, or other signs of infection; pain, redness, or swelling at injection site; paleness.
• Advise patient, family, or caregiver to report any of the following to health care provider: persistent appetite loss, diarrhea, nausea, or vomiting; persistent or worsening general body weakness or fatigue; sores in mouth; or any other bothersome symptom or feeling.
• Caution women of childbearing potential to avoid becoming pregnant during therapy.

Copyright © 2009 Wolters Kluwer Health.