AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• PEMEtrexed Sodium

Chemical Name:

• N -[4-2-(2-Amino-4,7-dihydro-4-oxo-1 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid disodium salt.

Molecular Formula:

• C₂₀H₁₉N₅Na₂O₆

Pemetrexed, a folic acid antagonist, is an antineoplastic agent.1,3,4,5

Malignant Pleural Mesothelioma

Pemetrexed is used in combination with cisplatin for the treatment of malignant pleural mesothelioma in adults whose disease is unresectable or who otherwise are not candidates for potentially curative surgery.1 This malignancy occurs infrequently, is linked to asbestos exposure, and previously was considered unresponsive to chemotherapy, with a median survival of 6-8 months following diagnosis.3,5 Pemetrexed is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.6

Efficacy of pemetrexed and cisplatin in the treatment of malignant pleural mesothelioma was established in a randomized, phase III, comparative, multicenter study in 448 adults who had not received previous chemotherapy.1,3 Patients were randomized to receive pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) on day 1 or cisplatin (75 mg/m²) on day 1; both regimens were administered every 21 days.1,3 Patients studied were predominantly older (median age: 61 years) white males; approximately 68% of patients had tumors of epithelial histology, and 78% had stage III or IV disease.1,3 After 117 patients were treated, the study protocol was changed and patients started receiving folic acid and vitamin B₁₂supplementation because of hematologic and GI toxicity.1,3 The primary outcome measure was survival.1,3 Patients receiving the combination regimen had a longer median survival (12.1 versus 9.3 months), a longer time to progression (5.7 versus 3.9 months), a higher overall response rate (41.3 versus 16.7%), and improvement in lung function compared with patients receiving cisplatin alone.1,3,5 Addition of folic acid and vitamin B₁₂ supplementation reduced toxicity and did not adversely affect survival.1,3

Non-small Cell Lung Cancer

Pemetrexed is used alone for the treatment of locally advanced or metastatic non-small cell lung cancer in adults who have received prior chemotherapy.1,4 This indication is based on the surrogate end point of tumor response rate; there are no controlled clinical studies to date demonstrating improvement in disease-related symptoms or increased survival with pemetrexed therapy.1

Pemetrexed has been evaluated in a randomized, phase III, multicenter study in adults with stage III or IV (25 or 75% of patients, respectively) non-small cell lung cancer not amenable to potentially curative therapy. 1,4 All patients in this study had received prior chemotherapy for advanced disease.1,4 Patients were randomized to receive pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) on day 1; the regimens were administered every 21 days.1,4 Patients receiving pemetrexed also received folic acid and vitamin B₁₂ supplementation.1,4 Response rates and clinical benefit (complete or partial response or stable disease) rates were similar in patients receiving pemetrexed or docetaxel.4 Overall response rates were 9.1 or 8.8% in patients receiving pemetrexed or docetaxel, respectively.1,4 Median survival (the primary end point of the study) was 8.3 or 7.9 months in those receiving pemetrexed or docetaxel, respectively;1,4 however, efficacy of pemetrexed in terms of survival could not be established, since a reliable and consistent effect of docetaxel on survival could not be estimated from historical study data, and crossover between treatments at the time of disease progression may have confounded interpretation of the survival data.1 Median progression-free survival was 2.9 months and 1-year survival rate was 29.7% in both treatment groups.1,4

Reconstitution and Administration

Pemetrexed is administered by IV infusion over 10 minutes.1

The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed with pemetrexed.1 The manufacturer recommends use of protective gloves when handling the drug.1 If pemetrexed comes in contact with skin or mucosa, affected skin areas should be washed immediately and thoroughly with soap and water and affected mucosa should be thoroughly rinsed with copious amounts of water.1

Pemetrexed is not a vesicant.1 Extravasation should be managed according to local standard of practice; there is no specific antidote for extravasation of pemetrexed.1

Vials labeled as containing 500 mg of pemetrexed should be reconstituted by adding 20 mL of 0.9% sodium chloride injection without preservatives to provide a solution containing 25 mg/mL.1 The vial should be gently swirled until the powder is completely dissolved.1 The appropriate volume of reconstituted solution must be further diluted with 0.9% sodium chloride injection without preservatives to a volume of 100 mL prior to administration.1 Pemetrexed is incompatible with diluents containing calcium (e.g., lactated Ringer's injection, Ringer's injection); pemetrexed should not be diluted with these solutions, diluents other than 0.9% sodium chloride injection without preservatives, or other drugs.1 Because reconstituted and/or diluted pemetrexed solutions contain no preservatives, any unused portions of these solutions should be discarded.1 When reconstituted and/or diluted as directed, pemetrexed solutions are stable for 24 hours at controlled room temperature under ambient lighting.1

General Dosage

Dosage of pemetrexed disodium heptahydrate is expressed in terms of anhydrous pemetrexed.1

All patients should be premedicated with a corticosteroid before pemetrexed administration to reduce the incidence and severity of cutaneous reactions.1 A regimen of oral dexamethasone 4 mg twice daily for 3 days, starting 1 day prior to pemetrexed administration, has been used in clinical studies.1

All patients should be instructed to take a low-dose oral folic acid preparation or a multivitamin preparation containing folic acid daily to reduce toxicity.1 At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of pemetrexed; dosing should continue during the full course of therapy and for 21 days after the last dose of pemetrexed.1 Folic acid dosages ranged from 0.35-1 mg daily in clinical studies; the most commonly used dosage was 0.4 mg daily.1 Patients also must receive one IM injection of vitamin B₁₂ during the week preceding the first dose of pemetrexed and every 3 cycles thereafter; injections administered subsequent to the initial dose may be given the same day as pemetrexed.1,3 A dose of 1 mg of vitamin B₁₂ was used in clinical studies.1

Malignant Pleural Mesothelioma

The recommended adult dosage of pemetrexed is 500 mg/m² infused IV over 10 minutes in conjunction with cisplatin 75 mg/m² infused IV over 2 hours beginning approximately 30 minutes after completion of the pemetrexed infusion on day 1 of a 21-day cycle.1 Patients should be adequately hydrated before and after administration of cisplatin; clinicians should consult published protocols for information related to specific regimens.1

Chemotherapy in subsequent cycles should be delayed until absolute neutrophil counts (ANCs) are at least 1500/mm³, platelet counts are at least 100,000/mm³, and creatinine clearances are at least 45 mL/minute.1

Non-small Cell Lung Cancer

The recommended adult dosage of pemetrexed is 500 mg/m² infused IV over 10 minutes on day 1 of a 21-day cycle.1

Chemotherapy in subsequent cycles should be delayed until ANCs are at least 1500/mm³, platelet counts are at least 100,000/mm³, and creatinine clearances are at least 45 mL/minute.1

Dosage Modification for Toxicity

After the first treatment cycle, subsequent doses of pemetrexed as a single agent or in combination with cisplatin should be adjusted based on nadir hematologic counts (i.e., ANCs, platelet counts) and maximum nonhematologic toxicity.1

Treatment may be delayed to allow sufficient time for recovery from hematologic toxicity; if pemetrexed therapy is resumed following such toxicity, subsequent doses should be reduced according to the nadir ANCs and platelet counts observed (see Table 1).1 Therapy should be discontinued if the patient experiences grade 3 or 4 hematologic toxicity after 2 dose reductions.1

If the patient experiences grade 3 or 4 nonhematologic toxicity (except neurotoxicity), therapy should be interrupted until the toxicity resolves or decreases in intensity to at least pretreatment values.1 If pemetrexed therapy is then resumed, subsequent doses should be reduced according to the type and severity of the toxicity (see Table 2).1 Therapy should be discontinued if the patient experiences grade 3 or 4 nonhematologic toxicity (except neurotoxicity) after 2 dose reductions.1 These recommendations for dosage modifications for grade 3 or 4 nonhematologic toxicity apply to grade 4 but not to grade 3 elevations in serum transaminase values; dosage modification is not required for grade 3 elevations in serum transaminase values.1,7

If the patient experiences grade 2 neurotoxicity, the pemetrexed dose may be maintained at the current level but subsequent doses of cisplatin should be reduced (see Table 3).1 Therapy should be discontinued immediately if grade 3 or 4 neurotoxicity occurs.1

Special Populations

In clinical trials, patients with creatinine clearances of 45 mL/minute and greater did not require dosage reductions other than those recommended for all patients.1 Information concerning patients with creatinine clearances less than 45 mL/minute is insufficient to date to make dosage recommendations for these patients, and use in such patients currently is not recommended.1

Dosage reductions other than those recommended for all patients are not needed in geriatric patients 65 years of age or older.1

Contraindications

Known hypersensitivity to pemetrexed or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hematologic Toxicity

The principal manifestations of hematologic toxicity include neutropenia, thrombocytopenia, and/or anemia; myelosuppression is the most common dose-limiting toxicity.1 Absolute neutrophil count (ANC) reaches nadir at day 8-10 and returns to baseline approximately 4-8 days after nadir.1

Folate and Vitamin B12 Supplementation

Patients must receive folic acid and vitamin B₁₂ to prevent treatment-related hematologic and GI toxicity.1 Patients receiving supplemental folic acid and vitamin B₁₂ in clinical studies had a reduction in grade 3/4 hematologic and nonhematologic toxicities (i.e., neutropenia, febrile neutropenia, infection with grade 3/4 neutropenia) and an overall reduction in toxicity.1,3

Sensitivity Reactions

Dermatologic Effects

Rash reported.1 Premedication with a corticosteroid reduces the incidence and severity of cutaneous reactions.1

General Precautions

Adequate Patient Evaluation and Monitoring

Pemetrexed should be administered only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Complete blood cell counts, including platelet counts, should be performed in all patients receiving pemetrexed.1 Patients should be monitored for nadir and recovery; blood cell counts were monitored before each dose and on days 8 and 15 of each treatment cycle in clinical studies.1

Renal and hepatic function should be monitored periodically.1

Other Considerations

Not known whether pemetrexed accumulates in fluid collections such as pleural effusions or ascites; such accumulations could increase toxicity.1,5 Some clinicians suggest that large effusions be drained before pemetrexed therapy.5

Specific Populations

Pregnancy

Category D.1 (See Users Guide.)

Lactation

Not known whether pemetrexed or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to pemetrexed in nursing infants, nursing should be discontinued prior to therapy.1

Pediatric Use

Safety and efficacy not established in children.1,3,4,7

Geriatric Use

Age-related differences in the pharmacokinetics of pemetrexed were not observed in adults 26-80 years of age.1

Age-based dosage adjustments are not necessary in geriatric patients 65 years of age or older.1

Hepatic Impairment

Pemetrexed has not been studied in patients with hepatic impairment.1 Patients with serum bilirubin concentrations exceeding 1.5 times the upper limit of normal were excluded from clinical studies.1 Patients with serum transaminase concentrations exceeding 3 times the upper limit of normal who had no evidence of hepatic metastases were excluded from clinical studies; patients with serum transaminase concentrations 3-5 times the upper limit of normal who had hepatic metastases were included in clinical studies.1

Pemetrexed is not appreciably metabolized by the liver.1 Elevated serum transaminase or total bilirubin concentrations do not affect pharmacokinetics of pemetrexed.1

Renal Impairment

Pemetrexed is eliminated principally unchanged by renal excretion; renal impairment is associated with reduced clearance of and increased systemic exposure to pemetrexed.1

Dosage adjustment is not needed in patients with creatinine clearance of 45 mL/minute or greater.1 Information concerning patients with creatinine clearance less than 45 mL/minute is insufficient to date to make dosage recommendations for these patients; use of the drug in these patients currently is not recommended.1 Repeat cycles of pemetrexed should be withheld until creatinine clearances are at least 45 mL/minute.1

Concomitant use of pemetrexed with cisplatin has not been evaluated in patients with moderate renal impairment.1

Caution is advised if nonsteroidal anti-inflammatory agents (NSAIAs) are used concomitantly with pemetrexed in patients with renal impairment.1,3 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Common Adverse Effects

Common adverse effects include hematologic effects, fever and infection, stomatitis/pharyngitis, rash/desquamation, nausea, fatigue, dyspnea, vomiting, constipation, chest pain, and anorexia.1,7

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely with drugs metabolized by cytochrome P-450 (CYP) isoenzymes 1A2, 2C9, 2D6, or 3A.1

Cisplatin

Pharmacokinetic interaction unlikely.1

Nonsteroidal Anti-inflammatory Agents

Pharmacokinetic interaction (decreased clearance of pemetrexed; increased pemetrexed AUC) with ibuprofen.1 The manufacturer states that ibuprofen (up to 400 mg 4 times daily) may be used concomitantly with pemetrexed in patients with normal renal function (creatinine clearance of 80 mL/minute or greater); however, caution is advised if ibuprofen is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance of 45-79 mL/minute).1 Patients with mild to moderate renal impairment should not receive nonsteroidal anti-inflammatory agents (NSAIAs) having short half-lives (e.g., ibuprofen) for 2 days before, the day of, and for 2 days after administration of pemetrexed.1,3,7

Data are not available to date regarding possible interactions with NSAIAs having longer half-lives,1 and the manufacturer states that all patients receiving such NSAIAs should interrupt therapy with the NSAIA for at least 5 days before, the day of, and for 2 days after administration of pemetrexed.1 If concomitant use of a NSAIA is necessary, the patient should be closely monitored for toxicity, particularly myelosuppression and renal and GI toxicity.1

Pharmacokinetic interaction unlikely with low to moderate aspirin dosage (325 mg every 6 hours).1 Effect of higher aspirin dosage on pemetrexed pharmacokinetics not known.1

Nephrotoxic Drugs

Possible pharmacokinetic interaction (delayed clearance of pemetrexed).1

Probenecid

Possible pharmacokinetic interaction (delayed clearance of pemetrexed).1 Pharmacokinetic interaction also possible with other substances secreted at the renal tubule.1

Vitamins

Pharmacokinetic interaction unlikely with oral folic acid and vitamin B₁₂ given IM.1

Description

Pemetrexed, a folic acid antagonist, exerts its antineoplastic activity by disrupting folate-dependent metabolic processes that are essential for cell replication.1,3 Pemetrexed inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and phosphoribosylglycinamide formyltransferase (glycinamide ribonucleotide formyltransferase), enzymes involved in de novo biosynthesis of thymidine and purine nucleotides.1,3 Pemetrexed enters cells through the reduced folate carrier and membrane folate binding protein transport systems and undergoes extensive intracellular polyglutamation by tetrahydrofolylpolyglutamate synthase (folylpolyglutamate synthase).1,3 The polyglutamate forms are retained for long periods in the cells and are inhibitors of thymidylate synthase and phosphoribosylglycinamide formyltransferase.1,3 Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues.1

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052).1 Synergistic inhibitory effects have been observed in the MSTO-211H mesothelioma cell line when pemetrexed was combined with cisplatin.1

Advice to Patients

Importance of taking folic acid and vitamin B₁₂ to reduce the risk of adverse effects.1,2 Importance of taking a corticosteroid for 3 days during each treatment cycle to reduce the risk of a skin reaction.1,2

Importance of recognizing and reporting adverse effects of pemetrexed, including myelosuppressive effects, infectious complications, and GI symptoms (i.e., diarrhea, mucositis).1,2 Necessity of monitoring blood cell counts and serum creatinine.1,2 Necessity of dosage adjustment or delay in treatment if toxicity occurs.1,2

Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.1 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1,2

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, especially nonsteroidal anti-inflammatory agents.1,2

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Eli Lilly and Company. Alimta^® (pemetrexed) for injection prescribing information. Indianapolis, IN; 2004 Aug 19.

2. Eli Lilly and Company. Information for patients and caregivers: Alimta^® (pemetrexed for injection). Indianapolis, IN; 2004 Aug 19.

3. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol . 2003; 21:2636-44. [PubMed 12860938]

4. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol . 2004; 22:1589-97. [PubMed 15117980]

5. Anon. Pemetrexed (Alimta) for mesothelioma. Med Lett Drugs Ther . 2004; 46:31-2. [PubMed 15079145]

6. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website; accessed 2004 Sep 7. [Web]

7. Eli Lilly and Company, Indianapolis, IN: Personal communication.