Generic Name: Pemetrexed Disodium
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N-[4-2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid disodium salt.
Molecular Formula: C20H19N5Na2O6
CAS Number: 150399-23-8

Introduction

Antineoplastic agent; a folic acid antagonist.1 3 4 5

Uses for Alimta

Malignant Pleural Mesothelioma

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 (designated an orphan drug by FDA for this indication).1 3 5 6

Slideshow: The Ferocity of Chemotherapy - Does The End Justify The Means?

Non-small Cell Lung Cancer

Monotherapy for the treatment of locally advanced or metastatic non-small cell lung cancer in adults who have received prior chemotherapy.1 4 Efficacy based on surrogate end points of tumor response rate; improvement in disease-related symptoms or increased survival not demonstrated in clinical studies.1

Alimta Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

Premedication

  • Consider pretreatment with a corticosteroid to reduce the incidence and severity of cutaneous reactions.1 Oral dexamethasone 4 mg twice daily for 3 days, starting 1 day before pemetrexed, used in clinical studies.1 (See Dermatologic Effects under Cautions.)

Vitamin Supplementation

  • To reduce toxicity, all patients should take low-dose oral folic acid (0.4 mg daily) or a multivitamin preparation containing folic acid for at least 5 daily doses during the 7-day period before the first dose of pemetrexed; continue folic acid during therapy and for 21 days after the last dose of pemetrexed.1

  • Administer one IM injection of vitamin B12 during the week before the first dose of pemetrexed and then once every 3 cycles; subsequent injections may be given the same day as pemetrexed.1 3 IM vitamin B12 1 mg used in clinical studies.1 (See Folate and Vitamin B12 Supplementation under Cautions.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Prepare and handle cautiously; use protective gloves.1 If skin contact occurs, immediately wash affected area(s) thoroughly with soap and water.1 If mucosa contact occurs, immediately flush thoroughly with water.1

Not a vesicant.1 Manage extravasation according to local practice standards.1

Reconstitution

Reconstitute vial containing 500 mg of pemetrexed with 20 mL of 0.9% sodium chloride injection (without preservatives) to provide a solution containing 25 mg/mL.1

Gently swirl vial until powder is completely dissolved.1 Must be diluted further before IV administration.1

Dilution

Following reconstitution, add the appropriate volume to 100 mL of 0.9% sodium chloride injection (without preservatives).1

Rate of Administration

Administer by IV infusion over 10 minutes.1

Dosage

Available as pemetrexed disodium heptahydrate; dosage expressed in terms of anhydrous pemetrexed.1

Adults

Malignant Pleural Mesothelioma
IV

500 mg/m2 on day 1 of a 21-day cycle.1 Used in conjunction with cisplatin 75 mg/m2 on day 1 of a 21-day cycle; initiate cisplatin infusion 30 minutes after completion of pemetrexed infusion.1

Consult published protocols for information on administration of cisplatin.1

Adjust subsequent dosages of pemetrexed and cisplatin based on nadir blood counts (i.e., ANCs, platelet counts) and maximum nonhematologic toxicity from preceding dose.1 (See Dose Modification for Toxicity under Dosage and Administration.)

Do not administer repeat course until ANCs ≥1500/mm3, platelet count ≥100,000/mm3, and Clcr ≥45 mL/minute.1

Non-small Cell Lung Cancer
IV

500 mg/m2 on day 1 of a 21-day cycle.1

Adjust subsequent dosages based on nadir blood counts (i.e., ANCs, platelet counts) and maximum nonhematologic toxicity from preceding dose.1 (See Dose Modification for Toxicity under Dosage and Administration.)

Do not administer repeat course until ANCs ≥1500/mm3, platelet count ≥100,000/mm3, and Clcr ≥45 mL/minute.1

Dosage Modification for Toxicity

Delay treatment to allow time for recovery from toxicity.1

Hematologic Toxicity

Reduce dose according to nadir ANC and platelet count.1 (See Table 1.)

Discontinue therapy if patient experiences grade 3 or 4 hematologic toxicity after 2 dose reductions.1

Table 1. Recommended Dosage Modification for Hematologic Toxicity of Pemetrexed Monotherapy or Pemetrexed and Cisplatin Combination Therapy

Toxicity

Dose of Pemetrexed

Dose of Cisplatin

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3

75% of previous dose

75% of previous dose

Nadir platelets <50,000/mm3, regardless of nadir ANC

50% of previous dose

50% of previous dose

Nonhematologic Toxicity (Except Neurotoxicity)

Reduce dose based on toxicity type and severity. (See Table 2.)1

Interrupt therapy for grade 3 (except grade 3 elevation in serum transaminase values) or 4 nonhematologic toxicity until resolution to at least pretreatment values.1

Dosage modification not required for grade 3 elevation in serum transaminase values.1 7

Discontinue if patient experiences grade 3 or 4 nonhematologic toxicity (except grade 3 elevation in serum transaminase values) after 2 dose reductions.1

Table 2. Recommended Dosage Modification for Nonhematologic Toxicity (Except Neurotoxicity) of Pemetrexed Monotherapy or Pemetrexed and Cisplatin Combination Therapy

Toxicity and National Cancer Institute (NCI) Common Toxicity Criteria Grade

Dose of Pemetrexed

Dose of Cisplatin

Any grade 3 or 4 nonhematologic toxicity (except neurotoxicity), excluding grade 3 or 4 mucositis or grade 3 elevation in serum transaminase values

75% of previous dose

75% of previous dose

Any diarrhea requiring hospitalization (regardless of grade) or grade 3 or 4 diarrhea

75% of previous dose

75% of previous dose

Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

Neurotoxicity

Reduce cisplatin dose for grade 2 neurotoxicity; no change in pemetrexed dose needed.1 (See Table 3.)

Discontinue immediately for grade 3 or 4 neurotoxicity.1

Table 3. Recommended Dosage Modifications for Neurotoxicity of Pemetrexed Monotherapy or Pemetrexed and Cisplatin Combination Therapy

NCI Common Toxicity Criteria Grade

Dose of Pemetrexed

Dose of Cisplatin

0–1

100% of previous dose

100% of previous dose

2

100% of previous dose

50% of previous dose

Special Populations

Renal Impairment

Clcr≥45 mL/minute: Routine dosage adjustment not required.1

Clcr<45 mL/minute: Insufficient information to make dosage recommendation; use not recommended.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustments except those recommended for all patients.1

Cautions for Alimta

Contraindications

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

Warnings/Precautions

Warnings

Hematologic Toxicity

Dose-limiting bone marrow suppression (neutropenia, thrombocytopenia, and/or anemia).1 ANC nadir at day 8–10, with return to baseline 4–8 days after nadir.1

Folate and Vitamin B12 Supplementation

Folic acid and vitamin B12 needed to prevent treatment-related hematologic and GI toxicity.1 Use of these supplements associated with overall reduction in toxicity and reduction in grade 3/4 hematologic and nonhematologic toxicities (i.e., neutropenia, febrile neutropenia, infection with grade 3/4 neutropenia).1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Sensitivity Reactions

Dermatologic Effects

Rash reported.1 Premedicate patients with corticosteroids to reduce incidence and severity of cutaneous reactions.1

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Prior to and during therapy, assess CBC and platelet counts.1 Monitor renal and hepatic function 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 large effusions be drained before therapy.5

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether premetrexed is distributed into milk.1 Discontinue nursing prior to therapy because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy not established.1

Hepatic Impairment

Patients with hepatic impairment excluded from clinical trials except those with liver metastases and transaminase concentrations 3–5 times the ULN.1

Dosage adjustment based on hepatic impairment (i.e., grade 4 elevations in serum transaminase values) experienced during therapy required.1 (See Nonhematologic Toxicity (except Neurotoxicity) under Dosage and Administration.)

Renal Impairment

Clearance may be decreased; dosage adjustment not needed in patients with Clcr≥45 mL/minute.1

Use not recommended in patients with Clcr<45 mL/minute.1

Withhold repeat cycles until Clcr≥45 mL/minute.1

Use of pemetrexed with cisplatin not evaluated in patients with moderate renal impairment.1

Caution advised if NSAIAs used in pemetrexed-treated patients with renal impairment.1 (See Specific Drugs under Interactions.)

Common Adverse Effects

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

Interactions for Alimta

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely with drugs metabolized by CYP1A2, 2C9, 2D6, or 3A.1

Nephrotoxic Drugs

Possible delayed clearance of pemetrexed.1

Specific Drugs

Drug

Interaction

Comments

Cisplatin

Pharmacokinetic interaction unlikely1

NSAIAs

Aspirin (325 mg every 6 hours) does not affect pemetrexed pharmacokinetics; effect of higher aspirin dosage not known1

Ibuprofen may increase pemetrexed AUC1

Effect of NSAIAs with longer half-life on pemetrexed pharmacokinetics not evaluated1

Caution if used concomitantly with ibuprofen in patients with mild to moderate renal impairment (Clcr 45–79 mL/minute)1

Patients with mild to moderate renal impairment should not take NSAIAs with short half-lives for 2 days before, the day of, and for 2 days after pemetrexed administration1 3 7

Patients with mild to moderate renal impairment should not take NSAIAs with longer half-lives for 5 days before, the day of, and for 2 days after pemetrexed administration1

Monitor for toxicity (e.g., myelosuppression and renal and GI toxicity) if concomitant use is necessary1

Probenecid

Possible delayed clearance of pemetrexed1

Similar interaction possible with other substances secreted at the renal tubule1

Vitamins

Decreased pemetrexed toxicity with concomitant oral folic acid and vitamin B121

Pharmacokinetic interaction unlikely with oral folic acid or vitamin B121

Alimta Pharmacokinetics

Absorption

Special Populations

In patients with renal impairment (Clcr 45–80 mL/minute), increased AUC.1

Distribution

Plasma Protein Binding

81%.1

Special Populations

Degree of renal impairment does not affect protein binding.1

Elimination

Metabolism

Not metabolized to an appreciable extent.1

Elimination Route

Principally eliminated in urine as unchanged drug.1

Half-life

3.5 hours.1

Special Populations

Clearance of pemetrexed decreases as renal function decreases.1

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

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1

Store reconstituted solution and infusion solutions at 25°C (may be exposed to 15–30°C) or refrigerate at 2–8°C; use solution within 24 hours of reconstitution; discard unused solution.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Use 0.9% sodium chloride injection (without preservatives) to reconstitute and dilute pemetrexed.1

Pemetrexed is not compatible with diluents containing calcium (e.g., Ringer’s injection; Ringer’s injection, lactated).1

Manufacturer recommends that pemetrexed not be administered with other drugs or diluents other than 0.9% sodium chloride injection.1

Actions

  • Disrupts folate-dependent metabolic processes that are essential for cell replication.1 3

  • Inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052).1 Synergistic inhibitory effects with cisplatin in the MSTO-211H mesothelioma cell line.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 plan 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 (e.g., NSAIAs) as well as concomitant illnesses.1 2

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pemetrexed Disodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

500 mg (of pemetrexed)

Alimta

Lilly

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. [IDIS 503150] [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. [IDIS 518149] [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.

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

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