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PEMEtrexed

Pronunciation

(pem e TREKS ed)

Index Terms

  • LY231514
  • Pemetrexed Disodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Alimta: 100 mg (1 ea); 500 mg (1 ea)

Brand Names: U.S.

  • Alimta

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Antifolate)

Pharmacology

Antifolate; disrupts folate-dependent metabolic processes essential for cell replication. Inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), the enzymes involved in folate metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and protein synthesis.

Distribution

Vdss: 16.1 L

Metabolism

Minimal

Excretion

Urine (70% to 90% as unchanged drug)

Half-Life Elimination

Normal renal function: 3.5 hours

Protein Binding

~81%

Special Populations: Renal Function Impairment

Cl decreases and AUC increases as renal function decreases; in patients with CrCl of 45, 50, and 80 mL/minute, AUC was increased 65%, 54%, and 13%, respectively, compared to patients with CrCl of 100 mL/minute

Use: Labeled Indications

Mesothelioma: Treatment of unresectable malignant pleural mesothelioma (in combination with cisplatin)

Non-small cell lung cancer (NSCLC), nonsquamous: Treatment of locally advanced or metastatic nonsquamous NSCLC (as initial treatment in combination with cisplatin; as maintenance treatment after 4 cycles of initial platinum-based first-line therapy; as single-agent treatment after prior chemotherapy)

Limitation of use: Not indicated for the treatment of squamous cell NSCLC

Use: Unlabeled

Treatment of bladder cancer (metastatic), cervical cancer (recurrent or persistent), ovarian cancer (recurrent or persistent), thymic malignancies (metastatic); treatment of malignant pleural mesothelioma (either as a single agent or in combination with carboplatin)

Contraindications

Severe hypersensitivity to pemetrexed or any component of the formulation

Canadian labeling: Additional contraindications; not in US labeling: Concomitant yellow fever vaccine

Dosing: Adult

Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1000 mcg daily orally (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1500/mm3, platelets ≥100,000/mm3, and CrCl ≥45 mL/minute.

Malignant pleural mesothelioma: IV: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin) or (off-label) in combination with carboplatin (Castagneto 2008; Ceresoli 2006) or (off-label) as single-agent therapy (Taylor 2008)

Non-small cell lung cancer, nonsquamous: IV:

Initial treatment: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin)

Maintenance or second-line treatment: 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent)

Bladder cancer, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity (Sweeney 2006)

Cervical cancer, persistent or recurrent (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs (Lorusso 2010) or 900 mg/m2 on day 1 of each 21-day cycle (Miller 2008)

Ovarian cancer, platinum-resistant (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle (Vergote 2009)

Thymic malignancies, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle for 6 cycles or until disease progression or unacceptable toxicity occurs (Loehrer 2006)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal function may be estimated using the Cockcroft-Gault formula (using actual body weight) or glomerular filtration rate (GFR) measured by Tc99m-DPTA serum clearance.

CrCl ≥45 mL/minute: No dosage adjustment necessary.

CrCl <45 mL/minute: Use is not recommended by the manufacturer (an insufficient number of patients have been studied for dosage recommendations).

According to a phase I study in advanced cancer patients with renal impairment, pemetrexed doses up to 500 mg/m2 (with vitamin supplementation) were well tolerated in patients with glomerular filtration rate (GFR) 40 to 79 mL/minute; however, accrual was halted in patients with GFR <29 mL/minute (due to toxicity) and accrual did not occur in patients with GFR 30 to 39 mL/minute. Patients with GFR ≥80 mL/minute tolerated doses of 600 mg/m2 (Mita 2006).

Concomitant NSAID use with renal dysfunction:

CrCl ≥80 mL/minute: No dosage adjustment necessary.

CrCl 45 to 79 mL/minute and NSAIDs with short half-lives (eg, ibuprofen, indomethacin, ketoprofen, ketorolac): Avoid NSAID for 2 days before, the day of, and for 2 days following a dose of pemetrexed.

Any creatinine clearance and NSAIDs with long half-lives (eg, nabumetone, naproxen, oxaprozin, piroxicam): Avoid NSAID for 5 days before, the day of, and 2 days following a dose of pemetrexed.

Dosing: Hepatic Impairment

Grade 3 (5.1 to 20 times ULN) or 4 (>20 times ULN) transaminase elevation during treatment: Reduce pemetrexed dose to 75% of previous dose (and cisplatin).

Dosing: Adjustment for Toxicity

Toxicity: Discontinue if patient develops grade 3 or 4 toxicity after two dose reductions 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 without bleeding (regardless of nadir ANC): Reduce dose to 75% of previous dose of pemetrexed (and cisplatin)

Nadir platelets <50,000/mm3 with bleeding (regardless of nadir ANC): Reduce dose to 50% of previous dose of pemetrexed (and cisplatin)

Nonhematologic toxicity ≥grade 3 (excluding neurotoxicity): Withhold treatment until recovery to baseline; upon recovery, reinitiate therapy as follows:

Grade 3 or 4 toxicity (excluding mucositis): Reduce dose to 75% of previous dose of pemetrexed (and cisplatin)

Grade 3 or 4 diarrhea or any diarrhea requiring hospitalization: Reduce dose to 75% of previous dose of pemetrexed (and cisplatin)

Grade 3 or 4 mucositis: Reduce pemetrexed dose to 50% of previous dose (continue cisplatin at 100% of previous dose)

Neurotoxicity:

Grade 0 to 1: Continue pemetrexed at 100% of previous dose (and cisplatin)

Grade 2: Continue pemetrexed at 100% of previous dose; reduce cisplatin dose to 50% of previous dose

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute with NS (preservative free); add 4.2 mL to the 100 mg vial and 20 mL to the 500 mg vial, resulting in a 25 mg/mL concentration. Gently swirl. Solution may be colorless to green-yellow. Further dilute in 100 mL NS prior to infusion (the manufacturer recommends a total volume of 100 mL); may also dilute in D5W (Zhang, 2006), although the manufacturer recommends NS.

Administration

IV: Infuse over 10 minutes. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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.

Compatibility

Stable in D5W (Zhang, 2006), NS; physically incompatible with calcium-containing products, including Ringer’s and lactated Ringer’s injection.

Y-site administration: Incompatible: Amphotericin B, calcium gluconate, cefazolin, cefotaxime, cefotetan, cefoxitin, ceftazidime, chlorpromazine, ciprofloxacin, dobutamine, doxorubicin, doxycycline, droperidol, gemcitabine, gentamicin, irinotecan, metronidazole, minocycline, mitoxantrone, nalbuphine, ondansetron, prochlorperazine edisylate, tobramycin, topotecan.

Storage

Store intact vials at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted solution in NS and infusion solutions (in D5W or NS) are stable for 24 hours when refrigerated at 2°C to 8°C (36°F to 46°F). Concentrations at 25 mg/mL are stable in polypropylene syringes for 2 days at room temperature (23°C) (Zhang, 2005).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

NSAID (Nonselective): May increase the serum concentration of PEMEtrexed. Management: Patients with mild-to-moderate renal insufficiency (estimated creatinine clearance 45-79 mL/min) should avoid NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (18% to 34%; dose-limiting)

Dermatologic: Rash/desquamation (10% to 14%)

Gastrointestinal: Nausea (12% to 31%), anorexia (19% to 22%), vomiting (6% to 16%), stomatitis (5% to 15%), diarrhea (5% to 13%)

Hematologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), leukopenia (6% to 12%; grades 3/4: 2% to 4%), neutropenia (6% to 11%; grades 3/4: 3% to 5%; dose-limiting; nadir: 8-10 days; recovery: 4-8 days after nadir)

Respiratory: Pharyngitis (15%)

1% to 10%:

Cardiovascular: Edema (1% to 5%)

Central nervous system: Fever (1% to 8%)

Dermatologic: Pruritus (1% to 7%), alopecia (1% to 6%), erythema multiforme (≤5%)

Gastrointestinal: Constipation (1% to 6%), weight loss (1%), abdominal pain (≤5%)

Hematologic: Thrombocytopenia (1% to 8%; grades 3/4: 2%; dose-limiting), febrile neutropenia (grades 3/4: 2%)

Hepatic: ALT increased (8% to 10%; grades 3/4: ≤2%), AST increased (7% to 8%; grades 3/4: ≤1%)

Neuromuscular & skeletal: Sensory neuropathy (≤9%), motor neuropathy (≤5%)

Ocular: Conjunctivitis (≤5%), lacrimation increased (≤5%)

Renal: Creatinine increased/creatinine clearance decreased (1% to 5%)

Miscellaneous: Allergic reaction/hypersensitivity (≤5%), infection (≤5%), sepsis (1%)

<1% (Limited to important or life-threatening): Arrhythmia, colitis, dehydration, esophagitis, gastrointestinal obstruction, hemolytic anemia, hepatobiliary failure, hypertension, interstitial pneumonitis, pancreatitis, pancytopenia, peripheral ischemia, pulmonary embolism, radiation recall (median onset: 6 days; range: 1-35 days), renal failure, Stevens-Johnson syndrome, supraventricular arrhythmia, syncope, thrombosis/embolism, toxic epidermal necrolysis, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause anemia, neutropenia, thrombocytopenia and/or pancytopenia; frequent laboratory monitoring is necessary (myelosuppression is often dose-limiting). Dose reductions in subsequent cycles may be required. Prophylactic folic acid and vitamin B12 supplements are necessary to reduce hematologic toxicity, febrile neutropenia and infection; initiate supplementation 1 week before the first dose of pemetrexed.

• Cutaneous reactions: May occur; pretreatment with dexamethasone is necessary to reduce the incidence and severity of cutaneous reactions. Rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

• Gastrointestinal toxicity: May occur; prophylactic folic acid and vitamin B12 supplements are necessary to reduce gastrointestinal toxicity; initiate supplementation 1 week before the first dose of pemetrexed.

• Hepatotoxicity: Serious hepatotoxicity (including rare fatalities) has been observed with monotherapy and in association with other chemotherapy, although underlying risk factors were present in some cases. Use caution with hepatic impairment not due to metastases; may require dose adjustment.

• Hypersensitivity: Hypersensitivity (including anaphylaxis) has been reported with use.

• Respiratory: Interstitial pneumonitis with respiratory insufficiency has been observed with use; interrupt therapy and evaluate promptly with progressive dyspnea and cough.

Disease-related concerns:

• Renal impairment: Decreased renal function results in increased toxicity. The manufacturer does not recommend use if CrCl <45 mL/minute. Use caution in patients receiving concurrent nephrotoxins; may result in delayed pemetrexed clearance.

• Third space fluid: Although the effect of third space fluid is not fully defined, studies have determined pemetrexed concentrations in patients with mild-to-moderate ascites/pleural effusions were similar to concentrations in trials of patients without third space fluid accumulation. Drainage of fluid from ascites/effusions may be considered, but is not likely necessary.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• NSAIDs: NSAIDs may reduce the clearance of pemetrexed. In patients with CrCl 45 to 79 mL/minute, interruption of NSAID therapy may be necessary prior to, during, and immediately after pemetrexed therapy.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• NSCLC appropriate use: Not indicated for use in patients with squamous cell NSCLC.

Monitoring Parameters

CBC with differential and platelets (before each cycle and as needed; monitor for nadir and recovery); renal function tests (serum creatinine, creatinine clearance, BUN; prior to each cycle and as needed) total bilirubin, ALT, AST (periodic); signs/symptoms of mucositis and diarrhea

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Based on the mechanism of action, pemetrexed may cause fetal harm if administered to a pregnant woman. Women of childbearing potential should use effective contraceptive measures to avoid becoming pregnant during treatment. A negative serum pregnancy test prior to treatment is recommended in the Canadian labeling. The Canadian labeling also recommends that males receiving therapy use effective contraceptive measures and not father a child during, and for up to 6 months after, therapy. Additionally, the Canadian labeling recommends counseling on sperm storage prior to treatment, as irreversible infertility has been reported in males.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, pharyngitis, or hair loss. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, shortness of breath, severe nausea, severe vomiting, severe diarrhea, severe constipation, bruising, bleeding, severe loss of strength and energy, severe skin irritation, dysphagia, severe mouth pain or irritation, burning or numbness feeling, or pale skin (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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