Pemetrexed: Drug information
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(For additional information see "Pemetrexed: Patient drug information")

For abbreviations and symbols that may be used in Lexicomp (show table)
Brand Names: US
  • Alimta
Brand Names: Canada
  • Alimta
Pharmacologic Category
  • Antineoplastic Agent, Antimetabolite;
  • Antineoplastic Agent, Antimetabolite (Antifolate)
Dosing: Adult

Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1,000 mcg orally once daily (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1,000 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 ≥1,500/mm3, platelets ≥100,000/mm3, CrCl ≥45 mL/minute, and recovery of nonhematologic toxicity to ≤ grade 2.

Malignant pleural mesothelioma: IV: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin); continue until disease progression or unacceptable toxicity 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 of locally advanced or metastatic NSCLC: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin) for up to 6 cycles or until disease progression or unacceptable toxicity

Maintenance treatment of locally advanced or metastatic NSCLC (after 4 cycles of initial platinum-based therapy): 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

Second-line treatment of recurrent/metastatic disease (after prior chemotherapy): 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

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.

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).

Renal toxicity during treatment: Withhold pemetrexed until CrCl is 45 mL/minute or higher.

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 ibuprofen use with renal dysfunction:

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

CrCl 45 to 79 mL/minute: Avoid ibuprofen for 2 days before, the day of, and for 2 days following a dose of pemetrexed. Monitor more frequently for myelosuppression, renal, and GI toxicities if concomitant ibuprofen administration cannot be avoided.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, pemetrexed pharmacokinetics do not appear to be affected based on elevated ALT, AST, or total bilirubin.

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).

Dosing: Adjustment for Toxicity

Note: Concomitant combination chemotherapy agents (eg cisplatin) may also require dosage modification.

Hematologic toxicity: Upon recovery, reinitiate therapy as follows:

ANC <500/mm3 and platelets ≥50,000/mm3: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm3 without bleeding: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm3 with bleeding: Reduce pemetrexed dose to 50% of previous dose

Recurrent grade 3 or 4 myelosuppression after 2 dose reductions: Discontinue

Nonhematologic toxicity: Withhold treatment until recovery to ≤ grade 2; upon recovery, reinitiate or discontinue therapy as follows:

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

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

Grade 3 or 4 mucositis: Reduce pemetrexed dose to 50% of previous dose

Grade 3 or 4 neurotoxicity: Permanently discontinue

Interstitial pneumonitis: Permanently discontinue

Radiation recall signs/symptoms: Permanently discontinue

Severe or life-threatening dermatologic toxicity: Permanently discontinue

Recurrent grade 3 or 4 nonhematologic toxicity after 2 dose reductions: Permanently discontinue

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)

Generic Equivalent Available (US)

No

Administration

IV: Infuse over 10 minutes. When used in combination with cisplatin, administer prior to cisplatin.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends double gloving, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) for preparation. Double gloving, a gown, and (if dosage form allows) CSTDs are required during administration (NIOSH 2016).

Use

Mesothelioma: Initial treatment of unresectable malignant pleural mesothelioma (in combination with cisplatin) or in patients who are not otherwise candidates for curative surgery

Non-small cell lung cancer (NSCLC), nonsquamous: Initial treatment of locally advanced or metastatic nonsquamous NSCLC (in combination with cisplatin); maintenance treatment of locally advanced or metastatic nonsquamous NSCLC if no progression after 4 cycles of initial platinum-based first-line therapy; single-agent treatment (after prior chemotherapy) of recurrent/metastatic nonsquamous NSCLC

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

Use: Off-Label

Bladder cancer, metastatic; Cervical cancer, persistent or recurrent; Malignant pleural mesothelioma (single agent and off-label combination); Ovarian cancer, platinum-resistant; Thymic malignancies, metastatic

Medication Safety Issues
Sound-alike/look-alike issues:

PEMEtrexed may be confused with methotrexate, PRALAtrexate

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

>10%:

Central nervous system: Fatigue (18% to 34%)

Dermatologic: Desquamation (≤14%), skin rash (≤14%)

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

Hematologic & oncologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), neutropenia (6% to 11%; grades 3/4: 3% to 5%)

Respiratory: Pharyngitis (≤15%)

1% to 10%:

Cardiovascular: Edema (5%)

Central nervous system: Neuropathy (sensory: 9%; motor: ≤5%)

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

Gastrointestinal: Mucositis (≤7%), constipation (6%), abdominal pain (1% to <5%)

Hematologic & oncologic: Thrombocytopenia (8%; grades 3/4: 2%), febrile neutropenia (<5%)

Hepatic: Increased serum ALT (8% to 10%), increased serum AST (7% to 8%)

Hypersensitivity: Hypersensitivity reaction (<5%)

Infection: Infection (1% to <5%), sepsis (1%)

Ophthalmic: Conjunctivitis (≤5%), increased lacrimation (1% to <5%)

Miscellaneous: Fever (8%)

<1%, postmarketing, and/or case reports: Bullous rash, colitis, depression, esophagitis, gastrointestinal obstruction, hemolytic anemia, interstitial pneumonitis, pain, pancreatitis, pulmonary embolism, radiation recall phenomenon, renal failure, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, syncope, toxic epidermal necrolysis, ventricular tachycardia

Contraindications

Severe hypersensitivity to pemetrexed or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Concomitant yellow fever vaccine

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Pemetrexed may cause severe myelosuppression, including anemia, neutropenia, thrombocytopenia and/or pancytopenia; frequent laboratory monitoring is necessary (myelosuppression is often dose-limiting). Severe myelosuppression may require blood transfusion. 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 and continue for 21 days after the last pemetrexed dose (the risk for myelosuppression is higher in patients who did not receive vitamin supplementation). Monitor blood counts at the beginning of each cycle, and as clinically indicated. Dose reductions in subsequent cycles may be required due to myelosuppression.

• Cutaneous reactions: Serious and occasionally fatal dermatologic toxicity 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. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering, or exfoliating dermatologic toxicity.

• Gastrointestinal toxicity: 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 and continue for 21 days after the last pemetrexed dose.

• Hypersensitivity: Hypersensitivity (including allergic reaction) has been reported with pemetrexed.

• Nephrotoxicity: Pemetrexed may cause severe (and potentially fatal) renal toxicity (renal toxicity may occur with single-agent pemetrexed or when used in combination with other chemotherapy agents). Measure creatinine clearance prior to each dose and monitor renal function throughout treatment. May require therapy discontinuation. Withhold pemetrexed treatment for creatinine clearance <45 mL/minute.

• Pulmonary toxicity: Interstitial pneumonitis has been observed with use; may be serious and/or fatal. Interrupt therapy and evaluate promptly for acute onset new or progressive pulmonary symptoms (eg, dyspnea, cough, or fever). If interstitial pneumonitis is confirmed, permanently discontinue pemetrexed.

• Radiation recall: Radiation recall may occur in patients administered pemetrexed who received radiation previously (weeks to years). Monitor for inflammation or blistering in areas of prior radiation treatment; permanently discontinue pemetrexed if radiation recall is confirmed.

Disease-related concerns:

• Renal impairment: Pemetrexed is primarily cleared by the kidneys; 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 on pemetrexed pharmacokinetics has not been 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.

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.

• Ibuprofen: Ibuprofen may reduce the clearance of pemetrexed. In patients with CrCl 45 to 79 mL/minute, interrupt ibuprofen therapy 2 days prior to, during, and 2 days after pemetrexed therapy. If concomitant use cannot be avoided, monitor for myelosuppression, renal, and gastrointestinal toxicity.

Metabolism/Transport Effects

Substrate of OAT3

Drug Interactions

(For additional information: Launch drug interactions program)

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

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

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

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

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

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

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

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

Ibuprofen: May increase the serum concentration of PEMEtrexed. Management: In patients with an estimated creatinine clearance of 45 to 79 mL/min, avoid ibuprofen for 2 days before, the day of, and 2 days following the administration of pemetrexed. Monitor for increased pemetrexed toxicities if combined. Risk D: 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. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

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

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Pyrimethamine: May enhance the adverse/toxic effect of PEMEtrexed. Risk C: Monitor therapy

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

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

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

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Risk C: Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: 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. Risk D: 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. Risk X: Avoid combination

Pregnancy Implications

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 reproductive potential should use effective contraception during treatment and for at least 6 months after the last pemetrexed dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last pemetrexed dose. Pemetrexed may impair fertility in males.

Breast-Feeding Considerations

It is not known if pemetrexed is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during treatment and for 1 week after the final dose.

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 pemetrexed dose. Institute vitamin B12 1 week before the first dose; administer every 9 weeks thereafter.

Monitoring Parameters

CBC with differential and platelets (before each cycle, on days 8 and 15 of 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, pulmonary toxicity, dermatologic toxicity, and radiation recall.

Mechanism of Action

Pemetrexed is an antifolate; it disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed 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.

Pharmacodynamics/Kinetics

Distribution: 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)

Pricing: US

Solution (reconstituted) (Alimta Intravenous)

100 mg (1): $799.82

500 mg (1): $3,999.12

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Alimta (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, IS, IT, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NL, NO, NZ, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, UA, VN);
  • Armisarte (IE);
  • Ciambra (IE);
  • Emetex (TH);
  • Empet (CR, DO, GT, HN, NI, PA, SV);
  • Enzastar (VN);
  • Jie Baili (CN);
  • Pemecine (KR);
  • Pemeker (EC);
  • Pemeted (LK);
  • Pemetrex (BD);
  • Pemex (LK);
  • Virplazit (CR, DO, GT, HN, NI, PA, SV)
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REFERENCES

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  2. Alimta (pemetrexed) [product monograph]. Mississauga, Ontario, Canada: Actavis Pharma Company; July 2014.
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  14. Miller DS, Blessing JA, Krasner CN, et al, “Phase II Evaluation of Pemetrexed in the Treatment of Recurrent or Persistent Platinum-Resistant Ovarian or Primary Peritoneal Carcinoma: A Study of the Gynecologic Oncology Group,” J Clin Oncol, 2009, 27(16):2686-91. [PubMed 19332726]
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