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  • CLASSES

    Folic Acid Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Pyrimidine-based antifolate that targets multiple enzymes, including thymidine synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase
    Used for the treatment of NSCLC and mesothelioma
    Requires supplementation with folic acid and vitamin B12 to mitigate hematologic and GI toxicities, and dexamethasone for cutaneous toxicities

    COMMON BRAND NAMES

    Alimta, PEMFEXY

    HOW SUPPLIED

    Alimta Intravenous Inj Pwd F/Sol: 100mg, 500mg
    Pemetrexed Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of malignant pleural mesothelioma.
    For the treatment of malignant pleural mesothelioma that is unresectable or in patients who are otherwise not candidates for surgery, in combination with cisplatin.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes on day 1, followed by cisplatin (75 mg/m2 IV beginning approximately 30 minutes after the end of the pemetrexed infusion), every 21 days until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. Treatment with pemetrexed plus cisplatin significantly improved the median overall survival for chemotherapy-naive patients with malignant mesothelioma compared with cisplatin monotherapy (13.3 months vs. 10 months); approximately 75% of patients had either stage 3 or 4 disease. The median time to progressive disease in the intent-to-treat group (regardless of supplementation) was 5.7 months in the pemetrexed group and 3.9 months in those who received cisplatin monotherapy, and the tumor response rate was 41.3% compared with 16.7%, respectively.

    For the treatment of previously untreated, advanced, unresectable malignant pleural mesothelioma, in combination with cisplatin and bevacizumab†.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes on day 1, followed by cisplatin (75 mg/m2 IV beginning approximately 30 minutes after the end of the pemetrexed infusion), plus bevacizumab (15 mg/kg IV), every 21 days for 6 cycles; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. Infuse the first bevacizumab infusion over 90 minutes; if tolerated, infuse the second over 60 minutes, and then if tolerated, subsequent infusions may be administered over 30 minutes. After completion of the last cycle of pemetrexed/cisplatin/bevacizumab, begin maintenance bevacizumab 15 mg/kg IV over 30 to 90 minutes every 21 days until disease progression or unacceptable toxicity. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed.

    For the treatment of previously untreated, advanced, unresectable malignant pleural mesothelioma, in combination with carboplatin†.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes on day 1, followed by carboplatin (AUC 5 IV beginning approximately 30 minutes after the end of the pemetrexed infusion), every 21 days for up to 6 cycles, or until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed.

    For the treatment of nonsquamous non-small cell lung cancer (NSCLC).
    NOTE: Pemetrexed is not indicated for the treatment of patients with squamous cell NSCLC.
    For the treatment of recurrent, metastatic, non-squamous NSCLC, after prior chemotherapy, as monotherapy.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes on day 1, every 21 days until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. Overall survival (8.3 months vs. 7.9 months), progression-free survival (2.9 months vs. 2.9 months), and overall response rate (8.5% vs. 8.3%)were not significantly different in patients receiving treatment with pemetrexed compared with docetaxel in a multicenter, open-label, non-inferiority study of patients with recurrent stage III/IV NSCLC after prior treatment with one prior chemotherapy regimen for advanced disease.

    For first-line treatment of locally advanced or metastatic, non-squamous NSCLC, in combination with cisplatin.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes, followed by cisplatin (75 mg/m2 IV beginning approximately 30 minutes after the end of the pemetrexed infusion) on day 1, every 21 days for up to 6 cycles or until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. Overall survival (10.3 months vs. 10.3 months), progression-free survival (4.8 months vs. 5.1 months), and overall response rate (27.1% vs. 24.7%) were not significantly different in chemotherapy naive stage IIIb/IV NSCLC patients randomized to treatment with pemetrexed plus cisplatin compared with gemcitabine plus cisplatin in a multicenter, open-label, non-inferiority study (n = 1,725); patients in both arms received folic acid, vitamin B12, and dexamethasone. Analysis of NSCLC histology revealed significantly worse median survival for pemetrexed/cisplatin patients with squamous-cell histology compared with gemcitabine/cisplatin (9.4 months vs. 10.8 months). Grade 3 or 4 neutropenia (27% vs. 15%), anemia (10% vs. 6%), and thrombocytopenia (13% vs. 4%) were all significantly higher in the cisplatin/gemcitabine arm.

    For maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC, whose disease has not progressed after 4 cycles of first-line platinum-based chemotherapy, as monotherapy.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes on day 1, every 21 days until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. Median progression-free survival (PFS) (4 months vs. 2 months) and overall survival (OS) (13.4 months vs. 10.6 months) were significantly improved following maintenance therapy with pemetrexed compared with placebo in patients with stage IIIb or IV NSCLC who had not progressed after 4 cycles of platinum-based first line chemotherapy in a multicenter, double-blind, phase 3 clinical trial (JMEN). In a subgroup analysis, while OS (15.5 months vs. 10.3 months) and PFS (4.4 months vs. 1.8 months) were significantly improved in patients with non-squamous NSCLC treated with pemetrexed, there was not a significant effect on patients with squamous-cell NSCLC. These results were consistent with the findings of another multicenter, double-blind, phase 3 trial (PARAMOUNT), where median PFS (4.1 months vs. 2.8 months) and OS (13.9 months vs. 11 months) were significantly improved following maintenance therapy with pemetrexed compared with placebo in patients with nonsquamous, stage IIIb or IV NSCLC that had not progressed after 4 cycles of pemetrexed/cisplatin first-line chemotherapy.

    For the first line treatment of stage IIIB or IV non-small cell lung cancer (NSCLC), in combination with carboplatin†.
    Intravenous dosage
    Adults

    500 mg/m2 IV on day 1 in combination with carboplatin (AUC 5 IV) on day 1, repeated every 3 weeks for up to 4 cycles; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. In a multicenter, randomized phase 3 trial, no significant differences were observed for the primary end point, health-related quality of life, or the secondary end point, overall survival for patients treated with pemetrexed/carboplatin compared with gemcitabine/carboplatin (n = 436); grade 3 or 4 toxicities were significantly worse in the gemcitabine/carboplatin arm.

    For first-line treatment of metastatic, EGFR- and ALK-negative, nonsquamous NSCLC, in combination with pembrolizumab and platinum chemotherapy.
    Intravenous dosage
    Adults

    500 mg/m2 IV with either carboplatin (AUC 5 IV) or cisplatin (75 mg/m2 IV) on day 1 repeated every 21 days for 4 cycles in combination with pembrolizumab (200 mg IV on day 1 every 3 weeks OR 400 mg IV on day 1 every 6 weeks). Administer pembrolizumab prior to pemetrexed and chemotherapy when given on the same day. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. Following completion of platinum-based therapy, pemetrexed may be continued as maintenance therapy, either alone or in combination with pembrolizumab (for up to 24 months), until disease progression or unacceptable toxicity. To prevent or minimize toxicities, all patients should also receive dexamethasone for 3 days beginning the day before each pemetrexed dose, folic acid beginning 7 days prior to the first pemetrexed dose, and vitamin B12 injection beginning one week prior to the first dose of pemetrexed. In a multicenter double-blind clinical trial (KEYNOTE-189), patients with previously untreated metastatic, EGFR- and ALK-negative, nonsquamous NSCLC, regardless of PD-L1 status, were randomized to treatment with pemetrexed plus either cisplatin or carboplatin, in combination with either pembrolizumab (n = 410) or placebo (n = 206). After a median follow-up of 31 months, the median overall survival (22 months vs. 10.6 months), progression-free survival (9 months vs. 4.9 months), and overall response rate (48.3% vs. 19.9%) were significantly improved in the pembrolizumab arm. The median duration of response was 12.5 months for patients who received pembrolizumab plus pemetrexed/platinum chemotherapy compared with 7.1 months in those receiving placebo plus pemetrexed/platinum chemotherapy.

    For the treatment of advanced unresectable squamous cell head and neck cancer†.
    Intravenous dosage
    Adults

    500 mg/m2 IV every 21 days was administered to 32 patients in a phase II trial. Nine patients had a partial response, 15 had stable disease, and 8 progressed, which resulted in an overall response rate of 26.5% and overall survival of 6.4 months. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment.

    For the second line treatment of metastatic transitional-cell bladder cancer†.
    Intravenous dosage
    Adults

    500 mg/m2 IV over 10 minutes, every 21 days until disease progression or unacceptable toxicity; after the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment. In a single-cohort phase II study, treatment with pemetrexed led to an overall response rate of 27.7% (complete response rate, 6.4%), a median overall survival time of 9.6 months, and a median time to disease progression of 2.9 months in 47 patients with stage IV transitional-cell carcinoma of the urothelium who had received 1 prior chemotherapy regimen and who had progressive disease following therapy for metastatic disease or within 12 months of neoadjuvant or adjuvant chemotherapy.

    For the treatment of metastatic breast cancer†.
    Intravenous dosage
    Adults

    Pemetrexed 500 mg/m2 to 600 mg/m2 IV on day 1, every 3 weeks has been studied in phase II studies. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment.

    For the first-line treatment of unresectable, locally advanced or metastatic pancreatic cancer, in combination with gemcitabine†.
    Intravenous dosage
    Adults

    At the time of review, evidence does not support the use of pemetrexed plus gemcitabine for this indication. In a phase III clinical trial, pemetrexed 500 mg/m2 IV on day 8 after gemcitabine (on days 1 and 8 of a 21-day cycle) did not improve survival end points, but did cause substantial additional toxicity.

    For the treatment of gastric cancer†.
    Intravenous dosage
    Adults

    500 mg/m2 IV every 21 days has been studied in a phase II study of 36 patients with stage IIIB or IV disease. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    500 mg/m2 IV infusion every 21 days.

    Geriatric

    500 mg/m2 IV infusion every 21 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage recommendations are not available for patients with hepatic impairment; it appears that dosage adjustments are not necessary.

    Renal Impairment

    Baseline Renal Impairment
    CrCL greater than or equal 45 mL/min (calculated using actual body weight): No dosage adjustment needed.
    CrCL less than 45 mL/min: Dosage recommendations are not available; do not administer pemetrexed.
    Treatment-Related Nephrotoxicity
    CrCL less than 45 mL/min: Hold pemetrexed therapy. Resume treatment when CrCL is greater than or equal to 45 mL/min.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    Emetic Risk
    Low
    Administer routine antiemetic prophylaxis prior to treatment.
    Extravasation Risk
    Nonvesicant

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Both the reconstituted Alimta solution and the Pemfexy solution should be clear, colorless to light yellow, or yellow-green.

    Intravenous Administration

    Administer pemetrexed as an IV infusion; do not give by IV injection.
    To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment.
    Each Pemfexy vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
     
    Lyophilized powder for injection (Alimta)
    Reconstitution:
    100 mg vial: Reconstitute with 4.2 mL of preservative-free 0.9% Sodium Chloride Injection, to achieve a concentration of 25 mg/mL.
    500 mg vial: Reconstitute with 20 mL of preservative-free 0.9% Sodium Chloride Injection, to achieve a concentration of 25 mg/mL.
    Do not use calcium-containing solutions for reconstitution.
    Gently swirl each vial until powder is completely dissolved.
    Further dilution is required prior to administration.
    Storage following reconstitution: Reconstituted vials may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours; discard the vial after 24 hours.
     
    Dilution:
    Dilute the appropriate dose of pemetrexed in preservative-free 0.9% Sodium Chloride Injection to a total volume of 100 mL.
    Storage following dilution: The diluted admixture may be stored in the refrigerator for up to 24 hours (after reconstitution) at 2 to 8 degrees C (36 to 46 degrees F).
     
    Intravenous Infusion:
    Administer pemetrexed as an IV infusion over 10 minutes. Do not give by IV injection.
     
    Solution for Injection (Pemfexy)
    Dilution:
    Dilute the appropriate dose of pemetrexed in 5% Dextrose Injection to a total volume of 100 mL. Do not use other diluents, such as Lactated Ringer's Injection or Ringer's Injection.
    Storage following dilution: Diluted solutions may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) or at ambient room temperature and room lighting for up to 48 hours. When prepared as directed, infusion solutions contain no antimicrobial preservatives; discard after 48 hours.
     
    Intravenous Infusion:
    Administer pemetrexed as an IV infusion over 10 minutes. Do not give by IV injection.

    STORAGE

    Alimta:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store unreconstituted product at 77 degrees F; excursions permitted to 59-86 degrees F
    PEMFEXY:
    - Diluted product if not used immediately should be refrigerated and used within 48 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused product 28 days after opening the bottle
    - Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pemetrexed use is contraindicated in patients who have had a severe hypersensitivity reaction to the product. Pemetrexed sterile lyophilized powder for injection contains mannitol.
    To reduce the severity of pemetrexed toxicity, including hematologic, gastrointestinal, and dermatologic toxicity, oral dexamethasone and vitamin supplementation with oral folic acid and IM vitamin B12 are recommended.

    Renal impairment

    Use pemetrexed with caution in patients with preexisting renal impairment, as severe and sometimes fatal nephrotoxicity has been reported in clinical trials. Monitor creatinine clearance (CrCL) before each dose of pemetrexed and periodically during treatment. No dosage reduction is required in patients with a CrCl of 45 mL/min or higher; however, pemetrexed is not recommended in patients with a CrCL less than 45 mL/min as its use has not been studied sufficiently in these patients.

    Bone marrow suppression, neutropenia, thrombocytopenia

    Use pemetrexed with caution in patients with any degree of preexisting bone marrow suppression. Severe myelosuppression has been reported, including thrombocytopenia requiring transfusions and neutropenia leading to infection. All patients should receive concomitant treatment with oral folic acid and intramuscular vitamin B12 prior to the first dose of pemetrexed and for at least 21 days after the last dose; the risk of myelosuppression is greater in patients who do not receive vitamin supplementation. Monitor complete blood counts on day 1, 8, and 15 of each cycle; do not administer pemetrexed if the absolute neutrophil count (ANC) is less than 1,500 cells/mm3 or the platelet count is less than 100,000 cells/mm3. An interruption of therapy or dose reduction may be necessary for myelosuppression in the previous cycle; permanently discontinue pemetrexed for an ANC less than 500 cells/mm3 or platelet count less than 50,000 cells/mm3.

    Pneumonitis, pulmonary disease

    Use pemetrexed with caution in patients with a history of pulmonary disease. Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Hold pemetrexed therapy and promptly evaluate any patient with an acute onset of new or progressive unexplained respiratory symptoms (e.g., dyspnea, cough, and fever). Permanently discontinue pemetrexed if pneumonitis is confirmed.

    Radiation therapy

    Use pemetrexed with caution in patients with a history of treatment with radiation therapy, as radiation recall can occur in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed for signs of radiation recall.

    Geriatric

    Monitor for an increased risk of pemetrexed-related adverse reactions in geriatric patients. Grade 3 or 4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia occurred more often patients 65 years of age and older, compared to younger patients, in at least 1 of 5 randomized clinical trials (n = 3,946).

    Children, infants, neonates

    The safety and efficacy of pemetrexed in children, infants, and neonates has not been established. The maximum tolerated dose (MTD) of pemetrexed was 1,910 mg/m2 IV every 21 days (60 mg/kg for patients less than 12 months old) in a dose-finding study in pediatric patients with recurrent sold tumors (n = 32). No tumor responses were observed at this dose in 72 pediatric patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. With concomitant dexamethasone, folic acid, and vitamin B12 supplementation, adverse reactions in pediatric patients were similar to those observed in adults.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during pemetrexed treatment and for at least 6 months after the last dose; female partners of male patients should avoid pregnancy during treatment and for 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, pemetrexed can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving pemetrexed should be apprised of the potential hazard to the fetus. Intravenous administration of pemetrexed to pregnant mice during organogenesis resulted in increased malformations (cleft palate, protruding tongue, enlarged or mis-shaped kidney, and fused lumbar vertebra) at doses (based on BSA) 0.03 times the recommended human dose of 500 mg/m2. At doses (based on BSA) greater than or equal to 0.0012 times the recommended human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays, including incomplete ossification of talus and skull bone, and decreased fetal weight.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during pemetrexed treatment. Pemetrexed can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after the last dose of pemetrexed. Males with female partners of reproductive potential should use effective contraception during and for at least 3 months after the last dose of pemetrexed. Females of reproductive potential should undergo pregnancy testing prior to initiation of pemetrexed. Women who become pregnant while receiving pemetrexed should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of pemetrexed on human fertility, male infertility has been observed in animal studies. Intraperitoneal administration to male mice at doses (based on BSA) of approximately 0.006 times the recommended human dose resulted in reduced fertility, hypospermia, and testicular atrophy; it is unknown whether these effects are reversible.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from pemetrexed, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether pemetrexed is present in human milk, although many drugs are excreted in human milk.

    Vaccination

    Vaccination with live vaccines should be avoided due to the risk of severe myelosuppression and neutropenia during pemetrexed therapy.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 3.0-23.0
    hypophosphatemia / Delayed / 0-14.0
    hyperglycemia / Delayed / 0-9.0
    hyponatremia / Delayed / 0-7.0
    anemia / Delayed / 3.0-6.0
    thrombosis / Delayed / 3.0-6.0
    thromboembolism / Delayed / 3.0-6.0
    thrombocytopenia / Delayed / 0-5.0
    fatigue / Early / 4.5-5.0
    erythema multiforme / Delayed / 0-5.0
    hypokalemia / Delayed / 0-5.0
    dehydration / Delayed / 0-4.0
    dyspnea / Early / 0-3.4
    hyperkalemia / Delayed / 0-3.1
    nausea / Early / 0.3-3.0
    hypocalcemia / Delayed / 0-2.8
    renal failure (unspecified) / Delayed / 0-2.2
    anorexia / Delayed / 0-2.0
    vomiting / Early / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    infection / Delayed / 0-2.0
    hypoalbuminemia / Delayed / 0-1.1
    pyrosis (heartburn) / Early / 0-1.0
    pharyngitis / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    stomatitis / Delayed / 0.3-1.0
    diarrhea / Early / 0-1.0
    GI obstruction / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    rash / Early / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    syncope / Early / 0-1.0
    arrhythmia exacerbation / Early / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    depression / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    hemolytic anemia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    pneumonitis / Delayed / 0-23.0
    hypertension / Early / 3.0-11.0
    chest pain (unspecified) / Early / 0-8.0
    constipation / Delayed / 0-6.0
    conjunctivitis / Delayed / 1.0-5.0
    edema / Delayed / 0-5.0
    esophagitis / Delayed / 0-1.0
    radiation recall reaction / Delayed / 0-1.0
    lymphopenia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    bullous rash / Early / Incidence not known

    Mild

    cough / Delayed / 0-24.0
    fever / Early / 1.0-15.0
    dysgeusia / Early / 0-11.0
    pruritus / Rapid / 1.0-7.0
    abdominal pain / Early / 0-5.0
    urticaria / Rapid / 0-5.0
    lacrimation / Early / 1.0-5.0
    asthenia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Diphenhydramine; Ibuprofen: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Famotidine; Ibuprofen: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Glucarpidase: (Moderate) Potential exogenous substrates of glucarpidase include reduced folates and folate antimetabolites. Thus, administration of pemetrexed with glucarpidase may be inadvisable because reduced concentrations of pemetrexed may occur.
    Hydrocodone; Ibuprofen: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Ibuprofen: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Ibuprofen; Oxycodone: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Ibuprofen; Pseudoephedrine: (Major) Avoid administration of ibuprofen for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCL) between 45 mL/min and 79 mL/min. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Concomitant use inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38, resulting in increased pemetrexed exposure. In vitro data predict that other NSAIDs would not inhibit the uptake of pemetrexed by OAT3, and thus would not increase the AUC of pemetrexed to a clinically significant extent. In patients with normal renal function (CrCL greaster than 80 mL/min), ibuprofen increased the AUC of pemetrexed by approximately 20%.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Reteplase, r-PA: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sapropterin: (Moderate) Significant increases in serum phenylalanine concentrations have been noted after methotrexate infusions of 58 g/m2 to 46 patients with an unknown PKU status. Increased concentrations occurred at the end of the infusion in 95% of methotrexate cycles, but large inter-individual variations in the concentrations existed. Individual predispositions may exist, as maximal phenylalanine concentrations were of the same magnitude in a given patient. Phenylalanine concentrations returned to baseline concentrations 24 hours after the end of the methotrexate infusion. Methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving sapropterin. Dihydropteridine reductase recycles quinonoid dihydropterin (q-BH2) back to the active cofactor BH4. Reduction of BH4 could make management of hyperphenylalaninemia more difficult. Drugs that inhibit folate metabolism should be used with caution in patients taking sapropterin.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Streptokinase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Tenecteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Thrombolytic Agents: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during pemetrexed treatment and for at least 6 months after the last dose; female partners of male patients should avoid pregnancy during treatment and for 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, pemetrexed can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving pemetrexed should be apprised of the potential hazard to the fetus. Intravenous administration of pemetrexed to pregnant mice during organogenesis resulted in increased malformations (cleft palate, protruding tongue, enlarged or mis-shaped kidney, and fused lumbar vertebra) at doses (based on BSA) 0.03 times the recommended human dose of 500 mg/m2. At doses (based on BSA) greater than or equal to 0.0012 times the recommended human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays, including incomplete ossification of talus and skull bone, and decreased fetal weight.

    Due to the potential for serious adverse reactions in nursing infants from pemetrexed, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether pemetrexed is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Pemetrexed is a folate analog inhibitor (antifolate) that disrupts folate-dependent metabolic processes essential for cell replication. In vitro, it inhibits folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Inhibition of TS leads to a reduction in thymidine, which is needed for DNA synthesis. Additionally, inhibition of GARFT prevents de novo purine biosynthesis, leading to further depletion of required cell precursors. Thus, both thymidine and hypoxanthine (a purine) are needed to rescue a cell from cytotoxicity from pemetrexed.
     
    Pemetrexed is taken into cells by membrane carriers (e.g., reduced folate carrier and membrane folate binding protein transport system), where it is converted by the enzyme folylpolyglutamate synthetase (FPGS) to polyglutamate forms. The polyglutamate forms of pemetrexed are retained in cells and are inhibitors of TS and GARFT. It appears that DHFR inhibition does not play a large role in the overall cytotoxic mechanism of pemetrexed.
     
    Pemetrexed is more rapidly polyglutamated than methotrexate resulting in higher intracellular levels of polyglutamate derivatives, which are not as susceptible to transport out of the cell. Natural folates within the cell modulate pemetrexed activity by competing for polyglutamation by FPGS. The risk of pemetrexed toxicity is increased when cellular folate levels are low, especially in bone marrow and GI cells.
     
    Mechanisms of resistance to pemetrexed have been investigated in in vitro studies. In a study examining pemetrexed in colon cancer cell lines, pemetrexed resistance was primarily due to upregulation of TS, rather than alterations in FPGS or reduced folate carriers. Interestingly, cells resistant to methotrexate due to impaired cellular transport via reduced folate carriers may retain partial sensitivity to pemetrexed. Impaired cellular transport of physiologic reduced folates via reduced folate carriers leads to smaller intracellular folate concentrations. As a result, competition by pemetrexed and intracellular folate concentrations for polyglutamation by FPGS is reduced. Cell lines with primarily resistance to 5-fluorouracil, an inhibitor of TS, have relatively low cross-resistance with pemetrexed.

    PHARMACOKINETICS

    Pemetrexed is given by intravenous (IV) infusion. Systemic exposure and maximum serum concentration increase proportionally with dose over a range of 0.2 mg/m2 to 838 mg/m2; the pharmacokinetics of pemetrexed did not change over multiple treatment cycles. Pemetrexed is 81% bound to plasma proteins. The peripheral volume of distribution of pemetrexed is significantly affected by the serum albumin concentration. Higher albumin concentrations yield smaller volume of distribution in the peripheral compartment. In a group of patients with different types of cancer, the central volume of distribution ranged from 5 L to 19.8 L and the peripheral volume ranged from 2.7 L to 11.7 L. The steady-state volume of distribution is 16.1 L.
     
    Most of pemetrexed is eliminated in the urine as unchanged drug, with 70% to 90% recovered in the first 24 hours. The systemic clearance is 91.8 mL/min and the elimination half-life is 3.5 hours in patients with normal renal function (CrCL greater than 90 mL/min).
     
    Affected cytochrome P450 isoenzymes and drug transporters: OAT3
    Pemetrexed is not metabolized to an appreciable extent. In vitro, pemetrexed is a substrate of organic anion transporter 3 (OAT3) and 4 (OAT4). Coadministration with ibuprofen, an OAT3 inhibitor, decreased the clearance and increased the AUC of pemetrexed by approximately 20% in patients with normal renal function (CrCL greater than 80 mL/min). Other in vitro studies with human liver microsomes predict that pemetrexed does not significantly inhibit CYP3A, CYP2D6, CYP2C9, or CYP1A2.