Pemetrexed is a pyrimidine-based antifolate that suppresses tumor growth by inhibiting both DNA synthesis and folate metabolism at multiple target enzymes, including thymidine synthetase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The multiple enzyme inhibition is unique, as methotrexate inhibits only dihydrofolate reductase, and 5-fluorouracil and raltitrexed inhibit only thymidine synthetase. Thus, pemetrexed may be useful for 5-fluorouracil-, methotrexate-, and raltitrexed-resistant cancers. Folic acid and vitamin B12 supplementation is needed to reduce hematologic and gastrointestinal toxicity and enable therapy continuation; dexamethasone is also required to mitigate cutaneous toxicity. Pemetrexed is FDA approved alone, in combination with cisplatin, and in combination with carboplatin and pembrolizumab for the treatment of non-small cell lung cancer (NSCLC), and in combination with cisplatin for mesothelioma.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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
Route-Specific Administration
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.
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)
-Each vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
Dilution:
-Dilute the appropriate dose of pemetrexed in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a total volume of 100 mL. Do not use other diluents, such as Lactated Ringer's Injection or Ringer's Injection.
-Pemetrexed (Pemfexy) is compatible with polyolefin bags with polyvinyl chloride (PVC) ports.
-Storage of undiluted pemetrexed in opened multidose vial: Store unused portion in vial refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 28 days.
-Storage following dilution: Diluted solutions may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for no more than 48 hours. Solutions diluted with 5% Dextrose Injection may also be stored 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.
Solution for Injection (Pemrydi RTU)
-Each vial contains an excess of pemetrexed to facilitate delivery of the labeled amount.
-Transfer the calculated dose of pemetrexed to an empty IV bag. Do not further dilute.
Intravenous Infusion:
-Immediately administer undiluted as an IV infusion over 10 minutes using an infusion pump. Do not give by IV injection.
Severe myelosuppression has occurred with pemetrexed treatment, requiring transfusions in some patients. In 3 clinical trials of patients treated with pemetrexed monotherapy, hematologic toxicities included anemia (15% to 19%; grade 3 or 4, 3% to 4.8%), neutropenia (6% to 11%; grade 3 or 4, 3% to 5%), and thrombocytopenia (8% or less; grade 3 or 4, 2% or less). In one trial of monotherapy, transfusions (primarily red blood cells, RBCs) were required in 9.5%, while in another, 13% of pemetrexed-treated patients needed RBC transfusions and 1.5% needed platelet transfusions. Erythropoietin stimulating agents (ESAs) were needed in 5.9% to 12% of patients who received pemetrexed monotherapy in clinical trials, while granulocyte colony stimulating factors (G-CSFs) were required in less than or equal to 6%. The risk of myelosuppression is increased in patients who do not receive supplementation with folic acid and vitamin B12; therefore, patients unable to take folic acid and vitamin B12 supplementation were excluded from the monotherapy trials. The incidence of hematologic toxicity, and especially neutropenia, was higher in patients treated with pemetrexed plus platinum chemotherapy (with or without pembrolizumab) separate clinical trials, which included both patients who received vitamin supplementation and those who did not, including neutropenia (24.8% to 56%; grade 3 or 4, 11.9% to 23%), anemia (26% to 48.5%; grade 3 or 4, 4% to 18.5%), and thrombocytopenia (10% to 23%; grade 3 or 4, 4% to 8.4%); lymphopenia occurred in 64% of patients treated with pemetrexed plus platinum chemotherapy with or without pembrolizumab (grade 3 or 4, 22% to 25%) in 1 clinical trial.The incidence of grade 3 to 4 neutropenia (38% vs. 23%) and thrombocytopenia (9% vs. 5%) were higher in patients treated with pemetrexed plus cisplatin without folic acid and vitamin B supplementation compared to patients who were fully supplemented prior to and throughout pemetrexed treatment in an exploratory analysis of 1 clinical trial. Grade 3 or 4 anemia, thrombocytopenia, and neutropenia were also more common in patients age 65 and older compared to younger patients.
Immune-mediated hemolytic anemia has been reported in postmarketing experience with pemetrexed.
Nausea (12 to 31%; grade 3 or 4, 0.3% to 3%), anorexia (19% to 22%; grade 3 or 4, 2%), vomiting (6% to 16%; grade 3 or 4, 2% or less), mucositis/stomatitis (5% to 7%; grade 3 or 4, 0.3% to 1%), and stomatitis/pharyngitis (15% or less; grade 3 or 4, 1% or less), were reported in patients treated with pemetrexed monotherapy in clinical trials. Because the risk of GI toxicity is increased in patients who do not receive supplementation with folic acid and vitamin B12, patients unable to take folic acid and vitamin B12 supplementation were excluded from monotherapy trials. The incidence of upper gastrointestinal toxicities was higher in patients treated with pemetrexed in combination with platinum chemotherapy (with or without pembrolizumab), including nausea (52% to 82%; grade 3 or 4, 3.5% to 12%), vomiting (23% to 57%; grade 3 or 4, 3% to 11%), anorexia/decreased appetite (20% to 30%; grade 3 or 4, 0.5% to 2%), and stomatitis/pharyngitis (14% to 23%; grade 3 or 4, 1% to 3%); dyspepsia or pyrosis (heartburn) was reported in 5% (grade 3 or 4, 1% or less) patients who received pemetrexed in combination with platinum chemotherapy. Vitamin supplementation was not consistently administered in the trials with platinum chemotherapy. In an exploratory analysis, grade 3 or 4 vomiting (31% vs. 11%) occurred more often in patients treated with cisplatin plus pemetrexed who did not receive vitamin supplementation compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of study enrollment. Less than 1% of patients treated with pemetrexed across clinical trials experienced severe esophagitis resulting in hospitalization.
Diarrhea (5% to 13%; grade 3 or 4, 1% or less) and constipation (6% or less) were reported in patients treated with pemetrexed monotherapy in clinical trials; abdominal pain (less than 5%) and GI obstruction (less than 1%) were also reported in patients who received pemetrexed monotherapy. Because the risk of GI toxicity is increased in patients who do not receive supplementation with folic acid and vitamin B12, patients unable to take folic acid and vitamin B12 supplementation were excluded from monotherapy trials. The incidence of constipation (12% to 35%; grade 3 or 4, 0.5% to 1%) and diarrhea (12% to 31%; grade 3 or 4, 1% to 5%) were higher in patients treated with pemetrexed in combination with platinum chemotherapy (with or without pembrolizumab); vitamin supplementation was not consistently administered in the trials with platinum chemotherapy. In an exploratory analysis, grade 3 or 4 diarrhea (9% vs. 4%) occurred more often in patients treated with cisplatin plus pemetrexed who did not receive vitamin supplementation compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of study enrollment. Colitis has been reported in postmarketing experience with pemetrexed.
Elevated hepatic enzymes including increased ALT (8% to 10%; grade 3 or 4, 2% or less) and increased AST (7% to 8%; grade 3 or 4, 1% or less) have been reported in patients treated with pemetrexed monotherapy in clinical trials. Increased AST (1% to less than 5%), increased ALT (1% to less than 5%), and increased GGT (less than 5%) also occurred in patients who received pemetrexed in combination with cisplatin in 2 randomized clinical trials. Elevated hepatic enzymes were more common in 1 other randomized clinical trial comparing pemetrexed and cisplatin plus either pembrolizumab or placebo including increased ALT (47% vs. 42%; grade 3 or 4, 3.8% vs. 2.6%), increased AST (47% vs. 40%; grade 3 or 4, 2.8% vs. 1%), and increased alkaline phosphatase (26% vs. 29%; grade 3 or 4, 1.8% vs. 2.1%); hypoalbuminemia also occurred in 26% versus 29% of patients in this trial, respectively (grade 3 or 4, 1.8% vs. 2.1%).
Pemetrexed may cause severe and sometimes fatal nephrotoxicity. Monitor creatinine clearance (CrCl) before each dose of pemetrexed and periodically during treatment; pemetrexed should not be administered to patients with a CrCl less than 45 mL/minute. Renal failure has been reported in 0.4% to 0.6% of patients when administered pemetrexed as monotherapy, and in 2.1% to 2.2% of patients when given in combination with cisplatin. Increased serum creatinine occurred in 10% to 11%, (grade 3 or 4, 1%) of patients treated with pemetrexed in combination with cisplatin in 2 randomized clinical trials; a similar incidence of increased creatinine occurred with cisplatin alone in one of these trials (10%; grade 3 or 4, 1%). The incidence of decreased creatinine clearance occurred with cisplatin alone in one of these trials (10%; grade 3 or 4, 1%). The incidence of decreased creatinine was also similar in patients treated with pemetrexed plus cisplatin compared with cisplatin alone in this trial (16% vs. 18%; grade 3 or 4, 1% vs. 2%). In another randomized clinical trial, increased creatinine occurred in 25% (grade 3 or 4, 1%) of patients treated with pemetrexed plus platinum chemotherapy compared with 37% of those who received pemetrexed, pembrolizumab, and platinum chemotherapy plus pembrolizumab (grade 3 or 4, 4.2%); 72% of patients in this trial received carboplatin.
Fatigue has been reported in 18% to 34% (grade 3 or 4, 4.5% to 5%) of patients treated with pemetrexed monotherapy and, including asthenia, in 43% to 58% (grade 3 or 4, 6% to 12%) of patients receiving pemetrexed in combination with platinum chemotherapy (with or without pembrolizumab) in clinical trials. Grade 3 or 4 fatigue was more common in patients age 65 and older compared to younger patients. Deydration occurred in 7% or fewer patients receiving pemetrexed plus cisplatin in 2 clinical trials (grade 3 or 4, 4% or less). Less than 1% of patients treated with pemetrexed monotherapy reported grade 3 or 4 pain (unspecified).
Severe and sometimes fatal bullous rash, blistering rash, and exfoliative skin toxicity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in postmarketing experience with pemetrexed. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering, or exfoliating skin toxicity. Rash or skin desquamation occurred in 7% to 17% (grade 3 or 4, 2.5% or less) of patients treated with pemetrexed, either as monotherapy or in combination with cisplatin or carboplatin; the incidence was slightly higher in patients receiving pemetrexed plus pembrolizumab and platinum chemotherapy (25%; grade 3 or 4, 2%) including genital rash, maculopapular rash, and pustular rash. Additional dermatologic toxicities included pruritus (7% or less), urticaria (less than 5%), and erythema multiforme (less than 5%). Mild alopecia occurred more often in patients treated with pemetrexed/cisplatin (11% to 12%) than in patients receiving pemetrexed monotherapy (1% to 6%; grade 3 or 4, 1% or less) or pemetrexed/carboplatin (3.2% or less) in clinical trials.
Pemetrexed has been associated with a radiation recall reaction 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.
Sensory neuropathy (peripheral neuropathy) (1% to 10%; grade 3 or 4, 1% or less) and motor neuropathy (less than 5%) have occurred in patients treated with pemetrexed in clinical trials, either as monotherapy or in combination with cisplatin. Mild dysgeusia also occurred in 8% of patients who received combination therapy with either cisplatin or carboplatin in 2 clinical trials. Patients treated with pemetrexed monotherapy did not report dysgeusia.
Cardiovascular adverse reactions have been reported in patients treated with pemetrexed. Chest pain (unspecified) was reported in less than 5% of patients treated with pemetrexed plus cisplatin in clinical trials; in an exploratory subgroup analysis of one trial, chest pain occurred more often in patients receiving supplemental folic acid and vitamin B12 compared to patients who were not fully supplemented (8% vs. 6%). Additionally, arrhythmias (arrhythmia exacerbation), including supraventricular arrhythmias and ventricular tachycardia, have occurred in less than 1% of pemetrexed-treated patients (both as monotherapy and in combination with cisplatin). Grade 3 or 4 syncope was reported in less than 1% of patients who received pemetrexed monotherapy.
Allergic reactions/hypersensitivity reactions (infusion-related reactions) occurred in less than 5% of patients treated with pemetrexed monotherapy in 2 clinical trials.
Ocular surface disease (including conjunctivitis) occurred in 1% to 5% of patients treated with pemetrexed in clinical trials, either as monotherapy or in combination with cisplatin. Increased lacrimation was also reported in 1% to less than 5% of patients who received pemetrexed monotherapy.
Serious cases of interstitial lung disease/pneumonitis, including fatal cases, have been reported in postmarketing experience with pemetrexed therapy. Pneumonitis resulted in a discontinuation of therapy in 2% of patients treated with pemetrexed in combination with pembrolizumab and platinum chemotherapy in a randomized clinical trial. Hold pemetrexed therapy and promptly evaluate any patient with an acute onset of new or progressive unexplained respiratory symptoms including dyspnea and cough; permanently discontinue pemetrexed if pneumonitis is confirmed. Cough (28%) and dyspnea (26%; grade 3 or 4, 5%) were reported in patients with NSCLC treated with pemetrexed in combination with platinum chemotherapy in a randomized clinical trial; in patients treated with pemetrexed and platinum chemotherapy in combination with pembrolizumab, cough and dyspnea were each reported in 21% of patients (grade 3 or 4 dyspnea, 3.7%).
Fever, with or without neutropenia, and infection have been reported in patients during pemetrexed clinical trials. In general, fever was reported in 1% to 15% of patients treated with pemetrexed, either as monotherapy or in combination with cisplatin, while febrile neutropenia was noted in less than 5% of patients. Infection occurred in less than or equal to 5% (grade 3 or 4, 2%) of pemetrexed-treated patients. Pneumonia was responsible for an interruption of therapy in 4% of patients with metastatic NSCLC treated with pemetrexed, pembrolizumab, and platinum-based chemotherapy. Sepsis, with or without neutropenia, and including fatalities, occurred in 1% of patients receiving pemetrexed across clinical trials. The incidence of grade 3 to 4 febrile neutropenia (9% vs. 0.6%) and neutropenic infection (6% vs. 0%) was higher in patients treated with pemetrexed plus cisplatin without folic acid and vitamin B supplementation compared to patients who were fully supplemented prior to and throughout pemetrexed treatment in an exploratory analysis of one clinical trial.
Grade 3 or 4 depression was reported in less than 1% of patients who received pemetrexed in a NSCLC maintenance trial.
Pancreatitis has been reported with pemetrexed treatment in postmarketing experience.
Thrombosis or thromboembolism has occurred in patients treated with pemetrexed; supplemental folic acid and vitamin B12 may increase the risk compared to patients who are not fully supplemented (6% vs. 3%). Pulmonary embolism occurred in less than 1% of fully supplemented patients treated with pemetrexed monotherapy in 1 clinical trial.
Hypertension has occurred in patients treated with pemetrexed; supplemental folic acid and vitamin B12 may increase the risk compared to patients who are not fully supplemented (11% vs. 3%). Grade 3 or 4 hypertension was more common in patients age 65 and older compared to younger patients. Edema occurred in 5% or fewer patients receiving pemetrexed monotherapy in randomized clinical trials and has also been reported in postmarketing experience with pemetrexed.
Electrolyte abnormalities were reported in patients treated with pemetrexed plus platinum-based chemotherapy, given with or without pembrolizumab, in a randomized clinical trial including hyponatremia (23% to 32%; grade 3 or 4, 6% to 7%), hypophosphatemia (28% to 30%; grade 3 or 4, 10% to 14%), hypocalcemia (17% to 24%; grade 3 or 4, 0.5% to 2.8%), hyperkalemia (19% to 24%; grade 3 or 4, 2.8% to 3.1%), and hypokalemia (20% to 21%; grade 3 or 4, 5%).
Hyperglycemia was reported in 60% to 63% (grade 3 or 4, 7% to 9%) of patients treated with pemetrexed and platinum-based chemotherapy, with or without pembrolizumab, in a randomized clinical trial.
Use pemetrexed with caution in patients with preexisting renal impairment, as severe and sometimes fatal nephrotoxicity (renal failure) has been reported in clinical trials. Monitor creatinine clearance (CrCl) before each dose of pemetrexed and periodically during treatment. Do not administer pemetrexed to patients with a CrCl less than 45 mL/minute.
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 (CBC) 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 recurrent grade 3 or 4 myelosuppression after 2 dose reductions.
Pemetrexed is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed. A sometimes fatal, serious rash including bullous, blistering, and exfoliative skin toxicity and cases suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis can occur with pemetrexed. Permanently discontinue pemetrexed therapy for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.
Use pemetrexed with caution in patients with a history of pulmonary disease or chronic lung disease (CLD). Serious interstitial lung disease (ILD)/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 ILD/pneumonitis is confirmed.
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.
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).
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 males treated with pemetrexed 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.
Counsel both men and women of child bearing potential 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.
Due to the potential for serious adverse reactions in a breastfed child from pemetrexed, advise patients 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 with live vaccines should be avoided due to the risk of severe myelosuppression and neutropenia during pemetrexed therapy. Live vaccines may induce the illness they are intended to prevent and the immune response to these vaccines may be decreased.
For the treatment of malignant pleural mesothelioma:
NOTE: Pemetrexed is designated as an orphan drug by the FDA for this indication.
-for the first-line 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 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. 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 carboplatin*:
Intravenous dosage:
Adults: 500 mg/m2 IV 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. 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 cisplatin and bevacizumab*:
Intravenous dosage:
Adults: 500 mg/m2 IV 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 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 nonsquamous non-small cell lung cancer (NSCLC):
NOTE: Pemetrexed is not indicated for the treatment of patients with squamous cell NSCLC.
-for the perioperative treatment of resectable non-small cell lung cancer (NSCLC) (tumors greater than or equal to 4 cm or node positive), in combination with pembrolizumab and cisplatin*:
NOTE: Pembrolizumab is FDA-approved in combination with platinum-based chemotherapy for the perioperative treatment of resectable NSCLC.
Intravenous dosage:
Adults: 500 mg/m2 IV in combination with cisplatin (75 mg/m2 IV) on day 1, every 3 weeks for up to 4 cycles as neoadjuvant therapy in combination with pembrolizumab (200 mg IV repeated every 3 weeks OR 400 mg IV repeated every 6 weeks for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity). Administer pembrolizumab prior to chemotherapy when given on the same day. Within 4 to 12 weeks after surgery, resume adjuvant pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks as monotherapy for 39 weeks or until disease recurrence or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized, double-blind clinical trial (KEYNOTE-671), perioperative treatment with pembrolizumab plus neoadjuvant platinum-based chemotherapy significantly improved the median overall survival (not reached vs. 52.4 months) and median event-free survival (not reached vs. 17 months) compared with perioperative placebo plus platinum-based chemotherapy in patients with previously untreated and resectable stage II, IIIA, or IIIB (N2) NSCLC. Platinum-based chemotherapy included cisplatin plus gemcitabine for patients with squamous histology and cisplatin plus pemetrexed for patients with nonsquamous histology.
-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 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 pemetrexed after pembrolizumab and prior to carboplatin or cisplatin 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 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 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 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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Dermatologic
-Severe and life-threatening skin toxicity: Permanently discontinue pemetrexed therapy.
Diarrhea
-Diarrhea requiring hospitalization: Hold pemetrexed therapy. When diarrhea resolves to grade 2 or less, resume treatment at a reduced dose (75% of the previous dose). If grade 3 or 4 diarrhea occurs after 2 dose reductions, discontinue pemetrexed therapy.
Hematologic
NOTE: Delay initiation of each cycle of therapy until the ANC is at least 1,500 cells/mm3 and platelet count is at least 100,000 cells/mm3.
-ANC nadir less than 500 cells/mm3 with platelets greater than or equal to 50,000 cells/mm3: Delay the next cycle of treatment until the ANC is greater than or equal to 1,500 cells/mm3 and platelets 100,000 cells/mm3 or higher. When ANC and platelets have recovered, begin the next cycle of therapy at a reduced dose of pemetrexed (75% of the previous dose). Discontinue pemetrexed for recurrent grade 3 or 4 myelosuppression after 2 dose reductions.
-Platelet count less than 50,000 cells/mm3 without bleeding: Delay the next cycle of treatment until the platelet count is at least 100,000 cells/mm3. When the platelet count has recovered, begin the next cycle of therapy at a reduced dose of pemetrexed (75% of the previous dose). Discontinue pemetrexed for recurrent grade 3 or 4 myelosuppression after 2 dose reductions.
-Platelet count less than 50,000 cells/mm3 with bleeding: Delay the next cycle of treatment until the platelet count is at least 100,000 cells/mm3. When the platelet count has recovered, begin the next cycle of therapy at a reduced dose of pemetrexed (50% of the previous dose). Discontinue pemetrexed for recurrent grade 3 or 4 myelosuppression after 2 dose reductions.
Mucositis
-Grade 3 or 4 mucositis: Hold pemetrexed therapy. When mucositis resolves to grade 2 or less, resume treatment at a reduced dose (50% of the previous dose). If grade 3 or 4 mucositis occurs after 2 dose reductions, discontinue pemetrexed therapy.
Neurotoxicity
-Grade 3 or 4: Permanently discontinue pemetrexed therapy.
Pneumonitis/Interstitial Lung Disease (ILD)
-Permanently discontinue pemetrexed therapy.
Other Grade 3 or 4 Nonhematologic Toxicity
-Hold pemetrexed therapy. When the toxicity resolves to grade 2 or less, resume treatment at a reduced dose (75% of the previous dose). If grade 3 or 4 toxicity occurs after 2 dose reductions, discontinue pemetrexed therapy.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Pemetrexed has not been formally studied in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Creatinine clearance greater than or equal 45 mL/min: No dosage adjustment needed.
-Creatinine clearance less than 45 mL/min: Do not administer pemetrexed.
Treatment-Related Nephrotoxicity
-Creatinine clearance less than 45 mL/min: Hold pemetrexed therapy. Resume treatment when Creatinine clearance is greater than or equal to 45 mL/min.
*non-FDA-approved indication
Acetaminophen; 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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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.
Chikungunya 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.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diclofenac: (Major) Avoid administration of diclofenac for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCl) between 45 mL/minute and 79 mL/minute due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity.
Diclofenac; Misoprostol: (Major) Avoid administration of diclofenac for 2 days before, the day of, and 2 days after administration of pemetrexed in patients with a creatinine clearance (CrCl) between 45 mL/minute and 79 mL/minute due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
Ibuprofen; Famotidine: (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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
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 due to the risk of increased pemetrexed exposure resulting in an increase in pemetrexed-related adverse reactions. If concomitant use is unavoidable, monitor these patients more frequently for myelosuppression, nephrotoxicity, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate and ibuprofen is an OAT3 inhibitor. Coadministration with ibuprofen 400 mg four times daily increased pemetrexed exposure by approximately 20% in patients with normal renal function (CrCl greater than 80 mL/min). In vitro data predict that other NSAIDS (e.g., naproxen, diclofenac, and celecoxib) would not increase pemetrexed exposure to a clinically significant extent.
Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
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.
Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
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.
Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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.
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.
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.
Pemetrexed is given by intravenous (IV) infusion. 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). Other in vitro studies with human liver microsomes predict that pemetrexed does not significantly inhibit CYP3A, CYP2D6, CYP2C9, or CYP1A2.
-Route-Specific Pharmacokinetics
Intravenous Route
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.
-Special Populations
Hepatic Impairment
There was no effect of elevated ALT, AST, or total bilirubin on the pharmacokinetics of pemetrexed; however, specific studies in patients with hepatic impairment have not been conducted.
Renal Impairment
Plasma clearance of pemetrexed decreases as renal function decreases, resulting in increased pemetrexed exposure. As compared with patients that had a creatinine clearance (CrCl) of 100 mL/min, the systemic exposure of pemetrexed increased by 13%, 54%, and 65% for patients with a CrCl of 80 mL/minute, 50 mL/minute, and 45 mL/minute, respectively, in a pharmacokinetic analysis. Pemetrexed is not recommended in patients with a creatinine clearance less than 45 mL/min. The ability of pemetrexed to be dialyzed is unknown.
Pediatrics
Single-dose pharmacokinetics of pemetrexed in patients aged 4 to 18 years (n = 22) were similar to those observed in adults in 2 clinical studies.
Geriatric
Age (26 to 80 years) does not have a clinically meaningful effect on the systemic exposure of pemetrexed, based on population pharmacokinetic analyses.
Gender Differences
Gender does not have a clinically meaningful effect on the systemic exposure of pemetrexed, based on population pharmacokinetic analyses.
Ethnic Differences
The pharmacokinetic parameters of pemetrexed are similar in Caucasian patients and Black or African American patients. Insufficient data are available for other ethnic groups.
Other
Third Space Fluid
Pemetrexed plasma concentrations in patients with various solid tumors with stable, mild-to-moderate third space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pemetrexed pharmacokinetics is unknown.
Pharmacodynamics
Pemetrexed showed synergistic inhibitory effects when combined with cisplatin on the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052).
Based on population pharmacodynamic analyses, the depth of the ANC nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.