Pemetrexed

Pemetrexed disodium · Injection, Powder, Lyophilized, For Solution · Intravenous

Prescription (Rx) Folate Analog Metabolic Inhibitor

Uses

Pemetrexed Injection is a folate analog metabolic inhibitor indicated:
• in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. ( 1.1 )
• in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. ( 1.1 )
• as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ( 1.1 )
• as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 ) Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 )
• initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 ) 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed Injection is indicated:
• in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
• in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC.
• as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
• as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies ( 14.1 )]. 1.2 Mesothelioma Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Dosage and administration

• The recommended dosage of Pemetrexed Injection administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. ( 2.1 )
• The recommended dosage of Pemetrexed Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. ( 2.1 , 2.2 )
• Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. (2.4)
• Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. ( 2.4 )
• Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. ( 2.4 ) 2.1 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation
• Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of Pemetrexed Injection and continuing until 21 days after the last dose of Pemetrexed Injection [see Warnings and Precautions ( 5.1 )].
• Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pemetrexed Injection [see Warnings and Precautions ( 5.1 )] . Do not substitute oral vitamin B 12 for intramuscular vitamin B 12 . Corticosteroids
• Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration. 2.2 Recommended Dosage and Administration Non-Squamous NSCLC
• The recommended dosage of Pemetrexed Injection when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, treatment with Pemetrexed Injection with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.
• The recommended dosage of Pemetrexed Injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.
• The recommended dosage of Pemetrexed Injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum based first-line chemotherapy.
• The recommended dosage of Pemetrexed Injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Mesothelioma
• The recommended dosage of Pemetrexed Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer Pemetrexed Injection if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of Pemetrexed Injection until:
• recovery of non-hematologic toxicity to Grade 0-2,
• absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and
• platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of Pemetrexed Injection in the next cycle as specified in Table 1 . For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information. Table 1: Recommended Dosage Modifications for Adverse Reactions* Toxicity in Most Recent Treatment Cycle Pemetrexed Injection Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions ( 5.1 )] ANC less than 500/mm 3 and platelets greater than or equal to 50,000/mm 3 OR Platelet count less than 50,000/mm 3 without bleeding.

Dosage forms and strengths

Injection: Pemetrexed Injection is a clear, colorless to yellow or green-yellow solution available in sterile single-dose vials as follows:
• 100 mg/4 mL (25 mg/mL)
• 500 mg/20 mL (25 mg/mL)
• 1000 mg/40 mL (25 mg/mL) Injection: 100 mg/4 mL (25 mg/mL), 500 mg/20 mL (25 mg/mL), 1000 mg/40 mL (25 mg/mL) in single-dose vials. ( 3 )

Contraindications

Pemetrexed Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )]. History of severe hypersensitivity reaction to pemetrexed. ( 4 )

Warnings and precautions

• Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed Injection when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 . Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection. ( 2.4 , 5.1 )
• Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. ( 2.3 , 5.2 )
• Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 )
• Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 )
• Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation Pemetrexed can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3 to 4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B 12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B 12 prior to the first dose of Pemetrexed Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection [see Dosage and Administration ( 2.4 )] . Obtain a complete blood count at the beginning of each cycle. Do not administer Pemetrexed Injection until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 . Permanently reduce Pemetrexed Injection in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3 in previous cycles [see Dosage and Administration ( 2.6 )] . In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3 to 4 neutropenia was 15% and 23%, the incidence of Grade 3 to 4 anemia was 6% and 4%, and incidence of Grade 3 to 4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions ( 6.1 )]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3 to 4 neutropenia ranged from 3% to 5%, and incidence of Grade 3 to 4 anemia ranged from 3% to 5%. 5.2 Renal Failure Pemetrexed can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions ( 6.1 )] . Determine creatinine clearance before each dose and periodically monitor renal function during treatment with Pemetrexed Injection. Withhold Pemetrexed Injection in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration ( 2.3 )] . 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with pemetrexed. Permanently discontinue Pemetrexed Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Withhold Pemetrexed Injection for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue Pemetrexed Injection. 5.5 Radiation Recall Radiation recall can occur with pemetrexed 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 Injection for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for Pemetrexed Injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration ( 2.5 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )] .

Side effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Myelosuppression [see Warnings and Precautions ( 5.1 )]
• Renal failure [see Warnings and Precautions ( 5.2 )]
• Bullous and exfoliative skin toxicity [see Warning and Precautions ( 5.3 )]
• Interstitial pneumonitis [see Warnings and Precautions ( 5.4 )]
• Radiation recall [see Warnings and Precautions ( 5.5 )]
• The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. ( 6.1 )
• The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. ( 6.1 )
• The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered in combination with pembrolizumab and platinum chemotherapy are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of pemetrexed, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received pemetrexed, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies ( 14.1 )] . The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline. Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed, pembrolizumab, and platinum. Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 Pemetrexed Pembrolizumab Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 Adverse Reaction All Grades * (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Disorders Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General Disorders and Administration Site Conditions Fatigue † 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Disorders Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue Disorders Rash ‡ 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal Disorders Cough 21 0 28 0 Dyspnea 21 3.7 26 5 * Graded per NCI CTCAE version 4.03. † Includes asthenia and fatigue. ‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum.

Drug interactions

7 DRUG INTERACTIONS OAT3 Inhibitors: Modify the ibuprofen dosage as recommended. Avoid other OAT3 inhibitors. ( 2.5 , 5.6 , 7 ) 7.1 Effects of Other Drugs on Pemetrexed Injection OAT3 Inhibitors Avoid concomitant administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [see Dosage and Administration ( 2.5 )] . Avoid concomitant administration of other OAT3 inhibitors before and after administration of Pemetrexed Injection, when possible. If concomitant administration cannot be avoided, monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity. Pemetrexed is an OAT3 substrate [see Clinical Pharmacology ( 12.3 )] . Concomitant use with an OAT3 inhibitor increases pemetrexed systemic exposure (AUC) [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of Pemetrexed Injection adverse reactions.

Use in specific populations

Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Pemetrexed Injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2 [see Data ] . Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3 )] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2 . At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Pemetrexed Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations ( 8.1 )]. Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Males Pemetrexed may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of pemetrexed in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473, N=32 and NCT00520936, N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. No new safety signals were observed. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients aged 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3 to 4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )].

Pregnancy

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on Pemetrexed Injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2 [see Data ] . Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3 )] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2 . At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

Pediatric use

8.4 Pediatric Use The safety and effectiveness of pemetrexed in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473, N=32 and NCT00520936, N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. No new safety signals were observed. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients aged 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

Geriatric use

8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3 to 4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )].

Overdosage

No drugs are approved for the treatment of pemetrexed overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable.

Description

Pemetrexed Injection is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium, has the chemical name N-[[4-[2-(2-Amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl] carbonyl] -L-glutamic acid disodium, 2.5H 2 O with a molecular formula of C 20 H 19 N 5 Na 2 O 6 2.5 H 2 O and a molecular weight of 516.41 The structural formula is as follows: Pemetrexed Injection is supplied as a sterile clear colorless to yellow or green-yellow solution for intravenous infusion available in single-dose vials. Each mL contains 25 mg pemetrexed (30.2 mg pemetrexed disodium 2.5 hydrate), 0.5 mg sodium thiosulfate pentahydrate, 50 mg propylene glycol, water for injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Pemetrexed Injection requires dilution prior to intravenous infusion. Pemetrexed Injection should be diluted in 0.9% sodium chloride injection (preservative-free) to achieve a total volume of 100 mL for intravenous infusion. chemical-structure

Mechanism of action

12.1 Mechanism of Action Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

How supplied

How Supplied Pemetrexed Injection is supplied as a sterile single-dose vial containing clear colorless to yellow or green-yellow solution in a clear glass vial with a grey rubber closure, aluminum cap, and light blue flip-off cap Strength/Fill volume NDC number Pack style 100 mg/4 mL NDC 0781-3518-76 Carton containing one (1) single-dose vial 500 mg/20 mL NDC 0781-3519-90 Carton containing one (1) single-dose vial 1,000 mg/40 mL NDC 0781-3520-91 Carton containing one (1) single-dose vial Storage and Handling Store solution at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep the vial in the carton box until the time of use. Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures [see References ( 15 )]. 1

Patient information

Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B 12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment-related toxicity [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 ) ]. Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia [see Warnings and Precautions ( 5.1 )] . Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output [see Warnings and Precautions ( 5.2 )] . Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes [see Warnings and Precautions ( 5.3 )] . Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough [see Warnings and Precautions ( 5.4 )] . Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated [see Warnings and Precautions ( 5.5 )] . Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [ see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.6 ), and Drug Interactions ( 7 )] . Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.3 )] . Lactation: Advise women not to breastfeed during treatment with Pemetrexed Injection and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )] . Manufactured by FAREVA Unterach GmbH for Sandoz Inc., Princeton, NJ 08540

Label text from the FDA structured product label by Sandoz Inc. (revised Dec 16, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Pemetrexed Disodium Hemipentahydrate in 24 products
Pemetrexed Disodium in 23 products
Pemetrexed Disodium Heptahydrate in 8 products
Pemetrexed Monohydrate in 3 products

Pemetrexed NDC products (58)

NDC	Strength & form	Labeler	Type
16729-244	Pemetrexed Disodium Hemipentahydrate 1 g/40mL Injection, Powder, Lyophilized, For Solution	Accord Healthcare Inc.	ANDA
16729-230	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Accord Healthcare Inc.	ANDA
16729-229	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Accord Healthcare Inc.	ANDA
68001-546	Pemetrexed Disodium 1000 mg/40mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-535	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-536	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-538	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-539	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-543	Pemetrexed Disodium 100 mg/4mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-544	Pemetrexed Disodium 500 mg/20mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
68001-545	Pemetrexed Disodium 750 mg/30mL Injection, Powder, Lyophilized, For Solution	BluePoint Laboratories	ANDA
31722-336	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Camber Pharmaceuticals, Inc.	ANDA
31722-337	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Camber Pharmaceuticals, Inc.	ANDA
55150-383	Pemetrexed Disodium Hemipentahydrate 1000 mg/40mL Injection, Powder, Lyophilized, For Solution	Eugia US LLC	ANDA
55150-382	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Eugia US LLC	ANDA
55150-381	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Eugia US LLC	ANDA
63323-622	Pemetrexed Disodium 1 g/40mL Injection, Powder, Lyophilized, For Solution	Fresenius Kabi USA, LLC	ANDA
63323-621	Pemetrexed Disodium 750 mg/30mL Injection, Powder, Lyophilized, For Solution	Fresenius Kabi USA, LLC	ANDA
63323-450	Pemetrexed Disodium 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Fresenius Kabi USA, LLC	ANDA
63323-134	Pemetrexed Disodium 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Fresenius Kabi USA, LLC	ANDA
71288-167	Pemetrexed Disodium Hemipentahydrate 500 mg/50mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
71288-166	Pemetrexed Disodium Hemipentahydrate 100 mg/10mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
71288-148	Pemetrexed Disodium Heptahydrate 1 g/40mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
71288-145	Pemetrexed Disodium Heptahydrate 100 mg/4.2mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
71288-146	Pemetrexed Disodium Heptahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
71288-147	Pemetrexed Disodium Heptahydrate 750 mg/30mL Injection, Powder, Lyophilized, For Solution	Meitheal Pharmaceuticals Inc.	ANDA
72603-425	Pemetrexed Disodium Hemipentahydrate 500 mg/50mL Injection, Powder, Lyophilized, For Solution	NorthStar RxLLC	ANDA
72603-325	Pemetrexed Disodium Hemipentahydrate 100 mg/10mL Injection, Powder, Lyophilized, For Solution	NorthStar RxLLC	ANDA
67184-0503	Pemetrexed Disodium Hemipentahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Qilu Pharmaceutical Co., Ltd.	ANDA
67184-0504	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Qilu Pharmaceutical Co., Ltd.	ANDA
25021-261	Pemetrexed Disodium Hemipentahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Sagent Pharmaceuticals	ANDA
25021-260	Pemetrexed Disodium Hemipentahydrate 100 mg/4.2mL Injection, Powder, Lyophilized, For Solution	Sagent Pharmaceuticals	ANDA
43547-632	Pemetrexed Disodium Hemipentahydrate 100 mg/1 Injection, Powder, For Solution	Solco Healthcare US, LLC	ANDA
70069-835	Pemetrexed Disodium Heptahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Somerset Therapeutics LLC	ANDA
70069-834	Pemetrexed Disodium Heptahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Somerset Therapeutics LLC	ANDA
72338-100	Pemetrexed Disodium Heptahydrate 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Waverley Pharma Inc	ANDA
72338-101	Pemetrexed Disodium Heptahydrate 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Waverley Pharma Inc	ANDA
70771-1691	Pemetrexed Disodium 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Zydus Lifesciences Limited	ANDA
70771-1693	Pemetrexed Disodium 1000 mg/40mL Injection, Powder, Lyophilized, For Solution	Zydus Lifesciences Limited	ANDA
70771-1692	Pemetrexed Disodium 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Zydus Lifesciences Limited	ANDA
70710-1674	Pemetrexed Disodium 1000 mg/40mL Injection, Powder, Lyophilized, For Solution	Zydus Pharmaceuticals USA Inc.	ANDA
70710-1654	Pemetrexed Disodium 100 mg/4mL Injection, Powder, Lyophilized, For Solution	Zydus Pharmaceuticals USA Inc.	ANDA
70710-1655	Pemetrexed Disodium 500 mg/20mL Injection, Powder, Lyophilized, For Solution	Zydus Pharmaceuticals USA Inc.	ANDA
0409-0020	Pemetrexed Disodium 100 mg/4mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0409-3532	Pemetrexed Disodium 1 g/40mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0409-2188	Pemetrexed Disodium 500 mg/20mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0409-1045	Pemetrexed Disodium 100 mg/4mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0409-0021	Pemetrexed Disodium 500 mg/20mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0409-0004	Pemetrexed Disodium 1 g/40mL Injection, Solution, Concentrate	Hospira, Inc.	NDA
0781-3520	Pemetrexed Disodium 1000 mg/40mL Injection, Solution	Sandoz Inc.	NDA
0781-3519	Pemetrexed Disodium 500 mg/20mL Injection, Solution	Sandoz Inc.	NDA
0781-3518	Pemetrexed Disodium 100 mg/4mL Injection, Solution	Sandoz Inc.	NDA
63759-3050	Pemetrexed Disodium Hemipentahydrate 1000 mg/100mL Injection	Shilpa Medicare Limited	NDA
63759-3049	Pemetrexed Disodium Hemipentahydrate 500 mg/50mL Injection	Shilpa Medicare Limited	NDA
63759-3048	Pemetrexed Disodium Hemipentahydrate 100 mg/10mL Injection	Shilpa Medicare Limited	NDA
0480-4516	Pemetrexed Monohydrate 25 mg/mL Solution, Concentrate	Teva Pharmaceuticals, Inc.	NDA
0480-4515	Pemetrexed Monohydrate 25 mg/mL Solution, Concentrate	Teva Pharmaceuticals, Inc.	NDA
0480-4514	Pemetrexed Monohydrate 25 mg/mL Solution, Concentrate	Teva Pharmaceuticals, Inc.	NDA

Frequently asked questions

What is Pemetrexed used for?

What are the side effects of Pemetrexed?

Who makes Pemetrexed?

Pemetrexed is listed by 18 labelers in the FDA NDC directory, including Accord Healthcare Inc., BluePoint Laboratories, Camber Pharmaceuticals, Inc., Eugia US LLC.