`
`
`CENTER FOR DRUG EVALUATION AND
`
`
`
`
`
`
`RESEARCH
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`
`
`
`APPLICATION NUMBER:
`
`
`
`209472Orig1s000
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`
`
`
`LABELING
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`
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`
`

`

` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`PEMFEXY safely and effectively. See full prescribing information for
`PEMFEXY.
`
`PEMFEXY™ (pemetrexed injection), for intravenous use
`
`Initial U.S. Approval: 2004
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`PEMFEXY is a folate analog metabolic inhibitor indicated for:
`
`
`
`in combination with cisplatin for the initial treatment of patients with
`•
`locally advanced or metastatic non-squamous, non-small cell lung cancer
`
`
`
`
`(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: PEMFEXY is not indicated for the treatment of
`
`
`patients with squamous cell non-small cell lung cancer. (1.1)
`
`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. (1.2)
`
`
`
`
`
`
`
`
`•
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`• The recommended dosage of PEMFEXY, administered as a single agent or
`
`with cisplatin, in patients with creatinine clearance of 45 mL/minute or
`
`greater, is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1
`
`
`of each 21-day cycle. (2.1, 2.2, 2.3)
`
`
`Initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days
`
`
`prior to the first dose of PEMFEXY and continue until 21 days after the
`last dose. (2.4)
`
`
`
`
`
`
`• Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose
`of PEMFEXY and every 3 cycles thereafter. (2.4)
`
`• Administer dexamethasone 4 mg orally twice daily the day before, the day
`
`
`
`
`of, and the day after PEMFEXY administration. (2.4)
`
`•
`
`
`
`
`
`--------------------------DOSAGE FORMS AND STRENGTHS-----------------
`
`
`Injection: 500 mg/20 mL (25 mg/mL) in a single-dose vial (3)
`•
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`
`
`
`
`
`• 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 PEMFEXY
`
`
`when the absolute neutrophil count is less than 1500 cells/mm3 and
`
`platelets are less than 100,000 cells/mm3. Initiate supplementation with oral
`folic acid and intramuscular vitamin B12 to reduce the severity of
`
`
`hematologic and gastrointestinal toxicity of PEMFEXY. (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. (5.6, 8.1, 8.3)
`
`•
`
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS------------------------------
`
`
`
`• 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)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eagle
`
`Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch.
`
`
`-------------------------------DRUG INTERACTIONS------------------------------
`Ibuprofen: Modify the ibuprofen dosage as recommended for patients with a
`
`
`creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7)
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`Lactation: Advise not to breastfeed. (8.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`
`
`Revised: 02/2020
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`1.1 Non-squamous Non-Small Cell Lung Cancer
` 
` 
`1.2 Mesothelioma
` 
` 
`2 DOSAGE AND ADMINISTRATION
` 
`2.1 Recommended Dosage for Non-squamous Non-Small Cell Lung
`
` 
`Cancer
` 
` 
`2.2 Recommended Dosage for Mesothelioma
`
` 
` 
`2.3 Renal Impairment
` 
` 
`2.4
`Premedication and Concomitant Medications to Mitigate Toxicity
` 
`2.5 Dosage Modification of Ibuprofen in Patients with Mild to
` 
`Moderate Renal Impairment Receiving PEMFEXY
` 
` 
`2.6 Dosage Modifications for Adverse Reactions
`
` 
` 
`2.7
`Preparation and Administration
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
`
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`
`5 WARNINGS AND PRECAUTIONS
` 
`5.1 Myelosuppression and Increased Risk of Myelosuppression without
`
` 
`Vitamin Supplementation
` 
` 
`5.2 Renal Failure
` 
` 
`5.3 Bullous and Exfoliative Skin Toxicity
` 
` 
`5.4
`Interstitial Pneumonitis
` 
` 
`5.5 Radiation Recall
` 
`5.6
`Increased Risk of Toxicity with Ibuprofen in Patients with Renal
`
` 
`Impairment
` 
` 
`5.7
`Embryo-Fetal Toxicity
` 
` 
`6 ADVERSE REACTIONS
` 
` 
`6.1 Clinical Trials Experience
` 
` 
`Postmarketing Experience
`6.2
`
`
`
`Reference ID: 4558342
`
`1
`
` 
`10
` 
`11
` 
`12
`
` 
`13
` 
`14
`
` 
` 
`7 DRUG INTERACTIONS
`
` 
` 
`Effect of Other Drugs on PEMFEXY
`7.1
`
` 
` 
`8 USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
` 
` 
`8.2
`Lactation
` 
` 
`8.3
`Females and Males of Reproductive Potential
`
` 
` 
`8.4
`Pediatric Use
` 
` 
`8.5 Geriatric Use
` 
` 
`8.6 Renal Impairment
` 
`OVERDOSAGE
` 
`DESCRIPTION
` 
`CLINICAL PHARMACOLOGY
` 
`Mechanism of Action
`
` 
`Pharmacodynamics
` 
`Pharmacokinetics
` 
`NONCLINICAL TOXICOLOGY
` 
`Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
`CLINICAL STUDIES
` 
`Non-Squamous NSCLC
` 
`Mesothelioma
` 
` 
`15
`REFERENCES
` 
` 
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
` 
` 
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
` 
`12.1
` 
`12.2
` 
`12.3
` 
`13.1
` 
`14.1
` 
`14.2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
` INDICATIONS AND USAGE
`
`•
`
`
`
`1.1 Non-squamous Non-Small Cell Lung Cancer
`PEMFEXY™ is indicated:
`
`in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-
`•
`squamous, non-small cell lung cancer (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: PEMFEXY is not indicated for the treatment of patients with squamous cell NSCLC [see
`
`
`Clinical Studies 14.1].
`
`•
`
`
`
`1.2 Mesothelioma
`PEMFEXY 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.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage for Non-squamous Non-Small Cell Lung Cancer
`
`
`• The recommended dosage of PEMFEXY, 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/m2 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 PEMFEXY 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/m2
`
`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 PEMFEXY 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/m2 as an
`intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or
`
`unacceptable toxicity.
`
`
` 2.2 Recommended Dosage for Mesothelioma
`
`The recommended dosage of PEMFEXY, when administered with cisplatin, in patients with a creatinine
`clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous
`infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.
`
`
`
`2.3 Renal Impairment
`
`PEMFEXY dosing recommendations are provided for patients with a creatinine clearance (calculated by
`Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration (2.1, 2.2)]. There is no
`
`
`recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific
`Populations (8.6)].
`
`Reference ID: 4558342
`
`2
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`

`

`
`
`75% of previous dose
`
`50% of previous dose
`Permanently discontinue.
`
`75% of previous dose
`
`50% of previous dose
`
` 2.4 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 PEMFEXY
`and continuing until 21 days after the last dose [see Warnings and Precautions (5.1)].
`Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of PEMFEXY and every 3 cycles
`
` thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with PEMFEXY [see
`Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12.
`Corticosteroids
`
`Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each
`PEMFEXY administration.
`2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment
`Receiving PEMFEXY
`In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen
`as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`• Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of
`PEMFEXY.
`
`
`• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant
`administration of ibuprofen cannot be avoided.
`2.6 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 PEMFEXY if the creatinine clearance is less than 45 mL/min.
`Delay initiation of the next cycle of PEMFEXY 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 PEMFEXY in the next cycle as specified in Table 1.
`For dosage modifications for cisplatin, refer to the prescribing information for cisplatin.
`
`Recommended Dosage Modifications for Adverse Reactions
`Table 1:
`PEMFEXY Dosage Modifications
`Toxicity in Most Recent Treatment Cycle
`
`for Next Cycle
`Myelosuppressive toxicity [see Warnings and Precautions (5.1)]
`ANC less than 500/mm3 and platelets greater than or equal to
`
`50,000/mm3
`
`
` OR
`Platelet count less than 50,000/mm3 without bleeding.
`Platelet count less than 50,000/mm3 with bleeding
`Recurrent Grade 3 or 4 myelosuppression after 2 dose
`reductions
`Non-hematologic toxicity
`
`Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic
`
` toxicity
`
` OR
` Diarrhea requiring hospitalization
`Grade 3 or 4 mucositis
`
`
`
`
`Reference ID: 4558342
`
`3
`
`

`

`
`
` Toxicity in Most Recent Treatment Cycle
`
`PEMFEXY Dosage Modifications
`for Next Cycle
`Withhold until creatinine clearance is 45
`
` mL/min or greater.
`Permanently discontinue.
`Permanently discontinue.
`
`
`
` Renal toxicity [see Warnings and Precautions (5.2)]
`
` Grade 3 or 4 neurologic toxicity
`Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose
`reductions
`Severe and life-threatening skin toxicity [see Warnings and
`Permanently discontinue.
`
`Precautions (5.3)]
`Interstitial pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue.
`a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2)
`
`2.7 Preparation and Administration
` PEMFEXY is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
`
`
` Calculate the dose of PEMFEXY and determine the number of vials needed. Withdraw the calculated dose
`
` of PEMFEXY from the vial(s) and discard vial with any unused portion. Each vial contains 500 mg
`pemetrexed per 20 mL (25 mg/mL). The vial contains an excess of pemetrexed to facilitate delivery of
`labeled amount.
`
` Dilute PEMFEXY with 5% Dextrose in Water, USP to achieve a total volume of 100 mL for intravenous
`infusion. Do not use other diluents, such as Lactated Ringer’s Injection, USP or Ringer’s Injection,
`USP.
`
`
` Visually inspect for particulate matter and discoloration prior to administration, whenever solution and
`container permit. Discard if particulate matter or discoloration is observed.
`
` Administer PEMFEXY as an intravenous infusion over 10 minutes.
`
` Store diluted PEMFEXY refrigerated at 2°C to 8°C (36 °F to 46°F) or at ambient room temperature and
`room lighting for no more than 48 hours. When prepared as directed, infusion solutions of PEMFEXY
`
` contain no antimicrobial preservatives. Discard after 48 hours.
`PEMFEXY is compatible with polyolefin infusion bags with polyvinyl chloride (PVC) ports.
` 3 DOSAGE FORMS AND STRENGTHS
`
`Injection: 500 mg pemetrexed per 20 mL (25 mg/mL) as a clear, colorless to yellow or green-yellow solution in
`a single-dose vial.
`
`4 CONTRAINDICATIONS
`PEMFEXY is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see
`
`
`Adverse Reactions (6.1)].
`
`5 WARNINGS AND PRECAUTIONS
`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 3-4 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
`4
`
`Reference ID: 4558342
`
`

`

`were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin
`treatment.
` Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of PEMFEXY;
`
`continue vitamin supplementation during treatment and for 21 days after the last dose of PEMFEXY to reduce
`the severity of hematologic and gastrointestinal toxicity of pemetrexed [see Dosage and Administration (2.4)].
`Obtain a complete blood count at the beginning of each cycle. Do not administer PEMFEXY until the ANC is at
`least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce PEMFEXY in
`patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous
`cycles [see Dosage and Administration (2.6)].
`In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4
`neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4
`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 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 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
`PEMFEXY. Withhold PEMFEXY 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
`PEMFEXY 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. Withhold PEMFEXY 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 PEMFEXY.
`
`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 PEMFEXY 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 PEMFEXY. If concomitant ibuprofen use cannot be avoided, monitor patients more
`frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal
`toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)].
`
`Reference ID: 4558342
`
`5
`
`

`

`5.7 Embryo-Fetal Toxicity
`
` Based on findings from animal studies and its mechanism of action, PEMFEXY can cause fetal harm when
`administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to
`pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and
`increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant
`women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception
`during treatment with PEMFEXY and for 6 months after the final dose. Advise males with female partners of
`
`reproductive potential to use effective contraception during treatment with PEMFEXY and for 3 months after
`the final dose [see Use in Specific Populations (8.1, 8.3)].
`
`
`ADVERSE REACTIONS
`6
`
`The following clinically significant adverse reactions are described elsewhere in 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)]
`
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in
`clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in 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 with cisplatin, are vomiting, neutropenia, anemia, stomatitis/pharyngitis,
`thrombocytopenia and constipation.
`Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
`
`
`Initial Treatment in Combination with Cisplatin
`The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial
`conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either
`pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each
`21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 in combination with cisplatin
`75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic
`acid and vitamin B12.
`Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of
`2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a
`calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal
`
` anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the
`study.
`The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median
`age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were
`Hispanic or Latino, 2.1% were Black or African American, and < 1% were other races; 36% had an ECOG PS
`0. Patients received a median of 5 cycles of pemetrexed.
`
`Table 2 provides the frequency and severity of adverse reactions that occurred in ≥ 5% of 839 patients receiving
`pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a
`statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for
`any specified adverse reaction listed in Table 2.
`
`Reference ID: 4558342
`
`6
`
`

`

`Table 2:
`
`
`
` Adverse Reactiona
`
`
`
`Adverse Reactions Occurring in ≥ 5% of Fully Vitamin-Supplemented Patients Receiving
`
`
` Pemetrexed in Combination with Cisplatin in Study JMDB
`
` Pemetrexed/Cisplatin
`
`(N=839)
`All Grades
`Grade 3-4
`
`(%)
`(%)
`90
`37
`
`Gemcitabine/Cisplatin
`
`(N=830)
`All Grades
`Grade 3-4
`
`(%)
`(%)
`
`91
`53
`
`
`46
`38
`27
`
`
`7
`
`53
`36
`24
`20
`12
`13
`6
`
`45
`
`21
`8
`
`
`12
`9
`
`10
`27
`13
`
`1
`
`4
`6
`1
`0
`0
`2
`0
`
`5
`
`1
`1
`
`1
`0
`
` All adverse reactions
`
` Laboratory
`Hematologic
`
`Anemia
` Neutropenia
`
` Thrombocytopenia
`
`
` Renal
`Elevated creatinine
`
`Clinical
`
` Gastrointestinal
`
`
` Nausea
`
` Vomiting
`
` Anorexia
` Constipation
`
` Stomatitis/Pharyngitis
`
` Diarrhea
` Dyspepsia/Heartburn
`
` Constitutional Symptoms
`Fatigue
` Dermatology/Skin
`
` Alopecia
` Rash/Desquamation
`
` Neurology
` Sensory neuropathy
`
`Taste disturbance
`
`
` a NCI CTCAE version 2.0.
`
`
`The following additional adverse reactions of pemetrexed were observed.
`Incidence 1% to < 5%
`Body as a Whole — febrile neutropenia, infection, pyrexia
`General Disorders — dehydration
` Metabolism and Nutrition — increased AST, increased ALT
`Renal — renal failure
`Eye Disorder — conjunctivitis
`Incidence < 1%
`Cardiovascular — arrhythmia
`General Disorders — chest pain
`Metabolism and Nutrition — increased GGT
`Neurology — motor neuropathy
`
`
`
`
`
`
`
`33
`29
`10
`
`10
`
`56
`40
`27
`21
`14
`12
`5
`
`43
`
`12
`7
`
`9
`8
`
`6
`15
`4
`
`1
`
`7
`6
`2
`1
`1
`1
`0
`
`7
`
`0
`0
`
`0
`0
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4558342
`
`7
`
`

`

` Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy
`
`The safety of pemetrexed was evaluated in Study JMEN, a randomized (2:1), placebo-controlled, multicenter
`trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of
`a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m2 or matching
`placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study
`
`arms were fully supplemented with folic acid and vitamin B12.
`Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention,
`inadequate bone marrow reserve and organ function or a calculated creatinine clearance < 45 mL/min. Patients
`unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin
`B12 or corticosteroids were also excluded from the study.
`
`The data described below reflect exposure to pemetrexed in 438 patients in Study JMEN. Median age was 61
`years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic
`or Latino, and < 2% were other races; 39% had an ECOG PS 0. Patients received a median of 5 cycles of
`pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%)
`completed at least six 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed.
`Table 3 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 438 pemetrexed-
`treated patients in Study JMEN.
`Table 3:
`Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in Study JMEN
`Pemetrexed
`Placebo
`
`
`(N=218)
`(N=438)
`All Grades
`All Grades
`Grade 3-4
`Grade 3-4
`
`
`(%)
`(%)
`(%)
`(%)
`
`66
`16
`37
`4
`
`Adverse Reactiona
`
`
`15
` 6
`
`10
`8
`
`25
`
`19
`19
` 9
`7
` 5
`
`10
`
` 9
`5
`
`3
`3
`
`0
`0
`
`5
`
`1
`2
`0
`1
`1
`
`0
`
`1
` 2
`
`6
`0
`
`
`4
`
`4
`
`
`11
`
`6
`
`5
`1
`
`2
`3
`
`
`3
`
`4
`
` 2
`
`1
`0
`
`0
`0
`
`1
`
`1
`0
`0
`0
`0
`
`0
`
`0
` 0
`
`
`All adverse reactions
`
`Laboratory
`
`Hematologic
`
`Anemia
`Neutropenia
`Hepatic
`
`Increased ALT
`Increased AST
` Clinical
`
` Constitutional Symptoms
`
`Fatigue
` Gastrointestinal
`
`Nausea
`Anorexia
`
`Vomiting
`Mucositis/Stomatitis
`
`Diarrhea
` Dermatology/Skin
`
`
` Rash/Desquamation
`Neurology
`
`Sensory neuropathy
`Infection
`
` NCI CTCAE version 3.0.
`
`
`
`a
`
`
`
`Reference ID: 4558342
`
`8
`
`

`

`The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for
`erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the
`placebo arm.
`The following additional adverse reactions were observed in patients who received pemetrexed.
`Incidence 1% to < 5%
`Dermatology/Skin — alopecia, pruritis/itching
`Gastrointestinal — constipation
`General Disorders — edema, fever
`Hematologic — thrombocytopenia
`Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation
`Incidence < 1%
`Cardiovascular — supraventricular arrhythmia
`Dermatology/Skin — erythema multiforme
`
`General Disorders — febrile neutropenia, allergic reaction/hypersensitivity
`Neurology — motor neuropathy
`Renal — renal failure
`Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy
`The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study
`conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally
`advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line
`therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo
`intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both
`study arms received folic acid and vitamin B12 supplementation.
`PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention,
`inadequate bone marrow reserve and organ function, or a calculated creatinine clearance < 45 mL/min. Patients
`unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin
`
` B12 or corticosteroids were also excluded from the study.
`The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61
`years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and < 1% were
`Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for
`pemetrexed and placebo arms.
`Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the
`placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in
`
`the placebo arm.
`Table 4 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 333 pemetrexed-
`
`treated patients in PARAMOUNT.
`Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in PARAMOUNT
`Table 4:
`Pemetrexed
`Placebo
`
`
`(N=167)
`(N=333)
`
`
`All Grades
`All Grades
`Grade 3-4
`Grades 3-4
`(%)
`(%)
`(%)
`(%)
`
`53
`17
`34
`4.8
`
`
`Adverse Reactiona
`
`All Adverse Reactions
`
`Laboratory
`
`Hematologic
`
`Anemia
` Neutropenia
`
`
`
`15
`9
`
`9
`
`4.8
`3.9
`
`4.8
`0.6
`
`0.6
`0
`
`Reference ID: 4558342
`
`

`

`4.5
`
`0.3
`0
`0.3
`
`0
`
`11
`
`2.4
`1.8
`2.4
`
`3.6
`
`0.6
`
`0
`0
`0
`
`0
`
`Clinical
`
`Constitutional Symptoms
`
`Fatigue
` Gastrointestinal
`Nausea
` Vomiting
`
`
`Mucositis/Stomatitis
` General Disorders
`
`Edema
`
`
`
` a NCI CTCAE version 3.0.
`
`The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions,
`erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%)
`
` were higher in the pemetrexed arm compared to the placebo arm.
`The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm.
`Incidence 1% to < 5%
`Blood/Bone Marrow — thrombocytopenia
`General Disorders — febrile neutropenia
`Incidence < 1%
`Cardiovascular — ventricular tachycardia, syncope
`General Disorders — pain
`Gastrointestinal — gastrointestinal obstruction
`Neurologic — depression
`Renal — renal failure
`Vascular — pulmonary embolism
`
`Treatment of Recurrent Disease After Prior Chemotherapy
`The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial
`conducted in patients who had progressed following platinum-based chemotherapy. Patients received
`pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All
`patients on the pemetrexed arm received folic acid and vitamin B12 supplementation.
`Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention,
`inadequate bone marrow reserve and organ function, or a calculated creatinine clearance < 45 mL/min. Patients
`unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin
`
` B12 or corticosteroids were also excluded from the study.
`The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58
`years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or
`African American, 1.8% were H