•
`
`•
`
`•
`
`•
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ALIMTA safely and effectively. See full prescribing information for
`ALIMTA.
`
`ALIMTA (pemetrexed for injection), for Intravenous Use
`Initial U.S. Approval: 2004
` --------------------------- RECENT MAJOR CHANGES --------------------------
`Indications and Usage (1.1)
`01/2019
`01/2019
`Dosage and Administration (2.1)
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`ALIMTA® is a folate analog metabolic inhibitor indicated:
`•
`in combination with pembrolizumab and platinum chemotherapy,
`for the initial treatment of patients with metastatic non-squamous
`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, 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: ALIMTA 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)
` ------------------------ DOSAGE AND ADMINISTRATION -----------------------
`•
`The recommended dose of ALIMTA 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/m2 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 dose of ALIMTA, 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)
`Initiate folic acid 400 mcg to 1000 mcg orally, once daily,
`beginning 7 days prior to the first dose of ALIMTA and continue
`until 21 days after the last dose of ALIMTA. (2.4)
`Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the
`first dose of ALIMTA and every 3 cycles. (2.4)
`Administer dexamethasone 4 mg orally, twice daily the day
`before, the day of, and the day after ALIMTA administration. (2.4)
` ----------------------DOSAGE FORMS AND STRENGTHS ---------------------
`For Injection: 100 mg or 500 mg lyophilized powder in 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 ALIMTA 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 ALIMTA. (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)
` ------------------------------- ADVERSE REACTIONS ------------------------------
`•
`The most common adverse reactions (incidence ≥20%) of
`ALIMTA, when administered as a single agent are fatigue,
`nausea, and anorexia. (6.1)
`The most common adverse reactions (incidence ≥20%) of
`ALIMTA when administered with cisplatin are vomiting,
`neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia,
`and constipation. (6.1)
`The most common adverse reactions (incidence ≥20%) of
`ALIMTA 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 Eli Lilly
`and Company at 1-800-LillyRx (1-800-545-5979) or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
` ------------------------------- DRUG INTERACTIONS ------------------------------
`Ibuprofen increased risk of ALIMTA toxicity in patients with mild to
`moderate renal impairment. 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: 01/2019
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1
`Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
`1.2
`Mesothelioma
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosage for Non-Squamous NSCLC
`2.2
`Recommended Dosage for Mesothelioma
`2.3
`Renal Impairment
`2.4
`Premedication and Concomitant Medications to Mitigate
`Toxicity
`Dosage Modification of Ibuprofen in Patients with Mild to
`Moderate Renal Impairment Receiving ALIMTA
`Dosage Modifications for Adverse Reactions
`2.6
`Preparation for Administration
`2.7
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`
`2.5
`
`5.2
`5.3
`5.4
`5.5
`5.6
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Myelosuppression and Increased Risk of
`Myelosuppression without Vitamin Supplementation
`Renal Failure
`Bullous and Exfoliative Skin Toxicity
`Interstitial Pneumonitis
`Radiation Recall
`Increased Risk of Toxicity with Ibuprofen in Patients with
`Renal Impairment
`Embryo-Fetal Toxicity
`5.7
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`
`Reference ID: 4383136
`
`

`

`
`
`Pregnancy
`8.1
`Lactation
`8.2
`Females and Males of Reproductive Potential
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Patients with Renal Impairment
`8.6
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Non-Squamous NSCLC
`14.2 Mesothelioma
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
`1.1
`ALIMTA® is indicated:
`•
`in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with
`metastatic non-squamous 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, 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: ALIMTA is not indicated for the treatment of patients with squamous cell, non-small cell lung
`cancer [see Clinical Studies (14.1)].
`
`1.2 Mesothelioma
`ALIMTA 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
`
`Recommended Dosage for Non-Squamous NSCLC
`2.1
`• The recommended dose of ALIMTA 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/m2 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 ALIMTA 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 dose of ALIMTA 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 dose of ALIMTA 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.
`
`
`
`Reference ID: 4383136
`
`

`

` •
`
` The recommended dose of ALIMTA 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.
`
`Recommended Dosage for Mesothelioma
`2.2
`• The recommended dose of ALIMTA 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.
`
`Renal Impairment
`2.3
`• ALIMTA 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)].
`
`Premedication and Concomitant Medications to Mitigate Toxicity
`2.4
`Vitamin Supplementation
`•
`Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of ALIMTA and
`continuing until 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].
`
` •
`
` Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter.
`Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [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 ALIMTA
`administration.
`
`Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving ALIMTA
`2.5
`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 ALIMTA.
`• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant
`administration of ibuprofen cannot be avoided.
`
`Dosage Modifications for Adverse Reactions
`2.6
`Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not
`administer ALIMTA if the creatinine clearance is less than 45 mL/min.
`
`Delay initiation of the next cycle of ALIMTA 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 ALIMTA in the next cycle as specified in Table 1.
`
`For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information.
`
`
`Reference ID: 4383136
`
`

`

`
`
`Table 1: Recommended Dosage Modifications for Adverse Reactionsa
`ALIMTA Dose Modification for
`Next Cycle
`
`Toxicity in Most Recent Treatment 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
`50% of previous dose
`Grade 3 or 4 mucositis
`Withhold until creatinine
`Renal toxicity [see Warnings and Precautions (5.2)]
`clearance is 45 mL/min or greater
`Permanently discontinue
`Grade 3 or 4 neurologic toxicity
`Permanently discontinue
`Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions
`Permanently discontinue
`Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)]
`Permanently discontinue
`Interstitial Pneumonitis [see Warnings and Precautions (5.4)]
`a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2).
`
`
`75% of previous dose
`
`50% of previous dose
`Discontinue
`
`75% of previous dose
`
`Preparation for Administration
`2.7
`• ALIMTA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
`
` •
`
` Calculate the dose of ALIMTA and determine the number of vials needed.
`
` •
`
` Reconstitute ALIMTA to achieve a concentration of 25 mg/mL as follows:
`• Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
`• Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
`• Do not use calcium-containing solutions for reconstitution.
`
` •
`
` Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from
`colorless to yellow or green-yellow. FURTHER DILUTION IS REQUIRED prior to administration.
`
` Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36-46°F)] for no longer than
`24 hours from the time of reconstitution. Discard vial after 24 hours.
`
` •
`
` •
`
`
`
`Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate
`matter is observed, discard vial.
`
` •
`
` •
`
` Withdraw the calculated dose of ALIMTA from the vial(s) and discard vial with any unused portion.
`
` Further dilute ALIMTA with 0.9% Sodium Chloride Injection (preservative-free) to achieve a total volume of 100 mL for
`intravenous infusion.
`
` •
`
` Store diluted, reconstituted product under refrigerated conditions [2-8°C (36-46°F)] for no more than 24 hours from the
`time of reconstitution. Discard after 24 hours.
`
`DOSAGE FORMS AND STRENGTHS
`3
`For injection: 100 mg or 500 mg pemetrexed as a white to light-yellow or green-yellow lyophilized powder in single-dose
`vials for reconstitution.
`
`CONTRAINDICATIONS
`4
`ALIMTA is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse
`Reactions (6.1)].
`
`Reference ID: 4383136
`
`

`

`WARNINGS AND PRECAUTIONS
`
`
`
` 5
`
`5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation
`ALIMTA 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 ALIMTA
`plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and
`vitamin B12 prior to and throughout ALIMTA plus cisplatin treatment.
`
`Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of ALIMTA; continue
`vitamin supplementation during treatment and for 21 days after the last dose of ALIMTA to reduce the severity of
`hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.4)]. Obtain a complete blood count
`at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at
`least 100,000 cells/mm3. Permanently reduce ALIMTA 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 ALIMTA 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%.
`
`Renal Failure
`5.2
`ALIMTA can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which
`patients received ALIMTA 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 ALIMTA 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 ALIMTA. Withhold ALIMTA in patients with a creatinine clearance
`of less than 45 mL/minute [see Dosage and Administration (2.3)].
`
`Bullous and Exfoliative Skin Toxicity
`5.3
`Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-
`Johnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and
`life-threatening bullous, blistering or exfoliating skin toxicity.
`
`Interstitial Pneumonitis
`5.4
`Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA 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 ALIMTA.
`
`Radiation Recall
`5.5
`Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor
`patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs
`of radiation recall.
`
`Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment
`5.6
`Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen,
`increasing the risks of adverse reactions of ALIMTA. 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 ALIMTA.
`If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including
`myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and
`Clinical Pharmacology (12.3)].
`
`Reference ID: 4383136
`
`

`

`
`Embryo-Fetal Toxicity
`5.7
`Based on findings from animal studies and its mechanism of action, ALIMTA 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 ALIMTA and for 6 months after the
`final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with
`ALIMTA and for 3 months after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology
`(12.1)].
`
`ADVERSE REACTIONS
`6
`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)]
`
`Clinical Trials Experience
`6.1
`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 ALIMTA, when administered as a single agent,
`are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of ALIMTA, when administered
`in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and
`constipation. The most common adverse reactions (incidence ≥20%) of ALIMTA, 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 ALIMTA, 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 ALIMTA, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by ALIMTA
`and pembrolizumab (n=405), or placebo, ALIMTA, and platinum every 3 weeks for 4 cycles followed by placebo and
`ALIMTA (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 ALIMTA 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.
`
`ALIMTA was discontinued for adverse reactions in 23% of patients in the ALIMTA, pembrolizumab, and platinum arm. The
`most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and
`pneumonitis (2%). Adverse reactions leading to interruption of ALIMTA occurred in 49% of patients in the ALIMTA,
`pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to
`interruption of ALIMTA 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 ALIMTA, pembrolizumab, and
`platinum.
`
`
`Reference ID: 4383136
`
`

`

`
`
`
`
`Adverse Reaction
`
`Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
`ALIMTA
`Placebo
`Pembrolizumab
`ALIMTA
`Platinum Chemotherapy
`Platinum Chemotherapy
`n=405
`n=202
`All Gradesa
`All Grades
`(%)
`(%)
`
`Grade 3-4
`(%)
`
`Grade 3-4
`(%)
`
`Gastrointestinal Disorders
`56
`Nausea
`35
`Constipation
`31
`Diarrhea
`24
`Vomiting
`General Disorders and Administration Site Conditions
`Fatigueb
`56
`Pyrexia
`20
`Metabolism and Nutrition Disorders
`Decreased appetite
`Skin and Subcutaneous Tissue Disorders
`Rashc
`Respiratory, Thoracic and Mediastinal Disorders
`Cough
`Dyspnea
`a Graded per NCI CTCAE version 4.03.
`b Includes asthenia and fatigue.
`c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash
`pustular.
`
`3.5
`1.0
`5
`3.7
`
`12
`0.2
`
`1.5
`
`2.0
`
`0
`3.7
`
`52
`32
`21
`23
`
`58
`15
`
`30
`
`17
`
`28
`26
`
`3.5
`0.5
`3.0
`3.0
`
`6
`0
`
`0.5
`
`2.5
`
`0
`5
`
`28
`
`25
`
`21
`21
`
`
`Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with
`ALIMTA, pembrolizumab, and platinum.
`
`
`Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189
`ALIMTA
`Placebo
`
`ALIMTA
`Pembrolizumab
`Platinum Chemotherapy
`Platinum Chemotherapy
`Grades 3-4
`All Gradesb
`All Grades
`Grades 3-4
`%
`%
`%
`%
`
`Laboratory Testa
`Chemistry
`Hyperglycemia
`Increased ALT
`Increased AST
`Hypoalbuminemia
`Increased creatinine
`Hyponatremia
`Hypophosphatemia
`Increased alkaline phosphatase
`Hypocalcemia
`Hyperkalemia
`Hypokalemia
`Hematology
`18
`81
`17
`85
`Anemia
`25
`64
`22
`64
`Lymphopenia
`19
`41
`20
`48
`Neutropenia
`8
`29
`12
`30
`Thrombocytopenia
`a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
`measurement available: ALIMTA/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and
`placebo/ALIMTA/platinum chemotherapy (range: 184 to 197 patients).
`b Graded per NCI CTCAE version 4.03.
`
`63
`47
`47
`39
`37
`32
`30
`26
`24
`24
`21
`
`9
`3.8
`2.8
`2.8
`4.2
`7
`10
`1.8
`2.8
`2.8
`5
`
`60
`42
`40
`39
`25
`23
`28
`29
`17
`19
`20
`
`7
`2.6
`1.0
`1.1
`1.0
`6
`14
`2.1
`0.5
`3.1
`5
`
`Reference ID: 4383136
`
`

`

`
`
`Initial Treatment in Combination with Cisplatin
`The safety of ALIMTA 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 ALIMTA 500 mg/m2
`intravenously and 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 and 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 ALIMTA 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 ethnicities; 36% had an ECOG PS 0. Patients received
`a median of 5 cycles of ALIMTA.
`
`Table 4 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving ALIMTA
`in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant
`reduction in adverse reaction rates for ALIMTA, as compared to the control arm, for any specified adverse reaction listed
`in Table 4.
`
`
`Table 4: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving ALIMTA in
`Combination with Cisplatin Chemotherapy in Study JMDB
`ALIMTA/Cisplatin
`(N=839)
`All Grades
`Grade 3-4
`(%)
`(%)
`90
`37
`
`Adverse Reactiona
`
`Gemcitabine/Cisplatin
`(N=830)
`All Grades
`Grade 3-4
`(%)
`(%)
`91
`53
`
`6
`15
`4
`
`1
`
`7
`
`7
`6
`2
`1
`1
`1
`0
`
`0
`0
`
`0
`0
`
`46
`38
`27
`
`7
`
`45
`
`53
`36
`24
`20
`12
`13
`6
`
`12
`9
`
`21
`8
`
`10
`27
`13
`
`1
`
`5
`
`4
`6
`1
`0
`0
`2
`0
`
`1
`0
`
`1
`1
`
`All adverse reactions
`Laboratory
`Hematologic
`Anemia
`Neutropenia
`Thrombocytopenia
`Renal
`Elevated creatinine
`Clinical
`Constitutional symptoms
`Fatigue
`Gastrointestinal
`Nausea
`Vomiting
`Anorexia
`Constipation
`Stomatitis/pharyngitis
`Diarrhea
`Dyspepsia/heartburn
`Neurology
`Sensory neuropathy
`Taste disturbance
`Dermatology/Skin
`Alopecia
`Rash/Desquamation
`a NCI CTCAE version 2.0.
`
`The following additional adverse reactions of ALIMTA were observed.
`
`
`33
`29
`10
`
`10
`
`43
`
`56
`40
`27
`21
`14
`12
`5
`
`9
`8
`
`12
`7
`
`Reference ID: 4383136
`
`

`

`
`
`
`
`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
`
`
`Maintenance Treatment Following First-line Non-ALIMTA Containing Platinum-Based Chemotherapy
`In Study JMEN, the safety of ALIMTA was evaluated in 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 ALIMTA 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 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 ALIMTA 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 ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of ALIMTA and a relative dose intensity
`of ALIMTA of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or
`more 21-day cycles of ALIMTA.
`
`Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 ALIMTA-treated patients in
`Study JMEN.
`
`
`Table 5: Adverse Reactions Occurring in ≥5% of Patients Receiving ALIMTA in Study JMEN
`Placebo
`ALIMTA
`(N=438)
`(N=218)
`Grade 3-4
`All Grades
`Grade 3-4
`All Grades
`(%)
`(%)
`(%)
`(%)
`66
`16
`37
`4
`
`Adverse Reactiona
`
`All adverse reactions
`Labo