`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
`
`
`
`
`---------------------------- 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
`
`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: 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: 08/2022
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`
`Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
`1.1
`
`
`1.2
`Mesothelioma
`2 DOSAGE AND ADMINISTRATION
`
`Recommended Dosage for Non-Squamous NSCLC
`2.1
`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
`
`Myelosuppression and Increased Risk of
`5.1
`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
`5.7
`Embryo-Fetal Toxicity
`
`6 ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`6.2
`Postmarketing Experience
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`
`
`Reference ID: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`8.2
`Lactation
`8.3
` Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`
`8.5
`Geriatric Use
`
`8.6
`Patients with Renal Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`
`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.
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
`
`
` 1.1
`
` Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
` ALIMTA® 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: 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: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` • 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: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`
`
`
`
`
` Table 1: Recommended Dosage Modifications for Adverse Reactionsa
`
`
` ALIMTA Dose Modification for
`
`
` Next Cycle
`
`
`
` 75% of previous dose
`
`
`
`
`
`
`
`
`
` 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
`
`
`
` Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue
`
`
`
`
`
` 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 50% of previous dose
`
`
`
` Discontinue
`
`
`
`
`
`
`
`
`
`
`
` 75% of previous dose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.7
`Preparation for Administration
`
`
`
`
`
` • ALIMTA is a hazardous 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.
`
`
`
`
`
`
`
`
`
`
`
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`• Store diluted, reconstituted product under refrigerated conditions [2-8°C (36-46°F)] for no more than 24 hours from the
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`time of reconstitution. Discard after 24 hours.
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`DOSAGE FORMS AND STRENGTHS
`3
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`For injection: 100 mg or 500 mg pemetrexed as a white to light-yellow or green-yellow lyophilized powder in single-dose
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`vials for reconstitution.
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`CONTRAINDICATIONS
`4
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`ALIMTA is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse
`
`
`Reactions (6.1)].
`
`Reference ID: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`5
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`WARNINGS AND PRECAUTIONS
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`5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation
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`ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to
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`neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.
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`In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile
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`neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received ALIMTA
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`plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and
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`vitamin B12 prior to and throughout ALIMTA plus cisplatin treatment.
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`Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of ALIMTA; continue
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`vitamin supplementation during treatment and for 21 days after the last dose of ALIMTA to reduce the severity of
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`hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.4)]. Obtain a complete blood count
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`at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at
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`least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count
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` of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)].
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`In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia
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`was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia
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`was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions
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`compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and
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`JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%,
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`and incidence of Grade 3-4 anemia ranged from 3% to 5%.
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`Renal Failure
`5.2
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`ALIMTA can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which
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`patients received ALIMTA with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal
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`failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN,
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`PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and
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`periodically monitor renal function during treatment with ALIMTA. Withhold ALIMTA in patients with a creatinine clearance
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`of less than 45 mL/minute [see Dosage and Administration (2.3)].
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`Bullous and Exfoliative Skin Toxicity
`5.3
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`Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-
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`Johnson Syndrome/Toxic epidermal necrolysis can occur with ALIMTA. Permanently discontinue ALIMTA for severe and
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`life-threatening bullous, blistering or exfoliating skin toxicity.
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`Interstitial Pneumonitis
`5.4
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`Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset
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`of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation.
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`If pneumonitis is confirmed, permanently discontinue ALIMTA.
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`Radiation Recall
`5.5
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`Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor
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`patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs
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`of radiation recall.
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`Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment
`5.6
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`Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen,
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`increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and
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`79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.
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`If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including
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`myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and
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`Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`Embryo-Fetal Toxicity
`5.7
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`Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a
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`pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the
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`period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower
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`than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. Advise females
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`of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the last dose.
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`Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA
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`and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
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`6
`ADVERSE REACTIONS
`
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`The following adverse reactions are discussed in greater detail in other sections of the labeling:
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`• Myelosuppression [see Warnings and Precautions (5.1)]
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`• Renal failure [see Warnings and Precautions (5.2)]
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`• Bullous and exfoliative skin toxicity [see Warning and Precautions (5.3)]
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`•
`Interstitial pneumonitis [see Warnings and Precautions (5.4)]
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`• Radiation recall [see Warnings and Precautions (5.5)]
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`Clinical Trials Experience
`6.1
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`Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly
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`compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
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`In clinical trials, the most common adverse reactions (incidence ≥20%) of ALIMTA, when administered as a single agent,
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`are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of ALIMTA, when administered
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`in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and
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`constipation. The most common adverse reactions (incidence ≥20%) of ALIMTA, when administered in combination with
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`pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite,
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`rash, vomiting, cough, dyspnea, and pyrexia.
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`Non-Squamous NSCLC
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`First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy
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`The safety of ALIMTA, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or
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`cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial
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`in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
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`A total of 607 patients received ALIMTA, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by ALIMTA
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`and pembrolizumab (n=405), or placebo, ALIMTA, and platinum every 3 weeks for 4 cycles followed by placebo and
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`ALIMTA (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical
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`condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior
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`26 weeks were ineligible [see Clinical Studies (14.1)].
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`The median duration of exposure to ALIMTA was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients
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`received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age
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`65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.
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`ALIMTA was discontinued for adverse reactions in 23% of patients in the ALIMTA, pembrolizumab, and platinum arm. The
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`most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and
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`pneumonitis (2%). Adverse reactions leading to interruption of ALIMTA occurred in 49% of patients in the ALIMTA,
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`pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to
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`interruption of ALIMTA in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%),
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`thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).
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`Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with ALIMTA, pembrolizumab, and
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`platinum.
`
`
`
`Reference ID: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
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` Adverse Reaction
`
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` 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
`
`
` (%)
` (%)
`
` Gastrointestinal Disorders
`
` 56
`
` Nausea
`
` 35
` Constipation
`
` 31
`
` Diarrhea
`
` 24
`
` Vomiting
` General Disorders and Administration Site Conditions
`
`
` Fatigueb
`
`
` 56
`
` 20
`
` Pyrexia
` Metabolism and Nutrition Disorders
`
`
` Decreased appetite
` Skin and Subcutaneous Tissue Disorders
`
`
` Rashc
` Respiratory, Thoracic and Mediastinal Disorders
`
`
` Cough
`
` Dyspnea
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`
`
` a Graded per NCI CTCAE version 4.03.
`
` b Includes asthenia and fatigue.
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`Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash
`
` c
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`pustular.
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` Grade 3-4
`
` (%)
`
`
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` Grade 3-4
`
` (%)
`
`
` 3.5
`
` 1.0
`
` 5
` 3.7
`
`
`
` 12
`
` 0.2
`
`
`
` 1.5
`
`
`
` 2.0
`
` 0
`
` 3.7
`
`
`
`28
`
`
`
` 25
`
`
` 21
`
` 21
`
`
` 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
`
`
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`Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with
`
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`ALIMTA, pembrolizumab, and platinum.
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`Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189
`
` ALIMTA
`
`
` Placebo
`
` Pembrolizumab
`
` ALIMTA
`
`
` Platinum Chemotherapy
`
` Platinum Chemotherapy
`
`
` All Gradesb
`
` All Grades
` Grades 3-4
`
`
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` 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
`
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` placebo/ALIMTA/platinum chemotherapy (range: 184 to 197 patients).
`
`
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`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: 5038970
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`Initial Treatment in Combination with Cisplatin
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`
`The safety of ALIMTA was evaluated in Study JMD