•
`
`•
`
`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 for the:
`
`initial treatment of patients with locally advanced or metastatic
`•
`non-squamous, non-small cell lung cancer (NSCLC) in
`combination with cisplatin. (1.1)
`
`• 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. (1.1)
`
`treatment of patients with recurrent, metastatic non-squamous,
`NSCLC after prior chemotherapy, as a single agent. (1.1)
`
`
`Limitations of Use:
`ALIMTA is not indicated for the treatment of patients with
`squamous cell NSCLC. (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 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 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)
`
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`1
`------------------------ 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)
`
`
`•
`
`
`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: 10/2017
`
`
`
`Reference ID: 4165466
`
`

`

`
`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 and Schedule for Non-Squamous
`
`2.1
`NSCLC
`
`
`Recommended Dosage and Schedule for Mesothelioma
`
` Renal Impairment
`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
`
`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
`
` Embryo-Fetal Toxicity
`
`2
`
`6 ADVERSE REACTIONS
`
`Clinical Trials Experience
`
`6.1
`6.2
` Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
` Lactation
`8.3
`Females and Males of Reproductive Potential
`
`8.4
` Pediatric Use
` 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
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
` Non-squamous NSCLC
`
`14.1
`
` Mesothelioma
`14.2
`
`15 REFERENCES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`2.2
`2.3
`2.4
`
`2.5
`
`5.2
`5.3
`5.4
`5.5
`5.6
`
`5.7
`
`
`
`
`
`Reference ID: 4165466
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`3
`
`
`
` FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`
`1.1
`Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
`ALIMTA® is indicated for:
`
`initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer
`•
`(NSCLC) in combination with cisplatin.
`• 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.
`treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy, as a single
`
`agent.
`
`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].
`
`•
`
`
`DOSAGE AND ADMINISTRATION
`
`
`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
`
`Recommended Dosage and Schedule for Non-Squamous NSCLC
`2.1
`• The recommended dose of ALIMTA in combination with cisplatin for initial treatment of 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 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 dose of ALIMTA for treatment of recurrent 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 and Schedule for Mesothelioma
`
`• The recommended dose of ALIMTA, administered in combination 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)].
`
`
`
`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 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.
`
`
`
`
`Reference ID: 4165466
`
`

`

`Corticosteroids
`• Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each ALIMTA
`administration.
`
`4
`
`
`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.
`
`
`
`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 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, refer to the prescribing information for cisplatin.
`
`
`Table 1: Recommended Dosage Modifications for Adverse Reactionsa
`
`ALIMTA Dose Modification for
`Toxicity in Most Recent Treatment Cycle
`
`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
`
`50% of previous dose
`
`Withhold until creatinine
`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)
`
` 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.
`
`
`
`
` 75% of previous dose
`
`
`
` 50% of previous dose
`Discontinue
`
`
`75% of previous dose
`
`
`Renal toxicity [see Warnings and Precautions (5.2)]
`
`
`Reference ID: 4165466
`
`

`

` • 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.
`
`5
`
`
`• 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.
`
`
`CONTRAINDICATIONS
`
`
`WARNINGS AND PRECAUTIONS
`
`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.
`
`4
`
`ALIMTA is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse
`Reactions (6.1)].
`
`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%.
`
`
`Reference ID: 4165466
`
`

`

`6
`
`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)].
`
`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 ALIMTA. Permanently discontinue ALIMTA for severe and
`life-threatening bullous, blistering or exfoliating skin toxicity.
`
`5.4
`Interstitial Pneumonitis
`
`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.
`
`5.5
`Radiation Recall
`
`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.
`
`
`5.6
`Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment
`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)].
`
`
`5.7
`Embryo-Fetal Toxicity
`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)].
`
`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)]
`
`
`ADVERSE REACTIONS
`
`
`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.
`
`Reference ID: 4165466
`
`

`

`7
`
`
`Non-Squamous NSCLC
`
`
`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 2 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 2.
`
`
`Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving ALIMTA in
`
`
`
`Combination with Cisplatin Chemotherapy in Study JMDB
`
`ALIMTA/Cisplatin
`Gemcitabine/Cisplatin
`(N=839)
`(N=830)
`
`
`
`
`
`
`Grade 3-4
`All Grades
`Grade 3-4
`All Grades
`(%)
`(%)
`(%)
`(%)
`
`90
`37
`91
`53
`
`Adverse Reactiona
`
`
`
`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.
`
`
`Reference ID: 4165466
`
`33
`29
`10
`
`
`10
`
`43
`
`56
`40
`27
`21
`14
`12
`5
`
`9
`8
`
`12
`7
`
`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
`
`

`

`The following additional adverse reactions of ALIMTA 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
`
`
`
`8
`
`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 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 ALIMTA-treated patients in
`
`Study JMEN.
`
`
`
`Reference ID: 4165466
`
`

`

`
`
` Adverse Reactiona
`
` Table 3: Adverse Reactions Occurring in ≥5% of Patients Receiving ALIMTA in Study JMEN
`
`ALIMTA
`Placebo
`
`
`(N=438)
`(N=218)
`
`
`
`
`
`
`Grade 3-4
`All Grades
`Grade 3-4
`All Grades
`(%)
`(%)
`(%)
`(%)
`
`
`66
`16
`37
`4
`
`9
`
`1
`0
`
`0
`0
`
`1
`
`1
`0
`0
`0
`0
`0
`
`0
`
`0
`
`
`15
`6
`
`
`10
`8
`
`
`25
`
`
`19
`
`19
`9
`7
`5
`5
`
`9
`
`
`10
`
`3
`3
`
`0
`0
`
`5
`
`1
`2
`0
`1
`1
`2
`
`1
`
`0
`
`6
`0
`
`4
`4
`
`
`11
`
`6
`5
`1
`2
`3
`2
`
`4
`
`3
`
`
`
`
`
`
`All adverse reactions
`Laboratory
`
`Hematologic
`
`Anemia
`Neutropenia
`Hepatic
`
`Increased ALT
`Increased AST
`Clinical
`
`Constitutional symptoms
`
`Fatigue
`Gastrointestinal
`
`Nausea
`Anorexia
`Vomiting
`Mucositis/stomatitis
`Diarrhea
`Infection
`Neurology
`
`
`Sensory neuropathy
`Dermatology/Skin
`
`Rash/desquamation
`
` a NCI CTCAE version 3.0
`
` 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 ALIMTA arm compared to the placebo arm.
`
`The following additional adverse reactions were observed in patients who received ALIMTA.
`
`
`Incidence 1% to<5%
`
`
`Dermatology/Skin — alopecia, pruritus/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 ALIMTA Plus Platinum Chemotherapy
`The safety of ALIMTA 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 ALIMTA in combination with cisplatin as first-line therapy for NSCLC. Patients were
`randomized to receive ALIMTA 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 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.
`
`
`Reference ID: 4165466
`
`

`

`10
` The data described below reflect exposure to ALIMTA 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 ALIMTA and placebo arms. Dose
`reductions for adverse reactions occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose
`
`delays for adverse reactions occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm.
`
`
`Table 4 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 ALIMTA-treated patients in
`PARAMOUNT.
`
`
`Adverse Reactiona
`
`
`
`Table 4: Adverse Reactions Occurring in ≥5% of Patients Receiving ALIMTA in PARAMOUNT
`ALIMTA
`Placebo
`
`
`(N=333)
`(N=167)
`
`
`
`
`
`
`Grade 3-4
`Grades 3-4
`All Grades
`All Grades
`(%)
`(%)
`(%)
`(%)
`
`
`53
`17
`34
`4.8
`
`
`All adverse reactions
`
`Laboratory
`
`Hematologic
`Anemia
`Neutropenia
`Clinical
`
`Constitutional symptoms
`Fatigue
`Gastrointestinal
`Nausea
`Vomiting
`Mucositis/stomatitis
`
`General disorders
`Edema
`
` a NCI CTCAE version 3.0
`
`
`
`
`15
`9
`
`
`18
`
`
`12
`6
`5
`
`5
`
`4.8
`3.9
`
`4.5
`
`0.3
`0
`0.3
`
`0
`
`4.8
`0.6
`
`
`11
`
`2.4
`1.8
`2.4
`
`3.6
`
`0.6
`0
`
`0.6
`
`0
`0
`0
`
`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
`ALIMTA arm compared to the placebo arm.
`
`The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA 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 ALIMTA 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 ALIMTA 500 mg/m2
`
`
`intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the ALIMTA 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 less than 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.
`
`
`Reference ID: 4165466
`
`

`

`11
`
` The data described below reflect exposure to ALIMTA 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 Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0.
`
` Table 5 provides the frequency an