1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

AXTLE is indicated for:

• 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: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1)].

1.2 Mesothelioma

AXTLE 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.

2.1 Recommended Dosage for Non-Squamous NSCLC

• The recommended dose of AXTLE 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/m2as 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 AXTLE 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/m2as 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 AXTLE 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/m2as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.2 Recommended Dosage for Mesothelioma

• The recommended dose of AXTLE, when administered with cisplatin, in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.3 Renal Impairment

• AXTLE 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 AXTLE and continuing until 21 days after the last dose of AXTLE [see Warnings and Precautions (5.1)].
• Administer vitamin B12,1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles thereafter. Subsequent vitamin B12injections may be given the same day as treatment with AXTLE[see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12for intramuscular vitamin B12.

Corticosteroids 

• Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each AXTLE administration.

2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving AXTLE

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 AXTLE.
• 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 AXTLE if the creatinine clearance is less than 45 mL/min.

Delay initiation of the next cycle of AXTLE until:

• recovery of non-hematologic toxicity to Grade 0-2,
• absolute neutrophil count (ANC) is 1500 cells/mm3or higher, and
• platelet count is 100,000 cells/mm3or higher.

Upon recovery, modify the dosage of AXTLE in the next cycle as specified in Table 1.

For dosing modifications for cisplatin, refer to the prescribing information.

2.7 Preparation for Administration

• AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures.1
• Calculate the dose of AXTLE and determine the number of vials needed.
• Reconstitute AXTLE to achieve a concentration of 25 mg/mL as follows:
• Reconstitute each 100-mg vial with 4.2 mL of 5% Dextrose Injection, USP (preservative-free)
• Reconstitute each 500-mg vial with 20 mL of 5% Dextrose 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 AXTLE from the vial(s) and discard vial with any unused portion.
• Further dilute AXTLE with 5% Dextrose Injection, USP 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.

5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

AXTLE can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin treatment.

Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of AXTLE; continue vitamin supplementation during treatment and for 21 days after the last dose of AXTLE to reduce the severity of hematologic and gastrointestinal toxicity of AXTLE [see Dosage and Administration (2.4)]. Obtain a complete blood count at the beginning of each cycle. Do not administer AXTLE until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce AXTLE in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)].

In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

5.2 Renal Failure

AXTLE can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with AXTLE. Withhold AXTLE 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 AXTLE. Permanently discontinue AXTLE for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

5.4 Interstitial Pneumonitis

Serious interstitial pneumonitis, including fatal cases, can occur with AXTLE treatment. Withhold AXTLE 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 AXTLE.

5.5 Radiation Recall

Radiation recall can occur with AXTLE in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue AXTLE for signs of radiation recall.

5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment

Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of AXTLE. 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 AXTLE. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)].

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, AXTLE 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Squamous NSCLC

Initial Treatment in Combination with Cisplatin

The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m2intravenously and cisplatin 75 mg/m2intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2intravenously on Days 1 and 8 and cisplatin 75 mg/m2intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12.

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed.

Table 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 2.

The following additional adverse reactions of pemetrexed were observed.

Incidence 1% to <5%

Body as a Whole — febrile neutropenia, infection, pyrexia

General Disorders — dehydration

Metabolism and Nutrition — increased AST, increased ALT

Renal — renal failure

Eye Disorder — conjunctivitis

Incidence <1%

Cardiovascular — arrhythmia

General Disorders — chest pain

Metabolism and Nutrition — increased GGT 

Neurology — motor neuropathy

Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy

In Study JMEN, the safety of pemetrexed 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 pemetrexed 500 mg/m2or 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 pemetrexed in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed.

Table 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN.

The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm.

The following additional adverse reactions were observed in patients who received pemetrexed.

Incidence 1% to <5%

Dermatology/Skin — alopecia, pruritis/itching

Gastrointestinal — constipation

General Disorders — edema, fever

Hematologic — thrombocytopenia

Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence <1%

Cardiovascular — supraventricular arrhythmia

Dermatology/Skin — erythema multiforme

General Disorders — febrile neutropenia, allergic reaction/hypersensitivity

Neurology — motor neuropathy

Renal — renal failure

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2or 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.

The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm.

Table 4 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients in PARAMOUNT.

The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm.

Incidence 1% to <5% 

Blood/Bone Marrow — thrombocytopenia

General Disorders — febrile neutropenia

Incidence <1%

Cardiovascular — ventricular tachycardia, syncope

General Disorders — pain

Gastrointestinal — gastrointestinal obstruction

Neurologic — depression

Renal — renal failure

Vascular — pulmonary embolism

Treatment of Recurrent Disease After Prior Chemotherapy

The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B12 supplementation.

Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance 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.

The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0.

Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table 5 below.

The following additional adverse reactions were observed in patients assigned to receive pemetrexed.

Incidence 1% to <5%

Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection

Dermatology/Skin — erythema multiforme

Neurology — motor neuropathy, sensory neuropathy

Incidence <1%

Cardiovascular — supraventricular arrhythmias

Renal — renal failure

Mesothelioma

The safety of pemetrexed was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2intravenously in combination with cisplatin 75 mg/m2intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented.

Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, 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 were also excluded from the study.

The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was 6 in the pemetrexed/cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia.

Table 6 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below.

The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin:

Incidence 1% to <5%

Body as a Whole — febrile neutropenia, infection, pyrexia

Dermatology/Skin — urticaria

General Disorders — chest pain 

Metabolism and Nutrition — increased AST, increased ALT, increased GGT

Renal — renal failure

Incidence <1%

Cardiovascular — arrhythmia

Neurology — motor neuropathy

Exploratory Subgroup Analyses based on Vitamin Supplementation

Table 7 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented).

The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented:

• hypertension (11% versus 3%),
• chest pain (8% versus 6%),
• thrombosis/embolism (6% versus 3%).

Additional Experience Across Clinical Trials

Sepsis, with or without neutropenia, including fatal cases: 1%

Severe esophagitis, resulting in hospitalization: <1%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System — immune-mediated hemolytic anemia

Gastrointestinal — colitis, pancreatitis

General Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — radiation recall

Respiratory — interstitial pneumonitis

Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, AXTLE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on pemetrexed use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2[see Data]. Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).        

8.2 Lactation

Risk Summary

There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from pemetrexed, advise women not to breastfeed during treatment with AXTLE and for one week after last dose.

8.3 Females and Males of Reproductive Potential

Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating AXTLE [see Use in Specific Populations (8.1)].

Contraception

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

AXTLE may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of AXTLE in pediatric patients have not been established.

The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72).

Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone.

No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

8.5 Geriatric Use

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

8.6 Patients with Renal Impairment

Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin.

Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of pemetrexed when pemetrexed was administered as a single agent in doses ranging from 0.2 to 838 mg/m2infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

Elimination

The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

Metabolism

Pemetrexed is not metabolized to an appreciable extent.

Excretion

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Specific Populations

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups

The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

Patients with Hepatic Impairment

Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies.

Patients with Renal Impairment

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

Third-Space Fluid

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known.

Drug Interaction Studies

Drugs Inhibiting OAT3 Transporter

Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).

In Vitro Studies

Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iµ]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions (7)].

Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Cisplatin

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins

Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

14.1 Non-squamous NSCLC

Initial Treatment in Combination with Cisplatin

The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m2approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m2on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2approximately 30 minutes after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival.

A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes.

Efficacy results in Study JMDB are presented in Table 8 and Figure 1.

In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 9 and Figures 2 and 3. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.

Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN.

A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies.

Efficacy results are presented in Table 10 and Figure 4.

The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 11 and Figures 5 and 6.

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m2intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization.

A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies.

Efficacy results for PARAMOUNT are presented in Table 12 and Figure 7.

Treatment of Recurrent Disease After Prior Chemotherapy

The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2intravenously or docetaxel 75 mg/m2as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure.

A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or

1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC.

The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 13 and 14, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)].

14.2 Mesothelioma

The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m2intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B12 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration.

A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70-80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population.

The efficacy results from Study JMCH are summarized in Table 15 and Figure 8.

Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm.