Pemetrexed

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 for injection, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The safety of pemetrexed for injection, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received pemetrexed for injection, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed for injection and pembrolizumab (n=405), or placebo, pemetrexed for injection, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed for injection (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible

The median duration of exposure to pemetrexed for injection was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

Pemetrexed for injection was discontinued for adverse reactions in 23% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed for injection in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed for injection occurred in 49% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed for injection in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).

Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed for injection, pembrolizumab, and platinum.

NauseaConstipationDiarrheaVomitingFatigue^bPyrexiaDecreased appetiteRash^cCoughDyspnea

Adverse Reaction	Pemetrexed for injection Pembrolizumab Platinum Chemotherapy n=405		Placebo Pemetrexed for injection Platinum Chemotherapy n=202
	All Gradesa (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Gastrointestinal Disorders
56	3.5	52	3.5
35	1.0	32	0.5
31	5	21	3.0
24	3.7	23	3.0
General Disorders and Administration Site Conditions
56	12	58	6
20	0.2	15	0
Metabolism and Nutrition Disorders
28	1.5	30	0.5
Skin and Subcutaneous Tissue Disorders
25	2.0	17	2.5
Respiratory, Thoracic and Mediastinal Disorders
21	0	28	0
21	3.7	26	5
aGraded per NCI CTCAE version 4.03. bIncludes asthenia and fatigue. cIncludes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed for injection, pembrolizumab, and platinum.

HyperglycemiaIncreased ALTIncreased ASTHypoalbuminemiaIncreased creatinineHyponatremiaHypophosphatemiaIncreased alkaline phosphataseHypocalcemiaHyperkalemiaHypokalemiaAnemiaLymphopeniaNeutropeniaThrombocytopenia

Laboratory Testa	Pemetrexed for injection Pembrolizumab Platinum Chemotherapy		Placebo Pemetrexed for injection Platinum Chemotherapy
	All Gradesb %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
63	9	60	7
47	3.8	42	2.6
47	2.8	40	1.0
39	2.8	39	1.1
37	4.2	25	1.0
32	7	23	6
30	10	28	14
26	1.8	29	2.1
24	2.8	17	0.5
24	2.8	19	3.1
21	5	20	5
Hematology
85	17	81	18
64	22	64	25
48	20	41	19
30	12	29	8
aEach test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Pemetrexed for injection/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed for injection/platinum chemotherapy (range: 184 to 197 patients). bGraded per NCI CTCAE version 4.03.

The safety of pemetrexed for injection 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 for injection 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 B₁₂or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed for injection 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 for injection.

Table 4 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed for injection in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed for injection, as compared to the control arm, for any specified adverse reaction listed in Table 4.

AnemiaNeutropeniaThrombocytopeniaElevated creatinineFatigueNauseaVomitingAnorexiaConstipationStomatitis/pharyngitisDiarrheaDyspepsia/heartburnSensory neuropathyTaste disturbanceAlopeciaRash/Desquamation

Adverse Reactiona	Pemetrexed for injection/Cisplatin (N=839)		Gemcitabine/Cisplatin (N=830)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
All adverse reactions	90	37	91	53
33	6	46	10
29	15	38	27
10	4	27	13
10	1	7	1
43	7	45	5
56	7	53	4
40	6	36	6
27	2	24	1
21	1	20	0
14	1	12	0
12	1	13	2
5	0	6	0
9	0	12	1
8	0	9	0
12	0	21	1
7	0	8	1
aNCI CTCAE version 2.0.

The following additional adverse reactions of pemetrexed for injection 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

In Study JMEN, the safety of pemetrexed for injection 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 for injection 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 B₁₂or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed for injection 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 for injection and a relative dose intensity of pemetrexed for injection 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 for injection.

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

AnemiaNeutropeniaIncreased ALTIncreased ASTFatigueNauseaAnorexiaVomitingMucositis/stomatitisDiarrheaSensory neuropathyRash/desquamation

Adverse Reactiona	Pemetrexed for injection (N=438)		Placebo (N=218)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
All adverse reactions	66	16	37	4
15	3	6	1
6	3	0	0
10	0	4	0
8	0	4	0
25	5	11	1
19	1	6	1
19	2	5	0
9	0	1	0
7	1	2	0
5	1	3	0
5	2	2	0
9	1	4	0
10	0	3	0
aNCI 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 Pemetrexed for injection arm compared to the placebo arm.

The following additional adverse reactions were observed in patients who received Pemetrexed for injection.

• 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

The safety of pemetrexed for injection 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 for injection in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed for injection 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 B₁₂supplementation.

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 B₁₂or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed for injection 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 for injection and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed for injection arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed for injection arm and 16% in the placebo arm.

Table 6 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed for injection-treated patients in PARAMOUNT.

AnemiaNeutropeniaFatigueNauseaVomitingMucositis/stomatitisEdema

Adverse Reactiona	Pemetrexed for injection (N=333)		Placebo (N=167)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grades 3-4 (%)
All adverse reactions	53	17	34	4.8
15	4.8	4.8	0.6
9	3.9	0.6	0
18	4.5	11	0.6
12	0.3	2.4	0
6	0	1.8	0
5	0.3	2.4	0
5	0	3.6	0
aNCI CTCAE version 3.0.

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

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed for injection 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 for injection 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 for injection 500 mg/m²intravenously or docetaxel 75 mg/m²intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed for injection arm received folic acid and vitamin B₁₂supplementation.

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 B₁₂or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed for injection 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 7 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed for injection-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed for injection, as compared to the control arm, for any specified adverse reaction listed in the Table 7 below.

AnemiaNeutropeniaThrombocytopeniaIncreased ALTIncreased ASTNauseaAnorexiaVomitingStomatitis/pharyngitisDiarrheaConstipationFatigueFeverRash/desquamationPruritusAlopecia

Adverse Reactiona	(N=265)		(N=276)
	All Grades (%)	Grades 3-4 (%)	All Grade (%)	Grades 3-4 (%)
	Pemetrexed for injection		Docetaxel
19	4	22	4
11	5	45	40
8	2	1	0
8	2	1	0
7	1	1	0
31	3	17	2
22	2	24	3
16	2	12	1
15	1	17	1
13	0	24	3
6	0	4	0
34	5	36	5
8	0	8	0
14	0	6	0
7	0	2	0
6	1	38	2
aNCI CTCAE version 2.0.

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

• 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

The safety of pemetrexed for injection 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 for injection 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 for injection in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed for injection in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B₁₂during 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 for injection 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 for injection/cisplatin fully supplemented group and 2 in the pemetrexed for injection/cisplatin never supplemented group. Patients receiving pemetrexed for injection in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed for injection dose intensity. The most common adverse reaction resulting in dose delay was neutropenia.

Table 8 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed for injection-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 for injection, as compared to the control arm, for any specified adverse reaction listed in the table below.

NeutropeniaAnemiaThrombocytopeniaElevated creatinineDecreased creatinine clearanceConjunctivitisNauseaVomitingStomatitis/pharyngitisAnorexiaDiarrheaConstipationDyspepsiaFatigueDehydrationSensory neuropathyTaste disturbanceRashAlopecia

Adverse Reactionb	(N=168)		(N=163)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
	Pemetrexed for injection/cisplatin		Cisplatin
56	23	13	3
26	4	10	0
23	5	9	0
11	1	10	1
16	1	18	2
5	0	1	0
82	12	77	6
57	11	50	4
23	3	6	0
20	1	14	1
17	4	8	0
12	1	7	1
5	1	1	0
48	10	42	9
7	4	1	1
10	0	10	1
8	0	6	0
16	1	5	0
11	0	6	0
aIn Study JMCH, 226 patients received at least one dose of pemetrexed for injection in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 8 provides the ADRs for subgroup of patients treated with pemetrexed for injection in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12during study therapy. bNCI CTCAE version 2.0.

The following additional adverse reactions were observed in patients receiving pemetrexed for injection 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

Table 9 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed for injection-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B₁₂from the time of enrollment in Study JMCH (fully-supplemented).

Grade 3-4 Adverse Reactions	Fully Supplemented Patients N=168 (%)	Never Supplemented Patients N=32 (%)
Neutropenia	23	38
Thrombocytopenia	5	9
Vomiting	11	31
Febrile neutropenia	1	9
Infection with Grade 3/4 neutropenia	0	6
Diarrhea	4	9
aNCI CTCAE version 2.0.

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%).

: 1%

<1%