Pemetrexed (Page 2 of 9)

3 DOSAGE FORMS AND STRENGTHS

Pemetrexed for injection, USP is a white to either light-yellow or green-yellow lyophilized cake or powder available in sterile single-dose vials containing 750 mg pemetrexed.

4 CONTRAINDICATIONS

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

Pemetrexed 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 pemetrexed; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed [see Dosage and Administration (2.4)]. Obtain a complete blood count at the beginning of each cycle. Do not administer pemetrexed until the ANC is at least 1500 cells/mm³ and platelet count is at least 100,000 cells/mm³. Permanently reduce pemetrexed 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

Pemetrexed 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 pemetrexed. Withhold pemetrexed 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 pemetrexed. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

5.4 Interstitial Pneumonitis

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

5.5 Radiation Recall

Radiation recall can occur with pemetrexed in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed 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 pemetrexed. 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 pemetrexed. 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, pemetrexed 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 pemetrexed and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

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)]

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. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

Non-Squamous NSCLC

First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy

The safety of pemetrexed, 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, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14.1)].

The median duration of exposure to pemetrexed 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 was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed 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, pembrolizumab, and platinum.

Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189

	Pemetrexed Pembrolizumab Platinum Chemotherapy n=405		Placebo Pemetrexed Platinum Chemotherapy n=202
Adverse Reaction	All Gradesa (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Gastrointestinal Disorders
Nausea	56	3.5	52	3.5
Constipation	35	1.0	32	0.5
Diarrhea	31	5	21	3
Vomiting	24	3.7	23	3
General Disorders and Administration Site Conditions
Fatigueb	56	12	58	6
Pyrexia	20	0.2	15	0
Metabolism and Nutrition Disorders
Decreased appetite	28	1.5	30	0.5
Skin and Subcutaneous Tissue Disorders
Rashc	25	2	17	2.5
Respiratory, Thoracic and Mediastinal Disorders
Cough	21	0	28	0
Dyspnea	21	3.7	26	5

^a Graded per NCI CTCAE version 4.03.

^b Includes asthenia and fatigue.

^c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

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

Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189

	Pemetrexed Pembrolizumab Platinum Chemotherapy		Placebo Pemetrexed Platinum Chemotherapy
Laboratory Testa	All Gradesb %	Grades 3-4 %	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	63	9	60	7
Increased ALT	47	3.8	42	2.6
Increased AST	47	2.8	40	1
Hypoalbuminemia	39	2.8	39	1.1
Increased creatinine	37	4.2	25	1
Hyponatremia	32	7	23	6
Hypophosphatemia	30	10	28	14
Increased alkaline phosphatase	26	1.8	29	2.1
Hypocalcemia	24	2.8	17	0.5
Hyperkalemia	24	2.8	19	3.1
Hypokalemia	21	5	20	5
Hematology
Anemia	85	17	81	18
Lymphopenia	64	22	64	25
Neutropenia	48	20	41	19
Thrombocytopenia	30	12	29	8

^a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pemetrexed/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).

^b Graded per NCI CTCAE version 4.03.

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/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 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 4 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 4.

Table 4: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB

Adverse Reactiona	Pemetrexed/Cisplatin (N=839)		Gemcitabine/Cisplatin (N=830)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
All adverse reactions	90	37	91	53
Laboratory
Hematologic
Anemia	33	6	46	10
Neutropenia	29	15	38	27
Thrombocytopenia	10	4	27	13
Renal
Elevated creatinine	10	1	7	1
Clinical
Constitutional symptoms
Fatigue	43	7	45	5
Gastrointestinal
Nausea	56	7	53	4
Vomiting	40	6	36	6
Anorexia	27	2	24	1
Constipation	21	1	20	0
Stomatitis/pharyngitis	14	1	12	0
Diarrhea	12	1	13	2
Dyspepsia/heartburn	5	0	6	0
Neurology
Sensory neuropathy	9	0	12	1
Taste disturbance	8	0	9	0
Dermatology/Skin
Alopecia	12	0	21	1
Rash/Desquamation	7	0	8	1

^a NCI CTCAE version 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/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 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 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN.

Table 5: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in Study JMEN

Adverse Reactiona	Pemetrexed (N=438)		Placebo (N=218)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
All adverse reactions	66	16	37	4
Laboratory
Hematologic
Anemia	15	3	6	1
Neutropenia	6	3	0	0
Hepatic
Increased ALT	10	0	4	0
Increased AST	8	0	4	0
Clinical
Constitutional symptoms
Fatigue	25	5	11	1
Gastrointestinal
Nausea	19	1	6	1
Anorexia	19	2	5	0
Vomiting	9	0	1	0
Mucositis/stomatitis	7	1	2	0
Diarrhea	5	1	3	0
Infection	5	2	2	0
Neurology
Sensory neuropathy	9	1	4	0
Dermatology/Skin
Rash/desquamation	10	0	3	0

^a NCI CTCAE version 3

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, 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