Pemetrexed (Page 2 of 6)

3 DOSAGE FORMS AND STRENGTHS

Injection: Pemetrexed Injection is a clear, colorless to slightly yellowish or slightly yellow-greenish solution available in sterile single-dose vials containing 100 mg/4 mL, 500 mg/20 mL, and 1 g/40 mL of pemetrexed.

4 CONTRAINDICATIONS

Pemetrexed 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.

Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of Pemetrexed Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection [see Dosage and Administration (2.3)]. Obtain a complete blood count at the beginning of each cycle. Do not administer Pemetrexed Injection until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce Pemetrexed Injection 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 (2.5)].

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 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 (2.2)].

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 Injection 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 Injection.

5.5 Radiation Recall

Radiation recall can occur with Pemetrexed Injection 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 Injection 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 Injection. 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 Injection.

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 (2.4), 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 the fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in 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.

Non-Squamous NSCLC

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 (Eastern Cooperative Oncology Group) performance status (PS) of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance (CLcr) < 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS) 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 to 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 2 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN.

Table 2: 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 3.0.

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 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

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 platinum-based chemotherapy as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 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.

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

Table 3: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT

Adverse Reactiona

Pemetrexed

(N=333)

Placebo

(N=167)

All Grades

(%)

Grade 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

All adverse reactions

53

17

34

4.8

Laboratory

Hematologic

Anemia

15

4.8

4.8

0.6

Neutropenia

9

3.9

0.6

0

Clinical

Constitutional symptoms

Fatigue

18

4.5

11

0.6

Gastrointestinal

Nausea

12

0.3

2.4

0

Vomiting

6

0

1.8

0

Mucositis/stomatitis

5

0.3

2.4

0

General disorders

Edema

5

0

3.6

0

a NCI 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 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 4 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 4 below.

Table 4: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI

Adverse Reactiona

Pemetrexed

(N=265)

Docetaxel

(N=276)

All Grades

(%)

Grades 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

Laboratory

Hematologic

Anemia

19

4

22

4

Neutropenia

11

5

45

40

Thrombocytopenia

8

2

1

0

Hepatic

Increased ALT

8

2

1

0

Increased AST

7

1

1

0

Clinical

Gastrointestinal

Nausea

31

3

17

2

Anorexia

22

2

24

3

Vomiting

16

2

12

1

Stomatitis/pharyngitis

15

1

17

1

Diarrhea

13

0

24

3

Constipation

6

0

4

0

Constitutional symptoms

Fatigue

34

5

36

5

Fever

8

0

8

0

Dermatology/Skin

Rash/desquamation

14

0

6

0

Pruritus

7

0

2

0

Alopecia

6

1

38

2

a NCI CTCAE version 2.0.

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

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%

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