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pemetrexed disodium (solution) vial Adverse Reactions (pemetrexed for injection)

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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/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 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.

Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB
Adverse Reaction*Pemetrexed/Cisplatin
(N=839)
Gemcitabine/Cisplatin
(N=830)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
NCI CTCAE version 2.0
All adverse reactions90379153
  Laboratory
    Hematologic
      Anemia3364610
      Neutropenia29153827
      Thrombocytopenia1042713
Renal
Elevated creatinine10171
Clinical
  Constitutional symptoms
Fatigue437455
Gastrointestinal
      Nausea567534
      Vomiting406366
      Anorexia272241
      Constipation211200
      Stomatitis/pharyngitis141120
      Diarrhea121132
      Dyspepsia/heartburn5060
Neurology
      Sensory neuropathy90121
      Taste disturbance8090
Dermatology/Skin
      Alopecia120211
      Rash/Desquamation7081

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

Table 3: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in Study JMEN
Adverse Reaction*Pemetrexed/Cisplatin
(N=438)
Placebo
(N=218)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
NCI CTCAE version 3.0
All adverse reactions6616374
  Laboratory
    Hematologic
      Anemia15361
      Neutropenia6300
Hepatic
      Increased ALT10040
      Increased AST8040
Clinical
  Constitutional symptoms
      Fatigue255111
Gastrointestinal
      Nausea19161
      Anorexia19250
      Vomiting9010
      Mucositis/stomatitis7120
      Diarrhea5130
Infection5220
Neurology
      Sensory neuropathy9140
Dermatology/Skin
      Rash/Desquamation10030

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

Table 4: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT
Adverse Reaction*Pemetrexed
(N=333)
Placebo
(N=167)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
NCI CTCAE version 3.0
All adverse reactions5317344.8
  Laboratory
    Hematologic
      Anemia154.84.80.6
      Neutropenia93.90.60
Clinical
  Constitutional symptoms
      Fatigue184.5110.6
Gastrointestinal
      Nausea120.32.40
      Vomiting601.80
      Mucositis/stomatitis50.32.40
General disorders
      Edema503.60

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.

Table 5: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI
Adverse Reaction*Pemetrexed
(N=265)
Docetaxel
(N=276)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
NCI CTCAE version 2.0
Laboratory
  Hematologic
    Anemia194224
    Neutropenia1154540
    Thrombocytopenia8210
  Hepatic
    Increased ALT8210
    Increased AST7110
Clinical
  Gastrointestinal
    Nausea313172
    Anorexia222243
    Vomiting162121
    Stomatitis/pharyngitis151171
    Diarrhea130243
    Constipation6040
Constitutional symptoms
    Fatigue345365
    Fever8080
Dermatology/Skin
    Rash/desquamation14060
    Pruritus7020
    Alopecia61382

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/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 intravenously 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.

Table 6: Adverse Reactions Occurring in ≥5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCH*
Adverse ReactionPemetrexed/cisplatin
(N=168)
Cisplatin
(N=163)
All Grades
(%)
Grade 3–4
(%)
All Grades
(%)
Grade 3–4
(%)
*
In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 6 provides the ADRs for subgroup of patients treated with pemetrexed in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy.
NCI CTCAE version 2.0
Laboratory
  Hematologic
    Neutropenia5623133
    Anemia264100
    Thrombocytopenia23590
Renal
    Elevated creatinine111101
    Decreased creatinine clearance161182
Clinical
  Eye Disorder
    Conjunctivitis5010
Gastrointestinal
    Nausea8212776
    Vomiting5711504
    Stomatitis/pharyngitis23360
    Anorexia201141
    Diarrhea17480
    Constipation12171
    Dyspepsia5110
Constitutional Symptoms
    Fatigue4810429
Metabolism and Nutrition
    Dehydration7411
Neurology
    Sensory neuropathy100101
    Taste disturbance8060
Dermatology/Skin
    Rash16150
    Alopecia11060

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).

Table 7: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCH*
Grade 3–4 Adverse ReactionsFully Supplemented Patients
N=168
(%)
Never Supplemented Patients
N=32
(%)
*
NCI CTCAE version 2.0
Neutropenia2338
Thrombocytopenia59
Vomiting1131
Febrile neutropenia19
Infection with Grade 3/4 neutropenia06
Diarrhea49

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

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