What is mechanism of action?

mechanism of action is Folic Acid Metabolism Inhibitors [MoA]

Pemetrexed Dipotassium

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Pemetrexed Dipotassium Prescribing Information

Pemetrexed for Injection is a folate analog metabolic inhibitor indicated:

in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. (
1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Pemetrexed for Injection 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:
Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer
[see Clinical Studies ]
.
)
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. (
1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Pemetrexed for Injection 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:
Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer
[see Clinical Studies ]
.
)
as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (
1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Pemetrexed for Injection 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:
Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer
[see Clinical Studies ]
.
)

Limitations of Use

: Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (

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

Pemetrexed for Injection 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:

Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer

[see Clinical Studies ]

)

initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (
1.2 Mesothelioma
Pemetrexed for Injection 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.
)

The recommended dose of Pemetrexed for Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m²as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (
2.1 Recommended Dosage for Non-Squamous NSCLC
- The recommended dose of Pemetrexed for Injection 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 Pemetrexed for Injection 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 Pemetrexed for Injection 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 Pemetrexed for Injection, 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.
)
Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed for Injection and continue until 21 days after the last dose of Pemetrexed for Injection. (
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 Pemetrexed for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
- Administer vitamin B_12,1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
  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 Pemetrexed for Injection administration.
)
Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles. (
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 Pemetrexed for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
- Administer vitamin B_12,1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
  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 Pemetrexed for Injection administration.
)
Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed for Injection administration. (
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 Pemetrexed for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
- Administer vitamin B_12,1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
  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 Pemetrexed for Injection administration.
)

Lactation: Advise not to breastfeed. (

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 Pemetrexed for Injection and for one week after last dose.

)

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed

[see Adverse Reactions (

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 B₁₂or 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 4.

Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB
^aNCI CTCAE version 2.0.
Adverse Reaction^a	Pemetrexed/Cisplatin (N=839)		Gemcitabine/Cisplatin (N=830)
Adverse Reaction^a	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

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 B₁₂or 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% Patients Receiving Pemetrexed in Study JMEN
^aNCI CTCAE version 3.0
Adverse Reaction^a	Pemetrexed (N=438)		Placebo (N=218)
Adverse Reaction^a	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

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 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 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.

Table4: Adverse ReactionsOccurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT
^aNCI CTCAE version 3.0
Adverse Reaction^a	Pemetrexed (N=333)		Placebo (N=167)
Adverse Reaction^a	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

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/m²intravenously or docetaxel 75 mg/m²intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed 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 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 7 below.

Table 5: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI
^aNCI CTCAE version 2.0.
Adverse Reaction^a	Pemetrexed (N=265)		Docetaxel (N=276)
Adverse Reaction^a	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

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 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 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^a
^aIn 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 8 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 B₁₂during study therapy.
^bNCI CTCAE version 2.0
Adverse Reaction^b	Pemetrexed /cisplatin (N=168)		Cisplatin (N=163)
Adverse Reaction^b	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Laboratory
Hematologic
Neutropenia	56	23	13	3
Anemia	26	4	10	0
Thrombocytopenia	23	5	9	0
Renal
Elevated creatinine	11	1	10	1
Decreased creatinine clearance	16	1	18	2
Clinical
Eye Disorder
Conjunctivitis	5	0	1	0
Gastrointestinal
Nausea	82	12	77	6
Vomiting	57	11	50	4
Stomatitis/pharyngitis	23	3	6	0
Anorexia	20	1	14	1
Diarrhea	17	4	8	0
Constipation	12	1	7	1
Dyspepsia	5	1	1	0
Constitutional Symptoms
Fatigue	48	10	42	9
Metabolism and Nutrition
Dehydration	7	4	1	1
Neurology
Sensory neuropathy	10	0	10	1
Taste disturbance	8	0	6	0
Dermatology/Skin
Rash	16	1	5	0
Alopecia	11	0	6	0

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 B₁₂from 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^a
^aNCI CTCAE version 2.0
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

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%

)]

Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed for Injection when the absolute neutrophil count is less than 1500 cells/mm³and platelets are less than 100,000 cells/mm³. Initiate supplementation with oral folic acid and intramuscular vitamin B₁₂to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed for Injection. (
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 Pemetrexed for Injection and continuing until 21 days after the last dose of Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
- Administer vitamin B_12,1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed for Injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with Pemetrexed for Injection
  [see Warnings and Precautions ]
  .
  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 Pemetrexed for Injection administration.
,
5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation
Pemetrexed for Injection 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 B₁₂prior to and throughout pemetrexed plus cisplatin treatment.
Initiate supplementation with oral folic acid and intramuscular vitamin B₁₂prior to the first dose of Pemetrexed for Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed for Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed for Injection
[see Dosage and Administration ]
. Obtain a complete blood count at the beginning of each cycle. Do not administer Pemetrexed for Injection until the ANC is at least 1500 cells/mm³and platelet count is at least 100,000 cells/mm³. Permanently reduce Pemetrexed for Injection in patients with an ANC of less than 500 cells/mm³or platelet count of less than 50,000 cells/mm³in previous cycles
[see Dosage and Administration ]
.
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 ]
. 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%.
)
Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (
2.3 Renal Impairment
- Pemetrexed for Injection 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 ]
  . There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min
  [see Use in Specific Populations ]
  .
,
5.2 Renal Failure
Pemetrexed for Injection 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 ]
. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with Pemetrexed for Injection. Withhold Pemetrexed for Injection in patients with a creatinine clearance of less than 45 mL/minute
[see Dosage and Administration ]
.
)
Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (
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 for Injection. Permanently discontinue Pemetrexed for Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.
)
Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (
5.4 Interstitial Pneumonitis
Serious interstitial pneumonitis, including fatal cases, can occur with Pemetrexed for Injection treatment. Withhold Pemetrexed for Injection 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 for Injection.
)
Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (
5.5 Radiation Recall
Radiation recall can occur with Pemetrexed for 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 for Injection for signs of radiation recall.
)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (
5.7 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, Pemetrexed for Injection 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 for Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed for Injection and for 3 months after the last dose
[see Use in Specific Populations and Clinical Pharmacology ]
.
,
8.1 Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, Pemetrexed for Injection can cause fetal harm when administered to a pregnant woman
[see Clinical Pharmacology ]
. 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 ]
.
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).
,
8.3 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 Pemetrexed for Injection
[see Use in Specific Populations ]
.
Contraception
Females
Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed for Injection 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 Pemetrexed for Injection and for 3 months after the last dose
[see Nonclinical Toxicology ]
.
Infertility
Males
Pemetrexed for Injection may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible
[see Nonclinical Toxicology ]
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