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Alimta

Alimta

SIDE EFFECTS

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%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥ 20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin

Table 4 provides the frequency and severity of adverse reactions that have been reported in > 5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

Reactionb ALIMTA/ cisplatin
(N=839)
Gemcitabine/ cisplatin
(N=830)
All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%)
All Adverse Reactions 90 37 91 53
Laboratory
  Hematologic
    Anemia 33 6 46 10
    Neutropenia 29 15 38 27
    Leukopenia 18 5 21 8
    Thrombocytopenia 10 4 27 13
  Renal
    Creatinine elevation 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
    Neuropathy-sensory 9 0 12 1
    Taste disturbance 8 0c 9 0c
  Dermatology/Skin
    Alopecia 12 0c 21 1c
    Rash/Desquamation 7 0 8 1
a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria version 2.0 for each Grade of toxicity.
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%

Body as a Whole — febrile neutropenia, infection, pyrexia

General Disorders — dehydration

Metabolism and Nutrition — increased AST, increased ALT

Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis

Incidence Less than 1%

Cardiovascular — arrhythmia

General Disorders — chest pain

Metabolism and Nutrition — increased GGT

Neurology — motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) – Maintenance
ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction Therapy

Table 5 provides the frequency and severity of adverse reactions reported in > 5% of the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.

All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy

Reactionb ALIMTA
(N=438)
Placebo
(N=218)
All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%)
All Adverse Reactions 66 16 37 4
Laboratory
  Hematologic
    Anemia 15 3 6 1
    Neutropenia 6 3 0 0
    Leukopenia 6 2 1 1
  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
    Neuropathy-sensory 9 1 4 0
Dermatology/Skin
    Rash/Desquamation 10 0 3 0
aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤ 6 cycles of ALIMTA, and compared to patients who received > 6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transffusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.

Incidence 1% to 5%

Dermatology/Skin — alopecia, pruritis/itching

Gastrointestinal — constipation

General Disorders — edema, fever (in the absence of neutropenia)

Hematologic — thrombocytopenia

Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate

Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%

Cardiovascular — supraventricular arrhythmia

Dermatology/Skin — erythema multiforme

General Disorders — febrile neutropenia, allergic reaction/hypersensitivity

Neurology — motor neuropathy

Renal — renal failure

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy

Table 6 provides the frequency and severity of adverse reactions reported in > 5% of the 500 patients with nonsquamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.

The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12.

Table 6: Selecteda Adverse Reactionsb Occurring in ≥ 5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

Adverse Reaction Organ System and Term ALIMTA
(N=333)
Placebo
(N=167)
All Gradesa Toxicity (%) Grade 3-4a Toxicity (%) All Gradesa Toxicity (%) Grades 3-4a Toxicity (%)
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
aAdverse reactions of any severity (all grades) occurring more frequently ( ≥ 5%) or Grade 3-4 adverse reactions occurring more frequently ( ≥ 2%) in ALIMTA-treated patients compared to those receiving placebo.
bNCI CTCAE Criteria version 3.0

Administration of RBC (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 ALIMTA arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

Incidence 1% to 5%

Blood/Bone Marrow — thrombocytopenia

General Disorders — febrile neutropenia

Incidence Less than 1%

Cardiovascular — ventricular tachycardia, syncope

General Disorders — pain

Gastrointestinal — gastrointestinal obstruction

Neurologic — depression

Renal — renal failure

Vascular — pulmonary embolism

Non-Small Cell Lung Cancer (NSCLC) – After Prior Chemotherapy

Table 7 provides the frequency and severity of adverse reactions that have been reported in > 5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa

Reactionb ALIMTA
(N=265)
Docetaxel
(N=276)
All Grades Toxicity (%) Grades 3-4 Toxicity (%) All Grades Toxicity (%) Grades 3-4 Toxicity (%)
Laboratory
  Hematologic
   Anemia 19 4 22 4
   Leukopenia 12 4 34 27
   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
   Pruritis 7 0 2 0
   Alopecia 6 1c 38 2c
aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in < 5% of patients that received ALIMTA treatment but > 5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel). The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA.

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

Renal — increased creatinine

Incidence Less than 1%

Cardiovascular — supraventricular arrhythmias

Malignant Pleural Mesothelioma (MPM)

Table 8 provides the frequency and severity of adverse reactions that have been reported in > 5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 8: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa

Reactionb ALIMTA/cisplatin
(N=168)
Cisplatin
(N=163)
All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%)
Laboratory
  Hematologic
    Neutropenia 56 23 13 3
    Leukopenia 53 15 17 1
    Anemia 26 4 10 0
    Thrombocytopenia 23 5 9 0
  Renal
    Creatinine elevation 11 1 10 1
    Creatinine clearance decreased 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
    Neuropathy-sensory 10 0 10 1
    Taste Disturbance 8 0c 6 0c
  Dermatology/Skin
    Rash 16 1 5 0
    Alopecia 11 0c 6 0c
aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”.
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA 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 Less than 1%

Cardiovascular — arrhythmia

Neurology — motor neuropathy

Effects of Vitamin Supplementations on Toxicity

Table 9 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 9: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence)

Adverse Eventa (%) Fully Supplemented Patients
(N=168)
Never Supplemented Patients
(N=32)
Neutropenia/granulocytopenia 23 38
Thrombocytopenia 5 9
Vomiting 11 31
Febrile neutropenia 1 9
Infection with Grade 3/4 neutropenia 0 6
Diarrhea 4 9
aRefer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Additional Experience Across Clinical Trials

Sepsis, which in some cases was fatal, occurred in approximately 1% of patients. Esophagitis occurred in less than 1% of patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ALIMTA. 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.

These reactions occurred with ALIMTA when used as a single-agent and in combination therapies.

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 has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis

Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.

Read the Alimta (pemetrexed) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥ 80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see CLINICAL PHARMACOLOGY].

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.

In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

Nephrotoxic Drugs

ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

Read the Alimta Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.

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