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) |
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| 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. |
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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) |
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| 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. |
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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) |
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| 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 |
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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) |
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| 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. |
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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) |
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| 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. |
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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.