ALIMTA- pemetrexed disodium injection, powder, lyophilized, for solution
Eli Lilly and Company
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ALIMTA safely and effectively. See full prescribing information for ALIMTA.
ALIMTA (pemetrexed for injection) Lyophilized Powder, for Solution for Intravenous Use Initial U.S. Approval: 2004 RECENT MAJOR CHANGESDosage and Administration, Premedication Regimen and Concurrent Medications (2.3) 10/2012 Warnings and Precautions, Requirement for Premedication and Concomitant Medication to Reduce Toxicity (5.1) 10/2012 Warnings and Precautions, Required Laboratory Monitoring (5.5) 10/2012 Warnings and Precautions, Third Space Fluid (5.7) --- removal 11/2011 INDICATIONS AND USAGEALIMTA® is a folate analog metabolic inhibitor indicated for:
Limitations of Use:
DOSAGE AND ADMINISTRATION
CONTRAINDICATIONSHistory of severe hypersensitivity reaction to pemetrexed. (4) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe most common adverse reactions (incidence ≥20%) with single-agent use are fatigue, nausea, and anorexia. Additional common adverse reactions when used in combination with cisplatin include vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSSee 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 02/2013 |
ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.
ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.
The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.
The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
Vitamin Supplementation
Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].
Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].
Corticosteroids
Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].
Monitoring
Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].
Dose Reduction Recommendations
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.
a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. |
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Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. | 75% of previous dose (pemetrexed and cisplatin). |
Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. | 75% of previous dose (pemetrexed and cisplatin). |
Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. | 50% of previous dose (pemetrexed and cisplatin). |
If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to guidelines in Table 2.
a NCI Common Toxicity Criteria (CTC). |
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b Excluding neurotoxicity (see Table 3). |
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Dose of ALIMTA (mg/m2) | Dose of Cisplatin (mg/m2) |
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Any Grade 3 or 4 toxicities except mucositis | 75% of previous dose | 75% of previous dose |
Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea | 75% of previous dose | 75% of previous dose |
Grade 3 or 4 mucositis | 50% of previous dose | 100% of previous dose |
In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
Dose of ALIMTA | Dose of Cisplatin | |
CTC Grade | (mg/m2) | (mg/m2) |
0-1 | 100% of previous dose | 100% of previous dose |
2 | 100% of previous dose | 50% of previous dose |
Discontinuation Recommendation
ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
Renally Impaired Patients
In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3)]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DPTA serum clearance method:
Males: | [140 - Age in years] × Actual Body Weight (kg) | = mL/min |
72 × Serum Creatinine (mg/dL) | ||
Females: | Estimated creatinine clearance for males × 0.85 |
Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].
As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available [see References (15)].
ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended. ALIMTA is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
Vitamin Supplementation
Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].
Corticosteroids
Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)].
ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].
ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.
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) [see Drug Interactions (7.1)].
Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].
Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].
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.
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. |
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b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. |
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c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. |
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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 (%) |
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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 |
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%
Incidence Less than 1%
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.
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. |
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b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity. |
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ALIMTA (N=438) | Placebo (N=218) |
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Reactionb | 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 |
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 (transfusions 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%
Incidence Less than 1%
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 non-squamous 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.
a Adverse 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. |
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b NCI CTCAE Criteria version 3.0 |
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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 (%) |
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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 |
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%
Incidence Less than 1%
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.
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. |
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b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0). |
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c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. |
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ALIMTA
(N=265) | Docetaxel
(N=276) |
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Reactionb | 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 |
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%
Incidence Less than 1%
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.
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. |
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b Refer 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”. |
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c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. |
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ALIMTA/cisplatin
(N=168) | Cisplatin
(N=163) |
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Reactionb | 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 |
The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.
Incidence 1% to 5%
Incidence Less than 1%
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.
a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0). |
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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 |
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%).
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.
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.
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 (12.3)].
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.
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.
Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)]
Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.
It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.
The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.
ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].
Of 3,946 patients (34.0% ≥65) studied across the five clinical trials [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in patients <65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia, fatigue, thrombocytopenia, hypertension, and neutropenia.
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.
There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.
The ability of ALIMTA to be dialyzed is unknown.
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight of 597.49. The structural formula is as follows:
ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.
Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
Absorption
The pharmacokinetics of ALIMTA administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
Distribution
Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Metabolism and Excretion
Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.
In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a role in active secretion of pemetrexed.
Effect of Age, Gender or Race
No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.
The pharmacokinetics of pemetrexed were not different in male and female patients.
The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.
Effect of Hepatic Insufficiency
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
Effect of Renal Insufficiency
Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Warnings and Precautions (5.4) and Dosage and Administration (2.4)].
Effect of Third Space Fluid
The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is not fully defined. A study of ALIMTA 500 mg/m2 was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrexed plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to ALIMTA treatment should be considered, but is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.
Effect of Ibuprofen
Ibuprofen doses of 400 mg four times a day reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see Drug Interactions (7.1)].
Effect of Aspirin
Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
Effect of Cisplatin
Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin administered intravenously at a dose of 75 mg/m2 after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)].
Patient demographics of the intent to treat (ITT) population are shown in Table 10. The demographics and disease characteristics were well balanced.
a Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type. |
||
b The subgroup of "other" represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. |
||
c Eastern Cooperative Oncology Group Performance Status. |
||
d ECOG PS was not reported for all randomized patients. Percentages are representative of N=861 for the ALIMTA plus cisplatin arm, and N=861 for the gemcitabine plus cisplatin arm. |
||
e Smoking history was collected for 88% of randomized patients (N=757 for the ALIMTA plus cisplatin arm and N=759 for the gemcitabine plus cisplatin arm). |
||
Patient characteristic | ALIMTA plus Cisplatin (AC)
(N=862) | Gemcitabine plus Cisplatin (GC)
(N=863) |
Age (yrs) | ||
Median (range) | 61.1 (28.8-83.2) | 61.0 (26.4-79.4) |
Gender | ||
Male/Female | 70.2%/29.8% | 70.1%/29.9% |
Origin | ||
Caucasian | 669 (77.6%) | 680 (78.8%) |
Hispanic | 27 (3.1%) | 23 (2.7%) |
Asian | 146 (16.9%) | 141 (16.3%) |
African descent | 18 (2.1%) | 18 (2.1%) |
Stage at Entry | ||
IIIb/IV | 23.8%/76.2% | 24.3%/75.7% |
Histology | ||
Nonsquamous NSCLCa | 618 (71.7%) | 634 (73.5%) |
Adenocarcinoma | 436 (50.6%) | 411 (47.6%) |
Large cell | 76 (8.8%) | 77 (8.9%) |
Otherb | 106 (12.3%) | 146 (16.9%) |
Squamous | 244 (28.3%) | 229 (26.5%) |
ECOG PSc,d | ||
0/1 | 35.4%/64.6% | 35.6%/64.3% |
Smoking Historye | ||
Ever/never smoker | 83.1%/16.9% | 83.9%/16.1% |
Patients received a median of 5 cycles of treatment in both study arms. Patients treated with ALIMTA plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.
The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the ALIMTA plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.
a Adjusted for gender, stage, basis of diagnosis, and performance status. |
||
b A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm. |
||
ALIMTA plus Cisplatin
(N=862) | Gemcitabine plus Cisplatin
(N=863) |
|
Median overall survival (95% CI) | 10.3 mos (9.8-11.2) | 10.3 mos (9.6-10.9) |
Adjusted hazard ratio (HR)a,b (95% CI) | 0.94 (0.84-1.05) | |
Median progression-free survival (95% CI) | 4.8 mos (4.6-5.3) | 5.1 mos (4.6-5.5) |
Adjusted hazard ratio (HR)a,b (95% CI) | 1.04 (0.94-1.15) | |
Overall response rate (95% CI) | 27.1% (24.2-30.1) | 24.7% (21.8-27.6) |
Figure 1: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC - ITT Population.
A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 12. This difference in treatment effect for ALIMTA based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study [see Clinical Studies (14.2, 14.3)].
a A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm. |
||||||
b Unadjusted for multiple comparisons. |
||||||
c HRs adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological). |
||||||
d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type. |
||||||
e The subgroup of "other" represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. |
||||||
Histology Subgroup | Median Overall Survival in Months
(95% CI) | Unadjusted Hazard Ratio (HR)a,b (95% CI) | Adjusted Hazard Ratio (HR)a,b,c
(95% CI) |
|||
ALIMTA plus Cisplatin | Gemcitabine plus Cisplatin | |||||
Nonsquamous NSCLCd
(N=1252) | 11.0 (10.1-12.5) | N=618 | 10.1 (9.3-10.9) | N=634 | 0.84 (0.74-0.96) | 0.84 (0.74-0.96) |
Adenocarcinoma (N=847) | 12.6 (10.7-13.6) | N=436 | 10.9 (10.2-11.9) | N=411 | 0.84 (0.71-0.98) | 0.84 (0.71-0.99) |
Large Cell (N=153) | 10.4 (8.6-14.1) | N=76 | 6.7 (5.5-9.0) | N=77 | 0.68 (0.48-0.97) | 0.67 (0.48-0.96) |
Othere
(N=252) | 8.6 (6.8-10.2) | N=106 | 9.2 (8.1-10.6) | N=146 | 1.12 (0.84-1.49) | 1.08 (0.81-1.45) |
Squamous Cell (N=473) | 9.4 (8.4-10.2) | N=244 | 10.8 (9.5-12.1) | N=229 | 1.22 (0.99-1.50) | 1.23 (1.00-1.51) |
ALIMTA Maintenance Following Non-ALIMTA Containing Platinum-Based, Induction Therapy
A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive ALIMTA or placebo immediately following platinum-based chemotherapy. Of the randomized patients, 47.2% versus 52.7% achieved a complete or partial response to induction therapy and 51.9% versus 47.3% had stable disease after induction therapy in the ALIMTA and placebo arms, respectively. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)].
The study was designed to demonstrate superior progression-free survival and overall survival of ALIMTA over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in Table 13. The demographics and baseline disease characteristics were well balanced between study arms.
a Stage at Entry was not reported for all randomized patients. Percentages are representative of N=440 for the ALIMTA arm and N=222 for the placebo arm. |
||
b Includes patients with adenocarcinoma, large cell, and other histologic diagnoses. |
||
c The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. |
||
d Eastern Cooperative Oncology Group Performance Status (ECOG PS) was not reported for all randomized patients. Percentages are representative of N=439 for the ALIMTA arm, and N=222 for the placebo arm. |
||
e Smoking history was not reported for all randomized patients. Percentages are representative of N=437 for the ALIMTA arm and N=221 for the placebo arm. |
||
Patient characteristic | ALIMTA (N=441) | Placebo (N=222) |
Age (yrs) | ||
Median (range) | 60.6 (25.6-82.6) | 60.4 (35.4-78.5) |
Gender | ||
Male/Female | 73.0%/27.0% | 72.5%/27.5% |
Ethnic Origin | ||
Caucasian | 279 (63.3%) | 149 (67.1%) |
East Asian | 104 (23.6%) | 50 (22.5%) |
Other | 58 (13.2%) | 23 (10.4%) |
Stage at Entrya | ||
IIIb/IV | 18.0%/82.0% | 21.2%/78.8% |
Histology (%) | ||
Nonsquamous NSCLCb | 325 (73.7%) | 156 (70.3%) |
Adenocarcinoma | 222 (50.3%) | 106 (47.7%) |
Large cell | 10 (2.3%) | 10 (4.5%) |
Otherc | 93 (21.1%) | 40 (18.0%) |
Squamous | 116 (26.3%) | 66 (29.7%) |
ECOG PSd | ||
0/1 | 40.1%/59.9% | 38.3%/61.7% |
Smoking Historye | ||
Ever/never smoker | 74.1%/25.9% | 71.5%/28.5% |
Time from start of induction therapy to study randomization (months) | ||
Median (range) | 3.25 (1.6-4.8) | 3.29 (2.7-5.1) |
Patients received a median of 5 cycles of ALIMTA and 3.5 cycles of placebo. Patients randomized to ALIMTA received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 98 patients (22.6%) completed ≥10 cycles of treatment with ALIMTA.
In the overall study population, ALIMTA was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value<0.00001). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, ALIMTA was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)). For the population of patients with squamous NSCLC, ALIMTA did not improve OS compared to placebo (median 9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 0.71-1.49)). This difference in treatment effect for ALIMTA based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies. [see Clinical Studies (14.1, 14.3)]
Efficacy results for the overall patient population are presented in Table 14 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 15 and Figure 4, below.
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy. |
||
b Values for PFS given based on independent review (ALIMTA N=387, Placebo N=194). |
||
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. |
||
Efficacy Parametera,b | ALIMTA (N=441) | Placebo (N=222) |
Median overall survivalc (95% CI) | 13.4 mos (11.9-15.9) | 10.6 mos (8.7-12.0) |
Hazard ratio (HR)c (95% CI) | 0.79 (0.65-0.95) | |
p-value | p=0.012 | |
Median progression-free survival (95% CI) | 4.0 mos (3.1-4.4) | 2.0 mos (1.5-2.8) |
Hazard ratio (HR)c (95% CI) | 0.60 (0.49-0.73) | |
p-value | p<0.00001 |
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy. All results unadjusted for multiple comparisons. |
||||
b Values for PFS are given based on independent review (ALIMTA N=387, Placebo N=194). |
||||
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. A HR >1.0 indicates that the result is better in the placebo arm than in the ALIMTA arm. |
||||
d Includes patients with adenocarcinoma, large cell carcinoma, and other histology. |
||||
e The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. |
||||
Overall Survival | Progression-Free Survivalb | |||
ALIMTA | Placebo | ALIMTA | Placebo | |
Median (months) | Median (months) | Median (months) | Median (months) | |
HRc (95% CI) | HRc (95% CI) | |||
Nonsquamous NSCLCd | 15.5 | 10.3 | 4.4 | 1.8 |
N=481 | 0.70 (0.56-0.88) | 0.47 (0.37-0.60) | ||
Adenocarcinoma | 16.8 | 11.5 | 4.6 | 2.7 |
N=328 | 0.73 (0.56-0.96) | 0.51 (0.38-0.68) | ||
Large cell carcinoma | 8.4 | 7.9 | 4.5 | 1.5 |
N=20 | 0.98 (0.36-2.65) | 0.40 (0.12-1.29) | ||
Othere | 11.3 | 7.7 | 4.1 | 1.6 |
N=133 | 0.61 (0.40-0.94) | 0.44 (0.28-0.68) | ||
Squamous cell | 9.9 | 10.8 | 2.4 | 2.5 |
N=182 | 1.07 (0.77-1.50) | 1.03 (0.71-1.49) |
Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy
A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate continuation of ALIMTA in patients with Stage IIIb/IV nonsquamous NSCLC. Patients completing induction treatment of four cycles of ALIMTA plus cisplatin with stable disease or better and PS 0/1 were randomized (2:1) to maintenance treatment with ALIMTA or placebo. Randomization was stratified by response to induction (complete response (CR)/partial response (PR) versus stable disease (SD)), disease stage (IIIb versus IV), and ECOG performance status (0 versus 1). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)]. The main efficacy outcome was investigator-assessed progression-free survival.
A total of 539 patients were randomized; all completed four cycles of ALIMTA and cisplatin induction prior to randomization. Of the randomized patients, 44% versus 42% achieved a complete or partial response to induction therapy and 53% versus 53% had stable disease after induction treatment in the ALIMTA or the placebo arms respectively.
Patient demographics of the intent to treat (ITT) population are shown in Table 16.
a Histological or cytological diagnosis of NSCLC defined as other than predominantly squamous cell histology (squamous cell and/or mixed small cell, non-small cell histology were not permitted on this study). |
||
b The subcategory of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma or large-cell carcinoma. |
||
c Smoking history was not reported for all randomized patients. |
||
Patient characteristic | ALIMTA (N=359) | Placebo (N=180) |
Age (yrs) | ||
Median | 61.0 | 62.4 |
Range | 31.9-78.7 | 34.9-83.3 |
Gender (%) | ||
Male | 201 (56%) | 112 (62%) |
Female | 158 (44%) | 68 (38%) |
Ethnic Origin (%) | ||
Caucasian | 339 (94%) | 171 (95%) |
Asian | 16 (4.5%) | 8 (4.4%) |
African | 4 (1.1%) | 1 (0.6%) |
Stage at Entry | ||
IIIb | 31 (9%) | 18 (10%) |
IV | 328 (91%) | 162 (90%) |
Histology (%) | ||
Nonsquamous NSCLCa | ||
Adenocarcinoma | 310 (86%) | 161 (89%) |
Large cell | 24 (7%) | 12 (7%) |
Otherb | 25 (7%) | 7 (3.9%) |
ECOG PS (%) | ||
0 | 113 (32%) | 60 (33%) |
1 | 245 (68%) | 118 (66%) |
Smoking Historyc | ||
Ever | 274 (76%) | 144 (80%) |
Never smoker | 83 (23%) | 34 (19%) |
Patients received a median of four cycles of ALIMTA maintenance or placebo. The percentages of patients that received post-study treatment were similar (64% in the ALIMTA arm and 72% in the placebo arm).
The trial showed a statistically significant improvement in progression-free survival and in overall survival for patients randomized to ALIMTA maintenance. Efficacy results are presented in Table 17 and Figure 5.
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of ALIMTA plus cisplatin induction therapy. |
||
b Values for PFS given based on investigator assessment. |
||
c A hazard ratio of less than 1 indicates that the maintenance treatment with pemetrexed is associated with lower risk of progression or death compared to treatment with placebo. |
||
Efficacy Parametera,b | ALIMTA
(N=359) | Placebo
(N=180) |
Median overall survivalc (95% CI) | 13.9 mos (12.8-16.0) | 11.0 mos (10.0-12.5) |
Hazard ratio (HR)c (95% CI) | 0.78 (0.64-0.96) | |
p-value | p=0.02 | |
Median progression-free survival (95% CI) | 4.1 mos (3.2-4.6) | 2.8 mos (2.6-3.1) |
Hazard ratio (HR)c (95% CI) | 0.62 (0.49-0.79) | |
p-value | p<0.0001 |
A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 18.
a Performance status was not reported for all randomized patients. Percentages are representative of N=264 for the ALIMTA arm and N=274 for the docetaxel arm. |
||
Patient characteristic | ALIMTA (N=283) | Docetaxel (N=288) |
Age (yrs) | ||
Median (range) | 59 (22-81) | 57 (28-87) |
Gender (%) | ||
Male/Female | 68.6/31.4 | 75.3/24.7 |
Stage at Entry (%) | ||
III/IV | 25.1/74.9 | 25.3/74.7 |
Diagnosis/Histology (%) | ||
Adenocarcinoma | 154 (54.4) | 142 (49.3) |
Squamous | 78 (27.6) | 94 (32.6) |
Bronchoalveolar | 4 (1.4) | 1 (0.3) |
Other | 47 (16.6) | 51 (17.7) |
Performance Status (%)a | ||
0-1 | 234 (88.6) | 240 (87.6) |
2 | 30 (11.4) | 34 (12.4) |
The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 19). The study did not show an overall survival superiority of ALIMTA.
ALIMTA (N=283) | Docetaxel (N=288) |
|
Median overall survival (95% CI) | 8.3 mos (7.0-9.4) | 7.9 mos (6.3-9.2) |
Hazard ratio (HR) (95% CI) | 0.99 (0.82-1.20) | |
Median progression-free survival (95% CI) | 2.9 mos (2.4-3.1) | 2.9 mos (2.7-3.4) |
Hazard ratio (HR) (95% CI) | 0.97 (0.82-1.16) | |
Overall response rate (95% CI) | 8.5% (5.2-11.7) | 8.3% (5.1-11.5) |
A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 20. This difference in treatment effect for ALIMTA based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study [see Clinical Studies (14.1, 14.2)].
a A HR that is less than 1.0 indicates that survival is better in the ALIMTA arm than in the docetaxel arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the docetaxel arm than in the ALIMTA arm. |
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b Unadjusted for multiple comparisons. |
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c HRs adjusted for ECOG PS, time since prior chemotherapy, disease stage, and gender. |
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d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type. |
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e The subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. |
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Histology Subgroup | Median Overall Survival in Months (95% CI) | Unadjusted Hazard Ratio (HR)a,b
(95% CI) | Adjusted Hazard Ratio (HR)a,b,c
(95% CI) |
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ALIMTA | Docetaxel | |||||
Nonsquamous NSCLCd
(N=399) | 9.3 (7.8-9.7) | N=205 | 8.0 (6.3-9.3) | N=194 | 0.89 (0.71-1.13) | 0.78 (0.61-1.00) |
Adenocarcinoma (N=301) | 9.0 (7.6-9.6) | N=158 | 9.2 (7.5-11.3) | N=143 | 1.09 (0.83-1.44) | 0.92 (0.69-1.22) |
Large Cell (N=47) | 12.8 (5.8-14.0) | N=18 | 4.5 (2.3-9.1) | N=29 | 0.38 (0.18-0.78) | 0.27 (0.11-0.63) |
Othere
(N=51) | 9.4 (6.0-10.1) | N=29 | 7.9 (4.0-8.9) | N=22 | 0.62 (0.32-1.23) | 0.57 (0.27-1.20) |
Squamous Cell (N=172) | 6.2 (4.9-8.0) | N=78 | 7.4 (5.6-9.5) | N=94 | 1.32 (0.93-1.86) | 1.56 (1.08-2.26) |
A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.
The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended [see Dosage and Administration (2.3)]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.
a Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review. |
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b Karnofsky Performance Scale. |
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Randomized and Treated Patients | Fully Supplemented Patients | |||
Patient characteristic | ALIMTA/cis (N=226) | Cisplatin (N=222) | ALIMTA/cis (N=168) | Cisplatin (N=163) |
Age (yrs) | ||||
Median (range) | 61 (29-85) | 60 (19-84) | 60 (29-85) | 60 (19-82) |
Gender (%) | ||||
Male | 184 (81.4) | 181 (81.5) | 136 (81.0) | 134 (82.2) |
Female | 42 (18.6) | 41 (18.5) | 32 (19.0) | 29 (17.8) |
Origin (%) | ||||
Caucasian | 204 (90.3) | 206 (92.8) | 150 (89.3) | 153 (93.9) |
Hispanic | 11 (4.9) | 12 (5.4) | 10 (6.0) | 7 (4.3) |
Asian | 10 (4.4) | 4 (1.9) | 7 (4.2) | 3 (1.8) |
African descent | 1 (0.4) | 0 | 1 (0.6) | 0 |
Stage at Entry (%) | ||||
I | 16 (7.1) | 14 (6.3) | 15 (8.9) | 12 (7.4) |
II | 35 (15.6) | 33 (15.0) | 27 (16.2) | 27 (16.8) |
III | 73 (32.4) | 68 (30.6) | 51 (30.5) | 49 (30.4) |
IV | 101 (44.9) | 105 (47.2) | 74 (44.3) | 73 (45.3) |
Unspecified | 1 (0.4) | 2 (0.9) | 1 (0.6) | 2 (1.2) |
Diagnosis/Histologya (%) | ||||
Epithelial | 154 (68.1) | 152 (68.5) | 117 (69.6) | 113 (69.3) |
Mixed | 37 (16.4) | 36 (16.2) | 25 (14.9) | 25 (15.3) |
Sarcomatoid | 18 (8.0) | 25 (11.3) | 14 (8.3) | 17 (10.4) |
Other | 17 (7.5) | 9 (4.1) | 12 (7.1) | 8 (4.9) |
Baseline KPSb (%) | ||||
70-80 | 109 (48.2) | 97 (43.7) | 83 (49.4) | 69 (42.3) |
90-100 | 117 (51.8) | 125 (56.3) | 85 (50.6) | 94 (57.7) |
Table 22 and Figure 6 summarize the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.
a p-value refers to comparison between arms. |
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Randomized and Treated Patients | Fully Supplemented Patients | |||
Efficacy Parameter | ALIMTA/cis (N=226) | Cisplatin (N=222) | ALIMTA/cis (N=168) | Cisplatin (N=163) |
Median overall survival | 12.1 mos | 9.3 mos | 13.3 mos | 10.0 mos |
(95% CI) | (10.0-14.4) | (7.8-10.7) | (11.4-14.9) | (8.4-11.9) |
Hazard ratio | 0.77 | 0.75 | ||
Log rank p-valuea | 0.020 | 0.051 |
Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.
Figure 6: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients.
Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the ALIMTA plus cisplatin arm compared to the control arm.
Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.
ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed.
NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.
ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed.
NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.
ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F). When prepared as directed, reconstituted and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard unused portion [see Dosage and Administration (2.5)].
ALIMTA is not light sensitive.
See FDA-Approved Patient Labeling (PPI)
Instruct patients to read the patient package insert before initiating ALIMTA.
Literature revised: January 18, 2013
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.
PV 8925 AMP
PATIENT INFORMATION
ALIMTA® (uh-LIM-tuh)
(pemetrexed for injection)
Read the Patient Information that comes with ALIMTA before you start treatment and each time you get treated with ALIMTA. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about ALIMTA.
What is ALIMTA?
ALIMTA is a treatment for:
To lower your chances of side effects of ALIMTA, you must also take folic acid and vitamin B12 prior to and during your treatment with ALIMTA. Your doctor will prescribe a medicine called a “corticosteroid” to take for 3 days during your treatment with ALIMTA.
In children, ALIMTA has not been shown to be effective. No important differences in side effects were seen in children compared to adults (see “What are the possible side effects of ALIMTA?”).
What should I tell my doctor before taking ALIMTA?
Tell your doctor about all of your medical conditions, including if you:
How is ALIMTA given?
What should I avoid while taking ALIMTA?
What are the possible side effects of ALIMTA?
Most patients taking ALIMTA will have side effects. Sometimes it is not always possible to tell whether ALIMTA, another medicine, or the cancer itself is causing these side effects. Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. These symptoms could mean you have an infection which may be severe and could lead to death.
The most common side effects of ALIMTA when given alone or in combination with cisplatin are:
Talk with your doctor, nurse, or pharmacist about any side effect that bothers you or that doesn't go away.
These are not all the side effects of ALIMTA. For more information, ask your doctor, nurse, or pharmacist.
General information about ALIMTA
Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. ALIMTA was prescribed for your medical condition.
This leaflet summarizes the most important information about ALIMTA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ALIMTA that is written for health professionals. You can also call 1-800-LILLY-RX (1-800-545-5979) or visit www.ALIMTA.com.
Revised October 2012
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
www.ALIMTA.com
Copyright © 2004, 2012, Eli Lilly and Company. All rights reserved.
PV 6758 AMP
PACKAGE LABELING
This section contains a representative sample of product package labeling. Product may be manufactured at other manufacturing sites.
PACKAGE CARTON – ALIMTA 100 mg single-use vial.
NDC 0002-7640-01
Single-Use Vial
VL7640
ALIMTA®
pemetrexed for injection
100 mg
For intravenous use only.
Rx only
www.ALIMTA.com
Lilly
ALIMTA
pemetrexed disodium injection, powder, lyophilized, for solution |
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ALIMTA
pemetrexed disodium injection, powder, lyophilized, for solution |
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Labeler - Eli Lilly and Company (006421325) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Evonik Degussa Corportation | 130890994 | ANALYSIS(0002-7623, 0002-7640) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Eli Lilly S.A. - Irish Branch | 986500023 | API MANUFACTURE(0002-7623, 0002-7640), ANALYSIS(0002-7623, 0002-7640) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Lilly France S.A.S. | 395346919 | ANALYSIS(0002-7623, 0002-7640) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Eli Lilly and Company (Indianapolis) | 006421325 | MANUFACTURE(0002-7623, 0002-7640), ANALYSIS(0002-7623, 0002-7640), PACK(0002-7623, 0002-7640), LABEL(0002-7623, 0002-7640) |