`
`
`
` 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 CHANGES -------------------------­
`
`
` Dosage and Administration, Premedication Regimen and Concurrent
`
`
`
`
` 10/2012
`
`
` Medications (2.3)
`
`
` Warnings and Precautions, Requirement for Premedication and Concomitant
`
`
` 10/2012
`
` Medication to Reduce Toxicity (5.1)
`
`
`
` 10/2012
` Warnings and Precautions, Required Laboratory Monitoring (5.5)
`
`
`
` 11/2011
` Warnings and Precautions, Third Space Fluid (5.7) --- removal
`
`
`
`
`
` ---------------------------- INDICATIONS AND USAGE --------------------------­
`
`
`
`ALIMTA® is a folate analog metabolic inhibitor indicated for:
`
`
`Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung
`•
`
`
`
`Cancer:
`
`Initial treatment in combination with cisplatin. (1.1)
`•
`
`
`
`
`
`• Maintenance treatment of patients whose disease has not
`
`
`progressed after four cycles of platinum-based first-line
`chemotherapy. (1.2)
`
`After prior chemotherapy as a single-agent. (1.3)
`•
`
`
`• Mesothelioma: in combination with cisplatin. (1.4)
`
`
`Limitations of Use:
`
`
`
`
`ALIMTA is not indicated for the treatment of patients with squamous
`•
`
`cell non-small cell lung cancer. (1.5)
`
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`
`
`•
`Combination use in Non-Small Cell Lung Cancer and Mesothelioma:
`Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each
`
`
`
`
`21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning
`
`
`
`
`
`
`30 minutes after ALIMTA administration. (2.1)
`
`Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose
`of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. (2.2)
`
`
`
`
`
`
`Prior to initiating ALIMTA, initiate supplementation with oral folic acid
`
`
`and intramuscular vitamin B12. Continue folic acid and vitamin B12
`
`
`
`
`
`supplementation throughout treatment. Administer corticosteroids the
`
`
`day before, the day of, and the day after ALIMTA administration. (2.3)
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`Nonsquamous Non-Small Cell Lung Cancer – Combination
`1.1
`
`
`with Cisplatin
`
`Nonsquamous Non-Small Cell Lung Cancer – Maintenance
`
`
`Nonsquamous Non-Small Cell Lung Cancer – After Prior
`
`Chemotherapy
`
`Mesothelioma
`1.4
`
`
`Limitations of Use
`1.5
`
`
`DOSAGE AND ADMINISTRATION
`
`Combination Use with Cisplatin for Nonsquamous Non-Small
`2.1
`
`
`Cell Lung Cancer or Malignant Pleural Mesothelioma
`
`
`
`
`Single-Agent Use as Maintenance Following First-Line
`
`
`
`Therapy, or as a Second-Line Therapy
`
`Premedication Regimen and Concurrent Medications
`
`
`
`Laboratory Monitoring and Dose Reduction/Discontinuation
`
`Recommendations
`
`Preparation and Administration Precautions
`2.5
`
`
`Preparation for Intravenous Infusion Administration
`2.6
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Requirement for Premedication and Concomitant Medication to
`5.1
`
`
`
`
`Reduce Toxicity
`
`Bone Marrow Suppression
`
`Decreased Renal Function
`
`
`2
`
`
`1.2
`
`1.3
`
`
`2.2
`
`
`2.3
`
`2.4
`
`
`5.2
`
`5.3
`
`
`Reference ID: 3247473
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
` 1
`
`
`
`
`Dose Reductions: Dose reductions or discontinuation may be needed
`
`
`based on toxicities from the preceding cycle of therapy. (2.4)
`
`
`
`
`---------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`•
`100 mg vial for injection (3)
`
`
`
`•
`500 mg vial for injection (3)
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`History of severe hypersensitivity reaction to pemetrexed. (4)
`
`
`
`
`------------------------ WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
`•
`Premedication regimen: 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. (5.1)
`
`
`
`Bone marrow suppression: Reduce doses for subsequent cycles based on
`
`
`hematologic and nonhematologic toxicities. (5.2)
`
`
`
`
`Renal function: Do not administer when CrCl <45 mL/min. (2.4, 5.3)
`
`
`NSAIDs with renal insufficiency: Use caution in patients with mild to
`
`
`moderate renal insufficiency (CrCl 45-79 mL/min). (5.4)
`Lab monitoring: Do not initiate a cycle unless ANC ≥1500 cells/mm3,
`
`
`
`
`platelets ≥100,000 cells/mm3, and CrCl ≥45 mL/min. (5.5)
`
`
`
`
`
`
`
`
`Pregnancy: Fetal harm can occur when administered to a pregnant
`
`
`
`
`woman. Women should be advised to use effective contraception
`
`
`measures to prevent pregnancy during treatment with ALIMTA. (5.6)
`
`
`
`
`-------------------------------ADVERSE REACTIONS -----------------------------­
`
`The 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 INTERACTIONS -----------------------------­
`
`
`•
`NSAIDs: Use caution with NSAIDs. (7.1)
`
`
`
`
`
`•
`Nephrotoxic drugs: Concomitant use of these drugs and/or substances
`
`
`
`which are tubularly secreted may result in delayed clearance. (7.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`
`
`
`
`Revised: 00/0000
`
`5.4
`
`
`6
`
`
`7
`
`
`8
`
`
`Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`
`
`
`with Mild to Moderate Renal Insufficiency
`
`
`
`Required Laboratory Monitoring
`5.5
`
`
`Pregnancy Category D
`5.6
`
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`
`
`6.2
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`7.1
`
`
`
`7.2
`Nephrotoxic Drugs
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`8.6
`Patients with Hepatic Impairment
`
`
`
`8.7
`Patients with Renal Impairment
`
`
`8.8
`Gender
`
`
`8.9
`Race
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` 14 CLINICAL STUDIES
` 14.1 Non-Small Cell Lung Cancer (NSCLC) – Combination with
`
`
` Cisplatin
`
`
`
` Non-Small Cell Lung Cancer – Maintenance
`
` 14.2
`
`
` Non-Small Cell Lung Cancer – After Prior Chemotherapy
`
` 14.3
`
` 14.4 Malignant Pleural Mesothelioma
`
`
`
`
`
`
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`16.2
`Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
` 2
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
` 1
` INDICATIONS AND USAGE
`
` 1.1
`
` Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin
`
`
`
`
` 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.
`
`
` Nonsquamous Non-Small Cell Lung Cancer - Maintenance
`
` 1.2
`
`
`
`
` 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.
`
`
` Nonsquamous Non-Small Cell Lung Cancer - After Prior Chemotherapy
`
`
`
` 1.3
` 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.
`
`
`
` 1.4 Mesothelioma
`
` ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose
` disease is unresectable or who are otherwise not candidates for curative surgery.
`
`
`
`
` Limitations of Use
`
`
` 1.5
` ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies
`
`
`
` (14.1, 14.2, 14.3)]
`
` DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
` Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma
`
`
` 2.1
`
` 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.
`
`
`Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy
`2.2
`
`
`
`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.
`
`Premedication Regimen and Concurrent Medications
`2.3
`
`
`
`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)].
`
`
`
`Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations
`2.4
`
`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.
`
`
`
`
`
`
`Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities
`
`Reference ID: 3247473
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` 3
` 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).
`
`
`
` a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
` Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b
`
`
`
` Dose of Cisplatin
`
` Dose of ALIMTA
`
`
` (mg/m2)
` (mg/m2)
`
`
` 75% of previous dose
` 75% of previous dose
`
` 75% of previous dose
`
` 75% of previous dose
`
`
` Any Grade 3 or 4 toxicities except mucositis
`
`
`
`
`
` Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or
`
`
` 4 diarrhea
`
` Grade 3 or 4 mucositis
`
`
`
` a NCI Common Toxicity Criteria (CTC).
`
`b Excluding neurotoxicity (see Table 3).
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
` 50% of previous dose
`
`
`
` 100% of previous dose
`
`
`
`
`
`
`
`
`
` CTC Grade
`
` 0-1
`
` 2
`
`
`
`
`
`Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity
` Dose of Cisplatin
`
`
` Dose of ALIMTA
`
`
` (mg/m2)
` (mg/m2)
`
`
`
` 100% of previous dose
` 100% of previous dose
` 50% of previous dose
`
` 100% 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:
`
`
`
` [140 - Age in years] × Actual Body Weight (kg)
`
`
`
` 72 × Serum Creatinine (mg/dL)
`
` Estimated creatinine clearance for males × 0.85
`
`
`
`
`
`
`
`= mL/min
`
`
`
`Males:
`
` Females:
`
`
`
`
`Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance
`
`
`
`
`is <80 mL/min [see Drug Interactions (7.1)].
`
`
`
`Preparation and Administration Precautions
`2.5
`
`
`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.
`
`
`
`Preparation for Intravenous Infusion Administration
`2.6
`
`
`1. Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.
`
`
`
`
`2. Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of
`
`
`
`
`
`ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount.
`
`
`3. Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each
`
`
`
`
`
`
`500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a
`
`
`
`
`
`solution containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is completely dissolved. The resulting
`
`
`
`
`
`Reference ID: 3247473
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
` solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality.
`
`
`
`
`
`
` The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
` 4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`
`
`
` whenever solution and container permit. If particulate matter is observed, do not administer.
`
`
` 5. An appropriate quantity of the reconstituted ALIMTA solution must be further diluted into a solution of 0.9% Sodium
`
`
` Chloride Injection (preservative free), so that the total volume of solution is 100 ml. ALIMTA is administered as an
`
`
`
` intravenous infusion over 10 minutes.
`
`
`
`
`
`
` 6. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours
`
`
` following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions
`
`
`
` of ALIMTA contain no antimicrobial preservatives. Discard any unused portion.
`
`
`
`
`
`
` 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.
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
` 3
` 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.
`
`
`
` CONTRAINDICATIONS
`
`
` 4
`
`
` ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
` 5
`
` WARNINGS AND PRECAUTIONS
`
` Requirement for Premedication and Concomitant Medication to Reduce Toxicity
`
`
`
` 5.1
`
` 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)].
`
`
`
`
`
`Bone Marrow Suppression
`5.2
`
`
`
`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)].
`
`
`5.3
`
`
`Decreased Renal Function
`
`
`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.
`
`
`
`
`
`Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency
`5.4
`
`
`
`
`
`
`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)].
`
`
`
`
`
`
`5.5
`Required Laboratory Monitoring
`
`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)].
`
`
`
`5.6
`Pregnancy Category D
`
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 3247473
`
`

`

`
`
`
`
` 5
`
` 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)].
`
`
` ADVERSE REACTIONS
` 6
` 6.1
`
` Clinical Trials Experience
`
` Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to
`
`
`
` rates in other clinical trials and may not reflect the rates observed in clinical practice.
` In clinical trials, the most common adverse reactions (incidence ≥20%) 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reactionb
`
`
`Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa
`
`
`
` Gemcitabine/cisplatin
`
` ALIMTA/cisplatin
`
`
` (N=839)
` (N=830)
`Grade 3-4
`Grade 3-4
`
` All Grades
`
` All Grades
`
` Toxicity (%)
`
` Toxicity (%)
` Toxicity (%)
`
` Toxicity (%)
`
`
`
` 90
`
` 37
` 91
`
` 53
`
`
`
` All Adverse Reactions
`
`
` Laboratory
`
`
` Hematologic
`
`
` Anemia
`
`
` Neutropenia
`
` Leukopenia
`
`
` Thrombocytopenia
`
` Renal
`
`
` Creatinine elevation
`
` Clinical
`
`
` Constitutional Symptoms
`
`
` Fatigue
`
` Gastrointestinal
`
`
` Nausea
`
`
` Vomiting
`
` Anorexia
`
`
`
` Constipation
` Stomatitis/Pharyngitis
`
`
`
` Diarrhea
` Dyspepsia/Heartburn
`
`
`
` Neurology
`
` Neuropathy-sensory
`
`
`
` Taste disturbance
`
` Dermatology/Skin
`
`
` 0c
`
` 21
`
` 12
`
`
` Alopecia
`
` 8
`
` 0
`
` 7
`
`
` Rash/Desquamation
`
` 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.
`
`b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.
`
`
`
`
`c
`According 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 33
`
` 29
`
` 18
`
` 10
`
`
`
` 10
`
`
`
` 43
`
`
` 56
`
` 40
`
` 27
`
` 21
`
` 14
`
` 12
`
` 5
`
`
` 9
`
` 8
`
`
` 6
`
` 15
`
` 5
`
` 4
`
`
`
` 1
`
`
`
` 7
`
`
` 7
`
` 6
`
` 2
`
` 1
`
` 1
`
` 1
`
` 0
`
`
` 0
`
` 0c
`
`
` 46
`
` 38
`
` 21
`
` 27
`
`
`
` 7
`
`
`
` 45
`
`
` 53
`
` 36
`
` 24
`
` 20
`
` 12
`
` 13
`
` 6
`
`
` 12
`
` 9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 10
`
` 27
`
` 8
`
` 13
`
`
`
` 1
`
`
`
` 5
`
`
` 4
`
` 6
`
` 1
`
` 0
`
` 0
`
` 2
`
` 0
`
`
` 1
`
` 0c
`
`
` 1c
`
` 1
`
`The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to
`
`
`
`
`receive ALIMTA plus cisplatin.
`
`
`Reference ID: 3247473
`
`

`

`
`
` 6
`
`
`
`
`
`
`
` 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
`
`
` ALIMTA
`
` (N=438)
`Grade 3-4
`
` All Grades
`
` Toxicity (%)
` Toxicity (%)
`
`
` 66
`
` 16
`
`
` Placebo
`
` (N=218)
`Grade 3-4
`
` All Grades
`
` Toxicity (%)
` Toxicity (%)
`
`
` 37
`
` 4
`
`Reactionb
`
`
`
`
`
`
`
`
`
`
` All Adverse Reactions
`
`
` Laboratory
`
`
` Hematologic
`
`
` Anemia
`
`
` Neutropenia
`
` Leukopenia
`
`
` Hepatic
`
`
`
` Increased ALT
`
` Increased AST
`
`
` Clinical
`
`
` Constitutional Symptoms
`
`
` Fatigue
`
` Gastrointestinal
`
`
` Nausea
`
`
` Anorexia
`
` Vomiting
`
`
` Mucositis/stomatitis
`
`
` Diarrhea
` Infection
`
`
`
` Neurology
`
`
`
` Neuropathy-sensory
`
` Dermatology/Skin
`
` 3
` 0
` 10
`
`
`
`
`
` Rash/Desquamation
`
` 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.
`
`
`b Refer 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%).
`
`
`
` 15
`
` 6
`
` 6
`
`
` 10
`
` 8
`
`
`
` 25
`
`
` 19
`
` 19
`
` 9
`
` 7
`
` 5
`
` 5
`
`
`
` 9
`
`
` 3
`
` 3
`
` 2
`
`
` 0
`
` 0
`
`
`
` 5
`
`
` 1
`
` 2
`
` 0
`
` 1
`
` 1
`
` 2
`
`
`
` 1
`
`
` 6
`
` 0
`
` 1
`
`
` 4
`
` 4
`
`
`
` 11
`
`
` 6
`
` 5
`
` 1
`
` 2
`
` 3
`
` 2
`
`
`
` 4
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
` 0
`
` 1
`
`
` 0
`
` 0
`
`
`
` 1
`
`
` 1
`
` 0
`
` 0
`
` 0
`
` 0
`
` 0
`
`
`
` 0
`
`
`
` 0
`
`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.
`
`
`
`
`Reference ID: 3247473
`
`

`

`
`
` 7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Adverse Reaction Organ System and Term
`
`
`
` 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%
`
` 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 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.
`
`
`
`
`
`Table 6: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following
`
`
`
`
`
`
`ALIMTA Plus Cisplatin Induction Therapy
`
`
` ALIMTA
`
` (N=333)
` Grade 3-4a
`
` All Gradesa
`
`
` Toxicity (%)
` Toxicity (%)
`
`
` 53
`
` 17
`
`
` Placebo
`
` (N=167)
` Grades 3-4a
`
` All Gradesa
`
`
` Toxicity (%)
`
`
` Toxicity (%)
`
` 34
`
` 4.8
`
`
`
` All Adverse Reactions
`
`
` Laboratory
`
` Hematologic
`
`
` Anemia
`
` Neutropenia
` Clinical
`
`
` Constitutional Symptoms
`
`
`
` Fatigue
` Gastrointestinal
`
`
`
` Nausea
`
` Vomiting
`
`
`
` Mucositis/stomatitis
`
` General Disorders
`
` 0
` 3.6
` 0
` 5
`
`
`
`
`
`
` Edema
` 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.
`
`
`
`b NCI 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.
`
`
`
`
`
`
`
`
`
`
`
` 15
`
` 9
`
`
`
` 18
`
`
` 12
`
` 6
`
` 5
`
`
` 4.8
`
` 3.9
`
`
`
` 4.5
`
`
` 0.3
`
` 0
` 0.3
`
`
`
` 4.8
`
` 0.6
`
`
`
` 11
`
`
` 2.4
`
` 1.8
`
` 2.4
`
`
` 0.6
`
` 0
`
`
`
` 0.6
`
`
` 0
`
` 0
`
` 0