-------------------------------CONTRAINDICATIONS------------------------------
`History of severe hypersensitivity reaction to pemetrexed. (4)
`------------------------ WARNINGS AND PRECAUTIONS -----------------------
`•
`Premedication regimen: Instruct patients to take folic acid and
`vitamin B12. Pretreatment with dexamethasone or equivalent reduces
`cutaneous reaction. (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 begin next cycle unless ANC u1500 cells/mm3,
`platelets u100,000 cells/mm3, and CrCl u45 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 u20%) 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 ibuprofen or other 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
`
`
`
`•
`
`•
`•
`
`•
`
`•
`
`
`
`
`
`
`
`
`
`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 disodium) Injection, Powder, Lyophilized, For
`Solution for Intravenous use
`Initial U.S. Approval: 2004
`--------------------------- RECENT MAJOR CHANGES --------------------------
`Indications and Usage, Non-Small Cell Lung Cancer — Combination with
`09/2008
`Cisplatin (1.1)
`
`
`
`
`
`Indications and Usage, Non-Small Cell Lung Cancer — Single-Agent (1.2)
`09/2008
`Dosage and Administration Combination Use with Cisplatin (2.1) 09/2008
`
`----------------------------INDICATIONS AND USAGE ---------------------------
`ALIMTA® is a folate analog metabolic inhibitor indicated for:
`
`Nonsquamous Non-Small Cell Lung Cancer: initial treatment in
`•
`combination with cisplatin. (1.1)
`Nonsquamous Non-Small Cell Lung Cancer as a single-agent after prior
`
`chemotherapy (1.2)
`
`•
` Mesothelioma: in combination with cisplatin (1.3)
`----------------------- 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)
`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)
`•
`
`•
`
`•
`
`•
`
`
`
`
`
`
`
`
`
`Revised:09/2008
`
`13
`
`14
`
` Nursing Mothers
`8.3
` Pediatric Use
`8.4
` Geriatric Use
`8.5
`Patients with Hepatic Impairment
`8.6
`Patients with Renal Impairment
`8.7
` Gender
`8.8
`
` Race
`8.9
`10 OVERDOSAGE
`
` DESCRIPTION
`11
`12
` CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
` NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` CLINICAL STUDIES
`14.1 Non-Small Cell Lung Cancer (NSCLC) — Combination with
`Cisplatin
`14.2 Non-Small Cell Lung Cancer — Single-Agent Use
`
`14.3
` Malignant Pleural Mesothelioma
`
` REFERENCES
`15
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2
`Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Need for Folic Acid and Vitamin B12
`
`
`17.2
`Low Blood Cell Counts
`17.3
` Gastrointestinal Effects
`17.4
`Concomitant Medications
`17.5
`FDA Approved Patient Labeling
`
`
`
`2
`
`3
`4
`5
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
` INDICATIONS AND USAGE
`Non-Small Cell Lung Cancer – Combination with Cisplatin
`1.1
`
`Non-Small Cell Lung Cancer – Single-Agent
`1.2
` Mesothelioma
`1.3
`
`DOSAGE AND ADMINISTRATION
`Combination Use with Cisplatin
`2.1
`2.2
` Single-Agent Use
`2.3
` Premedication Regimen
`2.4
`Laboratory Monitoring and Dose Reduction/Discontinuation
`Recommendations
`Preparation and Administration Precautions
`2.5
`Preparation for Intravenous Infusion Administration
`2.6
`DOSAGE FORMS AND STRENGTHS
` CONTRAINDICATIONS
` WARNINGS AND PRECAUTIONS
`5.1
` Premedication Regimen
`5.2
`Bone Marrow Suppression
`5.3
`Decreased Renal Function
`5.4
`Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to
`Moderate Renal Insufficiency
`
` Required Laboratory Monitoring
`5.5
`
`Pregnancy Category D
`5.6
`Third Space Fluid
`5.7
` ADVERSE REACTIONS
`Clinical Trials Experience
`6.1
`6.2
` Post-Marketing Experience
` DRUG INTERACTIONS
`
`7.1
`Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`
`7.2
` Nephrotoxic Drugs
`USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
`
`6
`
`7
`
`8
`
`
`
`1
`
`AVENTIS EXHIBIT 2204
`Mylan v. Aventis IPR2016-00712
`
`

`
`
`
` *Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`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. ALIMTA is not indicated for treatment of patients with squamous cell non-small
`cell lung cancer.
`1.2
`Non-Small Cell Lung Cancer — Single-Agent
`
`
`
`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. ALIMTA is not indicated for treatment of patients with squamous cell non-small cell
`lung cancer.
`
`1.3 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.
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`Combination Use with Cisplatin
`2.1
`
`
`Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma
`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. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin
`
`package insert for more information.
`Single-Agent Use
`2.2
`
`Non-Small Cell Lung Cancer
`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.
`2.3
`Premedication Regimen
`
`Vitamin Supplementation
`
`
`To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or
`
`
`
`multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the
`
`
`
`
`
`first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA.
`Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and
`
`every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic
`acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic
`
`
`
`
`
`
`acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].
`
`
`Corticosteroid
`Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone
`
`
`
`
`
`(or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth
`
`twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].
`2.4
`Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations
`
`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 u1500 cells/mm3, the platelet count is u100,000 cells/mm3, and
`
`creatinine clearance is u45 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
`
`75% of previous dose (both drugs).
` Nadir ANC <500/mm3 and nadir platelets u50,000/mm3 .
`
` Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC.
`
`
` 75% of previous dose (both drugs).
`
`
` Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC.
`
` 50% of previous dose (both drugs).
`
`
`
`a These criteria meet the CTC version 2.0 (NCI 1998) definition of uCTC Grade 2 bleeding.
`
`
`
`2
`
`

`
`
`
`
`
`50% of previous dose
`
`
`
`100% of previous dose
`
`
`
`
`If patients develop nonhematologic toxicities (excluding neurotoxicity) uGrade 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 ALIMTA
`Dose of Cisplatin
`(mg/m2)
`(mg/m2)
`75% of previous dose
`75% of previous dose
`75% of previous dose
`75% of previous dose
`
`
` Any Grade 3c 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).
`
`c Except Grade 3 transaminase elevation, for which no dose reduction is needed.
`
`
`
`
`
` 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.
`
`Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity
`
`
`Dose of ALIMTA
`
`Dose of Cisplatin
`(mg/m2)
`(mg/m2)
`100% of previous dose
`100% of previous dose
`
`
`100% of previous dose
`50% of previous dose
`
`
` CTC Grade
` 0-1
`
`2
`
`
`
`Discontinuation Recommendation
`
`
`ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity
`
`after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed.
`
`Renally Impaired Patients
`
`
`
`In clinical studies, patients with creatinine clearance u45 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:
`
`
`= mL/min
`
`
`
`[140 - Age in years] × Actual Body Weight (kg)
`72 × Serum Creatinine (mg/dL)
`
`Estimated creatinine clearance for males × 0.85
`
`
`
`
`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 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 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.
`
`3
`
`

`
`
`
` 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 at refrigerated or ambient room temperature [see USP Controlled Room
`
`
`
`
`Temperature] and lighting. 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 or to any other
`
`ingredient used in the formulation.
`
`WARNINGS AND PRECAUTIONS
`5
`5.1
`Premedication Regimen
`
` Need for Folate and Vitamin B12 Supplementation
`
`Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce
`
`treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and
`
`
`reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade
`
`
`
`3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.
`
`
`
`Corticosteroid Supplementation
`
`
`
`Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with
`dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [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 u45 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 with Mild to Moderate Renal Insufficiency
`5.4
`
`
`
`
`Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal
`
`
`
`
`
`
`insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions
`
`
`
`
`
`
`(7.1)].
`5.5
`
`
`
`Required Laboratory Monitoring
`Patients should not begin a new cycle of treatment unless the ANC is u1500 cells/mm3, the platelet count is
`
`u100,000 cells/mm3, and creatinine clearance is u45 mL/min [see Dosing 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
`
`becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with
`
`
`ALIMTA. [see Pregnancy (8.1)]
`
`
`Third Space Fluid
`5.7
`The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically
`
`significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.
`
`
`4
`
`

`
`
`
`
`
`6
`6.1
`
`
`
` Reactionb
`
`ADVERSE REACTIONS
`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 u20%) during therapy with ALIMTA as a single-agent were
`
`
`
`fatigue, nausea, and anorexia. Additional common adverse reactions (incidence u20%) 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) — Combination with Cisplatin
`
`
`
`Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC
`
`who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and
`
`received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC
`and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.
`
`
`
`
`
`Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa
`
`Gemcitabine/cisplatin
`ALIMTA/cisplatin
`(N=839)
`(N=830)
`All Grades
`Grade 3-4
`All Grades
`Grade 3-4
`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
` 1c
`
`0c
`21
`
`
`12
`Alopecia
`1
`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
`
`
`10
`27
`8
`13
`
`1
`
`5
`
`4
`6
`1
`0
`
`0
`2
`0
`
`1
`0c
`
`
`46
`38
`21
`27
`
`7
`
`45
`
`53
`36
`24
`20
`
`12
`13
`6
`
`12
`9
`
`
`
`The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to
`receive ALIMTA plus cisplatin.
`
`Incidence 1% to 5%
`
`Body as a Whole — febrile neutropenia, infection, pyrexia
`
`
`General Disorders — dehydration
`
`
`5
`
`

`
` 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) — Single-Agent
`
`
`
`
`Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly
`
`
`assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to
`
`
`
`receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior
`
`chemotherapy.
`
`
`
`
`
`
`Table 5: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa
`
`
`
`
`Docetaxel
`ALIMTA
`(N=265)
`(N=276)
`All Grades
`Grades 3-4
`All Grades
`Grades 3-4
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`
`
`
` Reactionb
`
`19
`12
`11
`8
`
`8
`7
`
`31
`22
`16
`
`15
`13
`6
`
`34
`8
`
` Laboratory
`
` Hematologic
`
`
`Anemia
`
` Leukopenia
`
`Neutropenia
` Thrombocytopenia
` Hepatic
`
`
`Increased ALT
`
`
`Increased AST
`
` Clinical
` Gastrointestinal
`
`Nausea
`
`
`Anorexia
`
`Vomiting
` Stomatitis/Pharyngitis
`
`Diarrhea
`
` Constipation
` Constitutional Symptoms
` Fatigue
` Fever
` Dermatology/Skin
`6
`14
` Rash/Desquamation
`0
`0
`
`
`
`
`2
`7
`Pruritis
`0
`0
`
` 2c
`1c
`38
`
`
`6
`Alopecia
` 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 for lab values for each Grade of toxicity (version 2.0).
`
`
`
`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.
`
`
`
`Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that
`
`
`received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).
`The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to
`receive ALIMTA.
`Incidence 1% to 5%
`
`Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection
`
`
`Dermatology/Skin — erythema multiforme
`
`
`Neurology — motor neuropathy, sensory neuropathy
`
`
`
`Renal — increased creatinine
`
`Incidence Less than 1%
`
`
`4
`4
`5
`2
`
`2
`1
`
`3
`2
`2
`
`1
`0
`0
`
`5
`0
`
`22
`34
`45
`1
`
`1
`1
`
`17
`24
`12
`
`17
`24
`4
`
`36
`8
`
`4
`27
`40
`0
`
`0
`0
`
`2
`3
`1
`
`1
`3
`0
`
`5
`0
`
`
`
`
`
`6
`
`

`
`Cardiovascular — supraventricular arrhythmias
`
`
` Malignant Pleural Mesothelioma (MPM)
`
`
`Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with
`
`mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned
`to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and
`vitamin B12.
`
`
`
`
`
`
`Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa
`
`
`ALIMTA/cisplatin
`Cisplatin
`(N=168)
`(N=163)
`All Grades
`Grade 3-4
`All Grades
`Grade 3-4
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`
`
`
` Reactionb
`
`3
`1
`0
`0
`
`1
`2
`
`0
`
`
`
`6
`4
`
`0
`1
`0
`1
`0
`
`9
`
`1
`
`1
`0c
`
`
`13
`17
`10
`9
`
`10
`18
`
`
`1
`
`77
`50
`
`6
`14
`8
`7
`1
`
`42
`
`1
`
`10
`6
`
`
`
`56
`53
`26
`23
`
`11
`16
`
`
`5
`
`82
`57
`
`23
`20
`17
`12
`5
`
`48
`
`7
`
`10
`8
`
`23
`15
`4
`5
`
`1
`1
`
`
`0
`
`12
`11
`
`3
`1
`4
`1
`1
`
`10
`
`4
`
`0
`0c
`
`
` Laboratory
`
` Hematologic
`
`Neutropenia
`
` Leukopenia
`
`
`Anemia
` Thrombocytopenia
` Renal
` Creatinine elevation
` Creatinine clearance decreased
`
` Clinical
`
` Eye Disorder
` Conjunctivitis
` Gastrointestinal
`
`Nausea
`
`Vomiting
` Stomatitis/Pharyngitis
`
`
`Anorexia
`
`Diarrhea
`
` Constipation
`
`Dyspepsia
` Constitutional Symptoms
` Fatigue
` Metabolism and Nutrition
`
`
`Dehydration
` Neurology
`
`
`Neuropathy-sensory
` Taste Disturbance
` Dermatology/Skin
`5
`16
`0
`1
` Rash
`
`0c
` 0c
`6
`
`
`11
`Alopecia
` 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 except the term “creatinine clearance decreased” which is derived
`
`
`from the CTC term “renal/genitourinary-other”.
`c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
`
`
`
`
`The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned
`
`to receive ALIMTA plus cisplatin.
`
`Incidence 1% to 5%
`Body as a Whole — febrile neutropenia, infection, pyrexia
`
`
`Dermatology/Skin — urticaria
`
`General Disorders — chest pain
`
`
`
`Metabolism and Nutrition — increased AST, increased ALT, increased GGT
`
`
`
`
`Renal — renal failure
`
`
`
`Incidence Less than 1%
`Cardiovascular — arrhythmia
`
`Neurology — motor neuropathy
`
`
`
`
`
`7
`
`

`
`
`
`
`
`Never Supplemented Patients
`(N=32)
`38
`9
`31
`9
`6
`9
`
` Effects of Vitamin Supplementations
`
` Table 7 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin
`
`
`
`
`supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence
`
`
`
`in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.
`
`
`Table 7: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the
`
`
`ALIMTA plus Cisplatin arm (% incidence)
`
`Fully Supplemented Patients
` Adverse Eventa (%)
`(N=168)
`
`
`23
` Neutropenia/granulocytopenia
`
`5
` Thrombocytopenia
`11
` Vomiting
`1
` Febrile neutropenia
`
`
`0
`Infection with Grade 3/4 neutropenia
`4
`Diarrhea
`
` a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).
`
`The following adverse events were greater in the fully supplemented group compared to the never supplemented group:
`
`
`hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).
`
`
`Subpopulations
`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%).
`
`Phase 2 Studies
`
`Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three
`
`
`
`single-agent ALIMTA studies (N=164) and the Phase 3 single-agent ALIMTA study described above, with the exception of
`neutropenia (12.8% versus 5.3%, respectively) and alanine transaminase elevation (15.2% versus 1.9%, respectively). These
`
`
`differences were likely due to differences in the patient population, since the Phase 2 studies included chemonaive and heavily
`
`pretreated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.
`Post-Marketing Experience
`6.2
`
`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 have occurred with ALIMTA when used as a single-agent and in combination therapies.
`Gastrointestinal — colitis
`
`Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously
`
`
`received radiotherapy.
`Respiratory — interstitial pneumonitis.
`
`DRUG INTERACTIONS
`7
`
`Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`7.1
`
`Ibuprofen
`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 u80 mL/min). Caution should be used when administering
`
`
`
`ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to
`
`79 mL/min) [see Clinic