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), for Intravenous Use
`Initial U.S. Approval: 2004
`
`RECENT MAJOR CHANGES
`Dosage 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
`
`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
`2
`75 mg/m 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 BI~. Continue folic acid and
`vitamin BI~ supplementation throughout treatment. Administer
`corticosteroids the day before, the day of, and the day after
`ALIMTA administration. (2.3)
`Dose Reductions: Dose reductions or discontinuation may be
`needed based on toxicities from the preceding cycle of therapy.
`(2.4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`.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 B~
`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 CrCI <45 mL/min. (2.4,
`5.3)
`NSAIDs with renal insufficiency: Use caution in patients with mild
`to moderate renal insufficiency (CrCI 45-79 mL/min). (5.4)
`Lab monitoring: Do not initiate a cycle unless ANC
`3
`3
`>1500 cells/mm , platelets >100,000 cells/mm, and CrCI
`>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: 09/2013
`
`1
`
`2
`
`3
`4
`
`1.2
`
`1.3
`
`INDICATIONS AND USAGE
`1.1 Nonsquamous Non-Small Cell Lung Cancer-
`Combination 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
`2.1 Combination Use with Cisplatin for Nonsquamous Non-
`Small 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
`CONTRAINDICATIONS
`
`2.2
`
`2.3
`2.4
`
`5.2
`5.3
`5.4
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Requirement for Premedication and Concomitant
`Medication to Reduce Toxicity
`Bone Marrow Suppression
`Decreased Renal Function
`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
`Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
`7.1
`Nephrotoxic Drugs
`7.2
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`Nursing Mothers
`8.3
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`Patients with Hepatic Impairment
`8.6
`Patients with Renal Impairment
`8.7
`
`6
`
`7
`
`8
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0001
`
`JOINT 1051-0001
`
`

`
`Gender
`8.8
`Race
`8.9
`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
`
`FULL PRESCRIBING INFORMATION
`
`14.1
`
`2
`Non-Small Cell Lung Cancer (NSCLC) - Combination with
`Cisplatin
`14.2 Non-Small Cell Lung Cancer - Maintenance
`14.3 Non-Small Cell Lung Cancer - A~er Prior Chemotherapy
`14.4 Malignant Pleural Mesothelioma
`REFERENCES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`
`15
`16
`
`17
`
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`1
`1.1
`
`INDICATIONS AND USAGE
`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.
`1.5
`Limitations of Use
`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
`2.1
`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. See cisplatin package insert for more information.
`Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy
`2.2
`2
`The recommended dose of ALIMTA is 500 mg/m administered as an intravenous infusion over 10 minutes on Day
`1 of each 21-day cycle.
`2.3 Premedication Regimen and Concurrent Medications
`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)].
`2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations
`Monitorinq
`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
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0002
`
`JOINT 1051-0002
`
`

`
`3
`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
`Nadir ANC <500/mm~ and nadir platelets >50,000/mm~. 75% of previous dose (pemetrexed and cisplatin).
`Nadir platelets <50,000/mm~ without bleeding regardless of nadir 75% of previous dose (pemetrexed and cisplatin).
`ANC.
`Nadir platelets <50,000/mm~ 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
`
`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
`NCI Common Toxicity Criteria (CTC).
`Excluding neurotoxicity (see Table 3).
`
`Dose of ALIMTA
`(mg/m2)
`75% of previous dose
`75% of previous dose
`
`Dose of Cisplatin
`(mg/m2)
`75% of previous dose
`75% of previous dose
`
`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.
`
`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 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-DTPA serum clearance method:
`
`Males:
`
`Females:
`
`[140 - A,qe in years] x Actual Body Wei,qht (k,q)
`72 x Serum Creatinine (mg/dL)
`Estimated creatinine clearance for males x 0.85
`
`= mL/min
`
`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)].
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0003
`
`JOINT 1051-0003
`
`

`
`4
`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 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.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`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.
`
`4
`
`CONTRAINDICATIONS
`ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
`
`WARNINGS AND PRECAUTIONS
`5
`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 B1; to reduce
`the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not
`substitute oral vitamin B1; for intramuscular vitamin B~;. 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 B~2 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 alter 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 B~2 died of drug-related toxicity following administration of ALIMTA alone.
`5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0004
`
`JOINT 1051-0004
`
`

`
`5
`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)].
`Required Laboratory Monitoring
`5.5
`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)].
`Pregnancy Category D
`5.6
`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)].
`
`6
`6.1
`
`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 _>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 Lunq 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
`ALIMTA/cisplatin
`Gemcitabine/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
`Alopecia
`
`33
`29
`18
`10
`
`6
`15
`5
`4
`
`46
`38
`21
`27
`
`10
`27
`8
`13
`
`[
`
`10 J 1 [ 7 J 1
`
`43 I 7 I 45 I 5
`
`56
`4O
`27
`21
`14
`12
`5
`
`9
`8
`
`7
`6
`2
`1
`1
`1
`0
`
`0
`0°
`
`53
`36
`24
`2O
`12
`13
`6
`
`12
`9
`
`4
`6
`1
`0
`0
`2
`0
`
`1
`0°
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0005
`
`JOINT 1051-0005
`
`

`
`1
`8
`0
`7
`I Rash/Desquamati°n
`I
`I
`I
`I
`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.
`
`6
`
`No clinically relevant differences in adverse reactions were seen in patients based on histology.
`In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions
`(RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the
`gemcitabine and cisplatin arm.
`The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly
`assigned to receive ALIMTA plus cisplatin.
`Incidence 1% to 5%
`Body as a Whole- febrile neutropenia, infection, pyrexia
`General Disorders -- dehydration
`Metabolism and Nutrition -- increased AST, increased ALT
`Renal-- creatinine clearance decrease, renal failure
`Special Senses -- conjunctivitis
`Incidence Less than 1%
`Cardiovascular- arrhythmia
`General Disorders -- chest pain
`Metabolism and Nutrition -- increased GGT
`Neurology-- motor neuropathy
`Non-Small Cell Lunq Cancer (NSCLC) - Maintenance
`ALIMTA Maintenance Followinq Non-ALIMTA Containinq, 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
`Placebo
`ALIMTA
`(N=438) (N=218)
`Reacti°nb All Grades Grade 3-4 All Grades Grade 3-4
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`66
`16
`37
`4
`
`All Adverse Reactions
`Laboratory
`Hematologic
`Anemia
`Neutropenia
`Leukopenia
`Hepatic
`Increased ALT
`Increased AST
`Clinical
`Constitutional Symptoms
`Fatigue
`Gastrointestinal
`Nausea
`Anorexia
`Vomiting
`M u cos it is/sto matit is
`Diarrhea
`Infection
`Neurology
`Neuropathy-sensory
`Dermatology/Skin
`
`Reference ID: 3372274
`
`15
`6
`6
`
`8
`
`25
`
`19
`19
`9
`7
`5
`5
`
`[
`
`3
`3
`2
`
`0
`
`5
`
`1
`2
`0
`1
`1
`2
`
`I
`
`611
`
`0
`1
`
`0
`1
`
`4
`
`1
`
`1~
`
`I
`
`6
`5
`1
`2
`3
`2
`4
`
`I
`
`0
`
`~
`
`1
`0
`0
`0
`0
`0
`o
`
`Sandoz Inc.
`Exhibit 1051-0006
`
`JOINT 1051-0006
`
`

`
`I Rash/Desquamati°n I 10 I 0 I 3 I 0
`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.
`
`7
`
`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%
`Dermatology/Skin -- alopecia, pruritis/itching
`Gastrointestinal- constipation
`General Disorders -- edema, fever (in the absence of neutropenia)
`Hematologic -- th rombocytopenia
`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 Followinq 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)
`
`Placebo
`(N=167)
`
`Adverse Reaction Organ System and Term
`
`All Adverse Reactions
`Laboratory
`Hematologic
`Anemia
`Neutropenia
`Clinical
`Constitutional Symptoms
`Fatigue
`Gastrointestinal
`Nausea
`Vomiting
`M u cos it is/sto matitis
`General Disorders
`Edema
`
`Reference ID: 3372274
`
`All Gradesa Grade 3-4a All Gradesa Grades 3-4a
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`53
`17
`34
`4.8
`
`15
`9
`
`4.8
`3.9
`
`[ 18
`
`[ 4.5 J
`
`12
`6
`5
`
`0.3
`0
`0.3
`
`4.8
`0.6
`
`11
`
`2.4
`1.8
`2.4
`
`[ 5 [ 0 l 3.6
`
`[
`]-
`
`L
`
`l
`
`L
`
`0.6
`0
`
`0.6
`
`0
`0
`0
`
`0
`
`Sandoz Inc.
`Exhibit 1051-0007
`
`JOINT 1051-0007
`
`

`
`8
`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.
`The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.
`Incidence 1% to 5%
`Blood/Bone Marrow- thrombocytopenia
`General Disorders -- febrile neutropenia
`Incidence Less than 1%
`Cardiovascular-- ventricular tachycardia, syncope
`General Disorders -- pain
`Gastrointestinal- gastrointestinal obstruction
`Neurologic -- depression
`Renal-- renal failure
`Vascular-- pulmonary embolism
`Non-Small Cell Lunq Cancer (NSCLC) - After Prior Chemotherapy
`Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients
`randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients
`randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic
`NSCLC and received prior chemotherapy.
`
`Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa
`ALIMTA
`Docetaxel
`(N=265)
`(N=276)
`All Grades
`Grades 3-4
`All Grades
`Grades 3-4
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`Toxicity (%)
`
`Reactionb
`
`Laboratory
`Hematologic
`Anemia
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Hepatic
`Increased ALT
`Increased AST
`Clinical
`Gastrointestinal
`Nausea
`Anorexia
`Vomiting
`Sto matitis/Ph a ryng itis
`Diarrhea
`Constipation
`Constitutional Symptoms
`Fatigue
`Fever
`Dermatology/Skin
`0
`6
`0
`14
`Rash/Desquamation
`0
`2
`0
`7
`Pruritis
`2°
`38
`Alopecia
`1 °
`6
`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.
`Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).
`According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
`
`19
`12
`11
`8
`
`8
`7
`
`31
`22
`16
`15
`13
`6
`
`34
`8
`
`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
`
`No clinically relevant differences in adverse reactions were seen in patients based on histology.
`
`Reference ID: 3372274
`
`Sandoz Inc.
`Exhibit 1051-0008
`
`JOINT 1051-0008
`
`

`
`9
`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 Who/e -- abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection
`Dermatology/Skin -- erythema multiforme
`Neurology-- motor neuropathy, sensory neuropathy
`Renal-- increased creatinine
`Incidence Less than 1%
`Cardiovascular-- supraventricular arrhythmias
`Mali,qnant 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
`suppleme