Date of Revision:

August 29, 2008

Control Number: 116924

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS. 13 DOSAGE AND ADMINISTRATION 14 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 22 SPECIAL HANDLING INSTRUCTIONS 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION. 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 41 TOXICOLOGY 43 REFERENCES 46

PART III: CONSUMER INFORMATION 48

ALIMTA(r) Pemetrexed Disodium for Injection 100 mg or 500 mg pemetrexed per vial

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

*For a complete listing see Dosage Forms, Composition and Packaging Section.

CONTRAINDICATIONS

ALIMTA (pemetrexed disodium) is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING Section.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

ALIMTA (pemetrexed disodium) should only be administered by, or under the supervision of, a physician who is experienced in cancer chemotherapy and in the management of related toxicities. Hepatotoxicity: See Hepatic/Biliary subsection below.

General

Information to be Provided to the Patient:

Physicians should discuss with patients and caregivers the expected adverse effects, particularly bone marrow suppression, with increased susceptibility to infection. Patients and caregivers should be advised to report the onset of fever, chills, diarrhea, and mouth ulcers immediately to their healthcare provider. Patients should be made aware that patient-specific dose modifications during therapy are expected and that they should take vitamin supplementation as directed by their healthcare provider. Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Males are advised not to father a child during treatment and up to 6 months thereafter.

Carcinogenesis and Mutagenesis

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. Because pemetrexed may cause irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment. See Part II: TOXICOLOGY Section.

Cardiovascular

No thorough clinical QT/QTc study was performed to rule out the effect of ALIMTA on QT prolongation. Routine ECG assessments during clinical trials did not identify any concerns regarding QT prolongation.

Gastrointestinal

Stomatitis, nausea, vomiting, and diarrhea are common in patients receiving ALIMTA with or without cisplatin. In rare cases gastrointestinal toxicity may lead to severe dehydration. Gastrointestinal toxicity should be vigorously managed (see ADVERSE REACTIONS - Clinical Trial Adverse Drug Reactions and DOSAGE AND ADMINISTRATION - Nonhematologic Toxicities).

Hepatic/Biliary

Serious hepatobiliary toxicity and rare cases of fatal hepatic failure, have been reported with ALIMTA alone or in association with other chemotherapeutic agents in clinical trials. Underlying risk factors for the development of hepatic toxicity including hepatic metastases and/or underlying hepatic disease have been present in some cases. A causal relationship between ALIMTA and these events has not been established.

Hematologic

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) (see ADVERSE REACTIONS Section); myelosuppression is usually the dose-limiting toxicity (see Laboratory Monitoring and Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION Section). Dose reductions for subsequent cycles are based on nadir Absolute Neutrophil Count (ANC), platelet count, and maximum nonhematologic toxicity seen in the previous cycle (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION Section). In the Phase 3 mesothelioma clinical trial, 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 pre-treatment with folic acid and vitamin B12 was administered. Therefore, patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylactic measure to reduce treatment-related toxicity (see DOSAGE AND ADMINISTRATION Section).

Immune

Cases of hypersensitivity, including anaphylaxis, have been reported in patients treated with ALIMTA.

Renal

Serious renal events, including acute renal failure, have been reported with ALIMTA alone or in association with other chemotherapeutic agents. Most, but not all, of the patients in whom these serious renal events occurred had underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes. A causal relationship between ALIMTA and these events has not been established.

Respiratory

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.

Skin

Treatment-related adverse events of ALIMTA seen in clinical trials have been reversible. Skin rash has been reported 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 Section). Radiation recall dermatitis has been reported in patients on ALIMTA who have previously received radiotherapy. Severity of symptoms can vary from mild dermatitis to necrosis (see REFERENCES Barlesi et al, Hureaux et al).

Special Populations

Pregnant Women:

ALIMTA may cause fetal harm when administered to a pregnant woman. In studies on mice, pemetrexed was found to be embryotoxic at a dose of 30 mg/m2 (1/17 the recommended human dose) and all litters were entirely resorbed at a dose of 150 mg/m2 (1/3 the recommended human dose) when given in gestation days 6 through 15. Incomplete ossification was observed at a dose of 0.6 mg/m2 (1/833 of the human dose). Pemetrexed was also fetotoxic (cleft palate) at a dose of 15 mg/m2 (1/33 the recommended human dose). There are no studies of ALIMTA in pregnant women. Patients should be advised to avoid becoming pregnant. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking ALIMTA, the patient should be informed of the potential hazard to the fetus.

Nursing Women:

It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pemetrexed, it is recommended that nursing be discontinued if the mother is treated with ALIMTA.

Pediatrics (<18 years of age):

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

Geriatrics (>65 years of age):

Dose adjustments based on age other than those recommended for all patients have not been necessary.

Patients with Hepatic Impairment:

Pemetrexed is not extensively metabolized by the liver. However, patients with hepatic impairment such as bilirubin >1.5 times the upper limit of normal (ULN) or transaminase >3 times the ULN (hepatic metastases absent) or >5 time the ULN (hepatic metastases present) have not been specifically studied. For dose adjustments based on hepatic impairment, refer to Laboratory Monitoring and Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION Section.

Patients with Renal Impairment:

ALIMTA is known to be primarily excreted by the kidney. There is limited clinical experience in patients with calculated creatinine clearance below 45 mL/min. Therefore, patients whose creatinine clearance is <45 mL/min should not receive ALIMTA. Decreased renal function will result in reduced clearance of ALIMTA compared with patients with normal renal function. For dose adjustments based on renal impairment, refer to Laboratory Monitoring and Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION Section.

Monitoring and Laboratory Tests

All patients receiving ALIMTA should have frequent complete blood counts, including differential and platelets as well as periodic blood chemistry tests performed. Patients should not begin a new treatment cycle unless the absolute neutrophil count (ANC) is >=1500 cells/mm3 and the platelet count is >=100,000 cells/mm3.

DRUG INTERACTIONS

Drug-Drug Interactions

Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of pemetrexed.

Ibuprofen:

Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance >=80 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). Clinical trials have shown a decrease in pemetrexed clearance following co-administration of ibuprofen. It is recommended that patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives at least 2 days prior to, on the day of, and at least 2 days after administration of ALIMTA.

NSAIDs:

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and at least 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal and gastrointestinal toxicity.

Aspirin:

Acetylsalicylic acid, administered in low to moderate doses (325 mg orally every 6 hours) does not affect the pharmacokinetics of pemetrexed.

Chemotherapeutic Agents:

The pharmacokinetics of pemetrexed are not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins:

Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes:

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of the metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. No studies were conducted to determine the cytochrome P450 isozyme induction potential of pemetrexed, because ALIMTA used as recommended (once every 21 days) would not be expected to cause any significant enzyme induction.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

ALIMTA (pemetrexed disodium) is for intravenous infusion only. It should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Recommended Dose and Dosage Adjustment

Malignant Pleural Mesothelioma (MPM)

Combination Use with Cisplatin: 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. In clinical trials the median number of cycles was 6 (range = 1 to 12 cycles). Please see Part II: CLINICAL TRIALS Section for further information.

Non-Small Cell Lung Cancer (NSCLC)

Combination Use with Cisplatin: 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 completion of the ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. In the clinical trial, treatment was administered up to a total of 6 cycles of therapy, and the median number of cycles was 5 (range 1-7). Please see Part II: CLINICAL TRIALS Section for further information. Single-Agent Use: 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. Optimal number of treatment cycles has not been established. Patients were administered ALIMTA until progression. The median number of cycles was 4 (range 1-20).

Premedication Regimen:

Corticosteroid

- Skin rash has been reported 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.

Vitamin Supplementation -

To reduce potential 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 (see Table 5). At least 5 daily doses of folic acid (400 ug/day) 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 (1000 ug) 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 ug, and the dose of vitamin B12 was 1000 ug. The most commonly used dose of oral folic acid in clinical trials was 400 ug (see WARNINGS AND PRECAUTIONS Section).

Table 5: Vitamin Supplementation

Laboratory Monitoring and Dose Reduction Recommendations:

Monitoring: Complete blood cell counts, including platelets, and blood chemistries should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is >=1500 cell/mm3, platelet count >=100,000 cells/mm3 and creatinine clearance >= 45 mL/min. Periodic chemistry tests should be collected to evaluate renal and hepatic function.

General 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 guidelines in Table 6-8, which are suitable for using ALIMTA as a single agent or in combination with cisplatin. ALIMTA therapy should be discontinued if a patient experiences any Grade 3 or 4 toxicity after 2 dose reductions.

Hematologic Toxicities:

In the event of hematologic toxicities, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 6.

Table 6: Dose Reduction for ALIMTA as Single-Agent or In Combination with Cisplatin - Hematologic Toxicities

a

These criteria meet the CTC version 2.0 (NCI 1998) definition of >=CTC Grade 2 bleeding.

Nonhematologic Toxicities: If patients develop nonhematologic toxicities (excluding neurotoxicity) >=Grade 3, ALIMTA 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 7.

Table 7: Dose Reduction for ALIMTA as Single-Agent or In Combination with Cisplatin - Nonhematologic Toxicitiesa,b

1. NCI Common Toxicity Criteria (CTC).

2. Guidelines for neurotoxicity are provided in Table 8, below.

Neurotoxicity

: In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 8. Patients should immediately discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 8: Dose Reduction for ALIMTA as Single-Agent or In Combination with Cisplatin - Neurotoxicity

Special Populations and Conditions:

Elderly Patients

: In clinical trials, no dose reductions other than those recommended for all patients were specifically recommended for elderly patients. However, in the study comparing first-line ALIMTA/cisplatin with gemcitabine/cisplatin in NSCLC patients, those patients aged

>= 65 years generally experienced more toxicity (e.g. neutropenia, febrile neutropenia, thrombocytopenia, nausea, renal failure) than patients aged < 65 years, regardless of treatment arm.

Children

: ALIMTA is not recommended for use in children as safety and efficacy have not yet been established in this group of patients.

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. 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:

a

To convert from SI (mL/sec) to (mL/min), multiply the mL/sec value by 60.

Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min (see DRUG INTERACTIONS Section).

Hepatically Impaired Patients

: ALIMTA is not extensively metabolized by the liver. Dose adjustments based on hepatic impairment experienced during treatment with pemetrexed are provided in Table 7 (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary and Special Populations, Patients with Hepatic Impairment subsections).

Missed Dose

If chemotherapy treatment is missed, physicians should advise patients to contact them in order to provide further instruction on the administration of folic acid and vitamin B12 (see DOSAGE AND ADMINISTRATION Section).

Administration

ALIMTA (pemetrexed disodium) is for intravenous infusion only.

PREPARATION AND ADMINISTRATION PRECAUTIONS:

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 Part II: REFERENCES). There is no general agreement that all of the procedures recommended in the guideline are necessary or appropriate. ALIMTA is not a vesicant. There is not a specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed with local standard practice for extravasation as with other non-vesicants.

Reconstitution:

The appropriate volume of reconstituted ALIMTA solution should be further diluted to a total volume of 100 mL with 0.9% Sodium Chloride Injection (preservative free) and administered as an intravenous infusion over 10 minutes.

PREPARATION FOR INTRAVENOUS INFUSION ADMINISTRATION:

1. Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.

2. Calculate the dose and the number of ALIMTA vials needed. Vials contain either 100 mg or 500 mg of pemetrexed. Each vial contains 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) to give a solution containing 25 mg/mL pemetrexed. Reconstitute each 500 mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/mL of pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless 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. As with all parenteral drug products, reconstituted vials and diluted admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

5. The appropriate volume of reconstituted ALIMTA solution should be further diluted to a total volume of 100 mL with 0.9% Sodium Chloride Injection (preservative free) and 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 (2-8degC) or ambient room temperature (15-30degC) 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), USP. ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP, and therefore those should not be used. Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended.

OVERDOSAGE

There have been few cases of ALIMTA (pemetrexed disodium) overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. There is no known antidote for ALIMTA overdose. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The ability of pemetrexed to be dialyzed is unknown. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting >=3 days, CTC Grade 4 neutropenia lasting >=3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ALIMTA (pemetrexed disodium) is an antifolate antineoplastic agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.

Pharmacodynamics

Pemetrexed is an antifolate containing the structurally novel pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting crucial folate-dependent metabolic processes that are essential for cell replication. In vitro studies have shown that pemetrexed behaves as a multi-targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate- dependent enzymes for the de novo bio-synthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells. Data indicate that overexpression of thymidylate synthase (TS) correlates with reduced sensitivity to pemetrexed in antifolate- resistant cell lines. Results in a recent study with specimens from chemonaive patients with NSCLC demonstrated lower levels of TS expression in adenocarcinoma as compared to squamous cell carcinoma tumors. Although these data suggest that pemetrexed may offer greater efficacy for patients with adenocarcinoma as compared to squamous carcinoma histology, this hypothesis requires further validation in studies that assess the predictive and prognostic value of TS expression in patients with NSCLC.

Pharmacokinetics

The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors.

Absorption:

Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.

Distribution:

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by renal impairment.

Metabolism:

Pemetrexed is not metabolized to an appreciable extent.

Excretion:

Pemetrexed is primarily eliminated in the urine with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. Pemetrexed total systemic clearance is 91.8 mL/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min [calculated using the standard Cockcroft and Gault formula or measured glomerular filtration rate using the Tc99m-DPTA serum clearance method]). Between patient variability in clearance is moderate at 19.3%. Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, is inversely proportional to the systemic exposure of ALIMTA. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mg *hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

Special Populations and Conditions

The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.

Pediatrics:

The safety and effectiveness of ALIMTA has not been established in pediatric patients.

Geriatrics:

No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.

Gender:

The pharmacokinetics of pemetrexed were not different in male and female patients.

Race:

The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.

Hepatic Insufficiency:

There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted (see WARNINGS AND PRECAUTIONS section).

Renal Insufficiency:

Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed in the presence of cisplatin decreases as renal function decreases, with increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

STORAGE AND STABILITY

ALIMTA should be stored at controlled room temperature 25degC; excursions permitted to 15-30degC. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8degC, or at 25degC, excursions permitted to 15-30degC. When prepared as directed, reconstituted and infusion solutions of ALIMTA contain no antimicrobial preservatives and should be used immediately. Discard unused portion. ALIMTA is not light sensitive.

SPECIAL HANDLING INSTRUCTIONS

Please see ADMINISTRATION Section.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms:

ALIMTA (pemetrexed disodium for injection) is available in sterile single-use vials containing either 100 mg or 500 mg of lyophilized pemetrexed. The drug product is white to either light yellowish or green-yellowish lyophilized solid.

Composition:

ALIMTA, Pemetrexed for Injection, is a single-use, sterile, lyophilized powder packaged in glass vials. Each 10 mL vial contains pemetrexed disodium equivalent to 100 mg of pemetrexed and 106 mg of mannitol. Each 50 mL vial contains pemetrexed disodium equivalent to 500 mg of pemetrexed and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide, may have been added to adjust pH.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: pemetrexed disodium Chemical name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid disodium salt Molecular formula and molecular mass: C20H19N5O6 *2Na *7H2O 597.49 Structural formula:

O N

HN H

CO2- Na+

*7H2O

N

H2N

pH of a 1% aqueous solution: 8 pKa: 11.34, 4.37, 3.23, 2.22

CLINICAL TRIALS

Malignant Pleural Mesothelioma: ALIMTA/Cisplatin versus Cisplatin

The safety and efficacy of ALIMTA were evaluated in chemonaive patients with malignant pleural mesothelioma (MPM) in combination with cisplatin.

Study Demographics and Trial Design

Table 9: Patient Demographics - Clinical Trials Supporting Efficacy of ALIMTA in the Treatment of Malignant Pleural Mesothelioma (MPM)

Randomized Trial

A Phase 3 multicentre, randomized, single-blind study in 448 chemonaive patients with MPM compared median survival in patients treated with ALIMTA in combination with cisplatin to those patients receiving cisplatin alone. ALIMTA (n=226) was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin (n=222) was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of the ALIMTA infusion. Both drugs were given on Day 1 of a 21-day cycle. Folic acid and vitamin B12 supplementation were added to both treatment arms to reduce white cell and GI toxicity observed in the first 117 treated patients. All patients received prophylactic dexamethasone a part of the treatment regimen to prevent/reduce skin toxicities. Patient demographics are shown in Table 10.

Table 10: Summary of Patient Characteristics

1. Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review.

2. Karnofsky Performance Scale.

Table 11 summarizes the number of cycles of treatment completed by all randomized and treated patients and fully supplemented patients. The fully supplemented patients completed a median of 6 cycles in the ALIMTA plus cisplatin treatment arm and 4 cycles in the cisplatin treatment arm. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms.

Table 11: Summary of Cycles Given in Randomized and Treated MPM Patients

All Patients (N=448) include all randomized and treated patients regardless of supplementation status

Table 12 summarizes the dose intensity administered to the treatment groups. Patients in both arms received more than 90% of the planned dose intensity.

Table 12: Summary of Dose Intensity (DI) in Randomized and Treated MPM Patients

All Patients (N=448) include all randomized and treated patients regardless of supplementation status

Study Results

Table 13 summarizes the efficacy results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial (fully supplemented patients). In the population of all treated patients regardless of supplementation status (primary analysis), patients receiving the combination of pemetrexed plus cisplatin had a significantly higher median survival time than the patients in the cisplatin monotherapy arm (Table 13; Figure 1). The 2.8-month difference in median survival (12.1 versus 9.3 months), was statistical significant (p-value 0.020).

Table 13: Efficacy of ALIMTA plus Cisplatin versus Cisplatin in Randomized and Treated MPM Patients

All Patients (N=448) include all randomized and treated patients regardless of supplementation status

* * p-value refers to comparison between arms.

1.00

Survival Distribution Function

Median Survival = 12.1 mos

0.50

Median Survival

= 9.3 mos

0.25

0.00

0 5 10 15 20 25 30

Survival Time (Months)

ALIMTA + Cisplatin (n=226) Cisplatin (n=222)

Figure 1: Kaplan-Meier Estimates of Survival Time

Objective tumour response criteria for malignant pleural mesothelioma is difficult to assess and response criteria are not universally agreed upon. However, based on a prospectively defined criteria, the objective tumour response rate for ALIMTA plus cisplatin was greater than the response rate for cisplatin alone (41.3% vs. 16.7%; p=0.001), as were the measures of time to progressive disease (5.7 vs. 3.9 months) and time to treatment failure (4.5 vs. 2.7 months; p=0.001). Vitamin supplementation was associated with further improvement in the objective tumour response rate for the ALIMTA plus cisplatin compared to cispatin alone patients (45.5% vs. 19.6%) as was time to progressive disease (6.1 vs. 3.9 months; p=0.008) and time to treatment failure (4.7 vs. 2.7 months; p=0.001). Quality of Life was measured using the Lung Cancer Symptom Scale (LCSS) which assessed 6 symptoms (anorexia, fatigue, pain, cough, hemoptysis, and dyspnea); 3 summary scales (symptom distress, interference with activity level, and global QoL); and an average of all the individual scales (Total LCSS). LCSS data had to be present at both baseline and at least one post-baseline assessment between cycle 1-6, to be included in the analysis and were available for 93.8% of the ALIMTA plus cisplatin patients and for 98.1% of the cisplatin monotherapy patients. At cycle 6, there was a significant difference in favour of the ALIMTA plus cisplatin patients for dyspnea, fatigue, symptom distress, interference with activity, and total LCSS. Pain scores improved for ALIMTA plus cisplatin patients and these scores were statistically different than those for cisplatin patients for cycles 3 through 6. Cycle 3 LS mean, (model-based mean from the repeated measures analysis) was -3.51 for Alimta/cisplatin and -3.27 for cisplatin; p=0.005. Cycle 6 LSMean was -1.23 for ALIMTA/cisplatin and 5.8 for cisplatin (p= 0.009). Pulmonary function tests were used to provide objective measures of lung function. Results for slow vital capacity (SVC), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) in absolute and percentage of predicted normal were assessed at baseline and repeated up to Cycle 6 for each treatment arm. For each parameter (SVC, FVC, and FEV1), lung volumes in the ALIMTA/cisplatin arm at Cycle 6 were higher than the cisplatin alone arm throughout treatment period. Similar results were seen when analyzed as changes from baseline. Averaging over the entire treatment period, the ALIMTA/cisplatin arm had statistically significantly greater pulmonary function for all three parameters [SVC (p= 0.001), FVC (p= 0.002), and FEV1 (p < 0.001)].

Non-Small Cell Lung Cancer (NSCLC): ALIMTA/Cisplatin versus Gemcitabine/Cisplatin

Study Demographics and Trial Design

Table 14Patient Demographics - Clinical Trial Supporting Efficacy of ALIMTA/Cisplatin versus Gemcitabine/Cisplatin in the Treatment of NSCLC

:

Approval of ALIMTA in combination with cisplatin in first line NSCLC is based on a single non-inferiority trial. A multi-center, randomized, Phase 3 study in 1725 chemonaive patients with NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin administered intravenously at a dose of 75 mg/m2 after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after administration of gemcitabine, on Day 1 of each 21-day cycle. Patients in both treatment arms received folic acid, vitamin B12, and dexamethasone. The study was designed to show non-inferiority of survival of ALIMTA and cisplatin to gemcitabine and cisplatin. Patient demographics of the intent to treat (ITT) population are shown in Table 15. The demographics and disease characteristics were well balanced. All patients had a good performance status of ECOG 0 or 1. The results of the protocol qualified (PQ) population analysis (N = 1666) were consistent with those of the ITT population analysis.

Table 15: Summary of Patient Characteristics

Abbreviations: ECOG PS = Eastern Cooperative Oncology Group performance status; N = number of patients

enrolled; n = number of patients in groups.

1. Smoking history was not recorded for all treated patients. Percentages are representative of N=757 for the ALIMTA plus cisplatin arm and N=759 for the gemcitabine plus cisplatin arm.

2. ECOG PS was not reported for all treated patients. Percentages are representative of N=861 for the ALIMTA plus cisplatin arm, and N=861 for the gemcitabine plus cisplatin arm.

Treatment was administered up to a total of 6 cycles of therapy as per study protocol. A median of 5 cycles of treatment was administered on both treatment arms. Patients treated with ALIMTA plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

Study Results

The primary endpoint of noninferior overall survival was met for ALIMTA plus cisplatin compared to gemcitabine plus cisplatin in the intent-to-treat (ITT) study population. The median survival time was 10.3 months in both treatment arms, with an adjusted hazard ratio of 0.94 (95% confidence interval 0.84 - 1.05), based on a noninferiority margin of 1.17647. This margin was derived from a single study (Sandler 2000). Progression-free survival (PFS) and objective response rate (ORR) were similar between treatment arms. Table 16 summarizes the study results in the overall study population.

Table 16: Efficacy of ALIMTA plus Cisplatin versus Gemcitabine plus Cisplatin in First-line Non-Small Cell Lung Cancer - ITT Population

Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent to treat; n = total population size.

1. Adjusted for gender, stage, basis of diagnosis, and performance status.

2. A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm.

3. Statistically significant for non-inferiority.

4. Number of qualified patients on the AC arm (N=762) and GC arm (N=755).

Figure 2 displays the Kaplan-Meier survival curve for the ITT population.

Survival Probability

Median (95% CI)

AC 10.3 (9.8, 11.2)

GC 10.3 (9.6, 10.9)

AC vs GC Adjusted HR (95% CI)

0.94 (0.84, 1.05)

0.6

0.5

0.4

0.3

0.2

0.1

0 6 12 18 24 30

Figure 2: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in Non-Small Cell Lung Cancer - ITT Population

Subsets of patients were examined in planned secondary analyses. The results of these analyses are shown in Figure 3.

Figure 3: Forest Plot for Overall Survival Adjusted Hazard Ratios of Subgroups ALIMTA + Cisplatin versus Gemcitabine + Cisplatin in First-line Non-Small Cell Lung Cancer - ITT Population

The effect of ALIMTA plus cisplatin on survival was similar regardless of age, gender, ethnic origin, smoking status, and performance status (0 or 1). A prespecified subgroup analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant differences in survival according to histology (see Table 17 below). In the subgroup analysis of patients with squamous cell histology, ALIMTA plus cisplatin was not shown to be non-inferior to the comparator, suggesting it may not be effective in patients with squamous cell histology NSCLC (see INDICATIONS AND CLINICAL USE).

Table 17: Overall Survival of ALIMTA plus Cisplatin versus Gemcitabine plus Cisplatin in Non-Small Cell Lung Cancer - Histologic Subgroups, ITT Population

1. HR was based on unadjusted analyses. A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm.

2. Log rank p <0.05 unadjusted for multiple comparisons.

Figure 4 displays the Kaplan-Meier curves for histology subgroups (adenocarcinoma and squamous cell carcinoma) in the ITT population.

Figure 4: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in First-line Non-Small Cell Lung Cancer - Histology Subgroups: Adenocarcinoma and Squamous Cell Carcinoma, ITT Population

No formal Quality of Life assessment was conducted during the trial. Patients treated with ALIMTA and cisplatin required fewer transfusions (16.4% versus 28.9%), red blood cell transfusions (16.1% versus 27.3%) and platelet transfusions (1.8% versus 4.5%). Patients also required lower administration of erythropoietin/darbopoietin (10.4% versus 18.1%), G-CSF/GM- CSF (3.1% versus 6.1%), and iron preparations (4.3% versus 7.0%). The incidence of hospitalization for a drug-related adverse event was 17.9% for patients treated with ALIMTA/cisplatin versus 16.9% for patients treated with gemcitabine/cisplatin.

Non-Small Cell Lung Cancer (NSCLC): ALIMTA versus Docetaxel

Study Demographics and Trial Design

Table 18Patient Demographics - Clinical Trial Supporting Efficacy of ALIMTA versus Docetaxel in the Treatment of NSCLC

:

A single, Phase 3 multi-center, randomized, open label study was conducted to compare the safety and efficacy of ALIMTA to docetaxel in patients with locally advanced or metastatic (Stage III or IV) NSCLC after prior chemotherapy. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and vitamin B12. A summary of the patient demographics and characteristics are shown in Tables 18 and 19, respectively.

Table 19: Summary of Patient Characteristics

Abbreviations: CR = complete response; ECOG = Eastern Cooperative Oncology Group; ITT = intent to treat; N = number of patients; PR = partial response; PS = performance status.

a

Performance status was not reported for all treated patients. Percentages are representative of N=264 for the ALIMTA and N=274 for the docetaxel arm.

Baseline demographic and disease characteristics were similar between the two treatment arms. Approximately three-quarters of the patients were men, reflecting the gender ratio of this disease observed in the general population. The median age of 58 years with a wide age range (22 to 87 years) corresponds with the expected demographics of the general NSCLC patient population. Approximately half of the patients had adenocarcinoma, and approximately 30% had squamous cell carcinoma. About three-quarters of patients presented with Stage IV disease at study entry, as would be expected for patients who experienced a relapse of a previously treated disease. Eighty-eight percent had good performance status. Approximately 90% of the patients had received prior platinum-containing regimens. Table 20 presents a summary of reported prior therapies for the intent to treat (ITT) population. The two treatment arms were well balanced with respect to all prior therapy categories.

Table 20: Summary of Reported Prior Therapies

Abbreviations: n = number of patients who received specified prior therapy; N = number of intent to treat (ITT) patients

Study Results

The primary endpoint was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99. The study did not achieve overall survival superiority of ALIMTA over docetaxel. Non-inferiority of ALIMTA to docetaxel could not be demonstrated because a reliable and consistent survival effect of docetaxel required for a non-inferiority analyses could not be estimated from historical trials. However, the similarity of the response rate, median survival rate and 1-year survival rate between ALIMTA and docetaxel was sufficient evidence to consider ALIMTA as a treatment option for patients with NSCLC after prior chemotherapy. See Table 21.

Table 21: Efficacy of ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer

Abbreviations: CI = confidence interval; HR = hazard ratio; N = number of intent to treat (ITT) patients

Number of qualified patients on the ALIMTA arm (N=264) and docetaxel arm (N=274).

Figure 5 displays the Kaplan-Meier (K-M) survival time graph for the ITT population. Graphs of survival distributions for ALIMTA and docetaxel arms are superimposable.

Survival Distribution Function

D o cet a x e l

M e d ia n S u r v iv a l: 7 .9 m o s

P e r c e n t r e ta in e d : 1 0 2 % 95% C I: ( 5 2% , 157 % )

N oni nf e r i o r i t y p- v a l u e : 0 .0 4 7

AL I M T A

M e dia n S u r v i v a l : 8.3 m o s

0 3 6 9 12 15 18 21 24 27 30

Survival Time(Months)

Alimta Docetaxel

Figure 5: Kaplan-Meier Estimates of Survival Time for ALIMTA versus Docetaxel.

There were no significant differences in the results of the secondary endpoints between patients on the ALIMTA arm and docetaxel arm. See Table 22.

Table 22: Secondary Efficacy Endpoints - ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer

Progression-free Survival (months)

ALIMTA Docetaxel

No. of patients evaluated Median

2.9

2.9

HR (95% CI) 0.97 (0.82-1.16)

Wald p-value 0.759

Time to Progressive Disease (months)

No. of patients evaluated Median

3.4

3.5

HR (95% CI) 0.97 (0.80-1.17)

Wald p-value 0.721

Time to Treatment Failure (months)

No. of patients evaluated Median

2.3

2.1

HR (95% CI) 0.84 (0.71-0.997)

Time to Tumour Response (months)

Duration of Clinical Response (months)

No. of patients evaluated Median

4.6

5.3

HR (95% CI) 0.77 (0.40-1.47)

Wald p-value 0.427

Duration of Clinical Benefit (months)

No. of patients evaluated Median

5.4

5.2

HR (95% CI) 0.91 (0.71-1.16)

Wald p-value 0.450

No differences were identified between the two treatment arms in any of the patient Lung Cancer Symptom Scales (LCSS). Both treatment arms reported initial increases in average symptom burden index, symptom distress, and interference with activity level that subsequently stabilized. Both arms reported initial deterioration in global quality of life and total LCSS, which subsequently stabilized.

DETAILED PHARMACOLOGY

Pharmacodynamics:

Preclinical studies have shown that pemetrexed inhibited, although with different potency (Table 23) the in vitro growth of multiple cell lines, including mesothelioma (MSTO-211H, NCI-H2052), non-small cell lung (A549, LX-1), breast (MCF7, ZR-75-1), colorectal (GC3, HT8, WiDr), leukemia (CCRF-CEM, L1210), and ovarian (IGROV1, SKOV3) carcinomas, as well as cells of these tumor types derived from fresh patient specimens. Additionally, these in vitro studies have shown that in certain cell lines, additive or greater than additive growth inhibitory activity could possibly be obtained when pemetrexed was optimally combined with radiation (WiDr colon, MCF7 breast, HeLa cervix, and LX1 lung carcinomas) as well as other antineoplastic agents, such as cisplatin (NCI-H23 and NCI-H460 lung carcinoma), carboplatin (NCI-H23 lung, SKOV3 ovarian, HT29 colorectal carcinomas), oxaliplatin (HT29 colon carcinoma), doxorubicin (ZR-75-1 breast carcinoma), gemcitabine (HCT8 and HT29 colorectal carcinoma), docetaxel and paclitaxel (NCI-H460 lung carcinoma). In particular, studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin. However, the ratios pemetrexed/cisplatin used in these experiments were different than the ratio used in humans. In vitro studies have also suggested that pemetrexed may be active against certain tumor cells that are resistant to methotrexate, 5-fluorouracil, and raltitrexed. Additionally, preclinical animal studies have suggested that folic acid can reduce the severity of the drug-induced toxicity with preservation of the antitumor activity of pemetrexed on several cell lines. Furthermore, folic acid and vitamin B12 were shown not to have negative impact on the antitumor activity of pemetrexed in mice. However, no studies of this type have been done on mesothelioma bearing animals.

Table 23: IC50 Values of Pemetrexed for Representative Tumor Cell Lines

Tumor Typea IC

(nM)

Mesothelioma MSTO-211H 30

Mesothelioma NCI-H2052 209

NSCLC LX-1 4

NSCLS A549 156

CCRF CEM leukemia 23 to 54

L1210 murine leukemia 14

Colon carcinoma GC3 34

Colon carcinoma HCT8 220

Breast carcinoma MCF7 8.1 to 31

Breast carcinoma ZR-75-1 110

Ovarian carcinoma IGROV-1 44

a

Examples included here are for commonly available cell lines that have not undergone drug selection or been subjected to genetic alterations.

Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to non-vitamin-supplemented patients were characterized using a population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, is influenced primarily by the magnitude of systemic exposure (AUC). A 5- to 6-fold increase in pemetrexed AUC produces a 5- to 6-fold lowering of the ANC nadir. Though less pronounced than AUC, increased cystathionine or homocysteine concentrations correlate with a lowering of the ANC nadir, supporting the use of vitamin supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. Time to ANC nadir also correlates with pemetrexed systemic exposure (AUC), and varied from 8 to 9.6 days after pemetrexed administration over a range of exposures from 38.3 to 316.8 ug *hr/mL. Return to baseline ANC occurs from 4.2 to 7.5 days following the nadir over the same range of exposures.

TOXICOLOGY

ALIMTA (pemetrexed disodium) has been evaluated in a comprehensive series of toxicology studies (see Table 24).

Table 24: Toxicology Program for Pemetrexed Disodium

Study Type and Duration Route of Administration

Species

Single-dose toxicity Intravenous Mouse, rat, dog Repeat-dose toxicity

2-weeks (daily) Intraperitoneal Mouse 6-weeks (daily, twice/week, once/week) Intraperitoneal Mouse 6-month (once/week) Intraperitoneal

Mouse

2-weeks (daily; twice/week) Intravenous Dog

6-weeks (daily, twice/week, once/week) Intravenous Dog

1-month (once/week), 3 weeks reversibility Intravenous Dog

9-month (once every 3 weeks) Intravenous Dog Genotoxicity

Reproductive and Developmental Toxicity

Other Toxicity Studies

Intravenous dosing is the route of administration in humans. All toxicology studies in dogs were conducted by intravenous administration of pemetrexed. The intraperitoneal route was used to assess its repeat-dose toxicity in mice. Pharmacokinetic studies indicated that pemetrexed was rapidly absorbed when administered by the intraperitoneal route, with overall pharmacokinetic profile comparable to the intravenous route. The route of administration of pemetrexed was changed from intraperitoneal to intravenous in the developmental toxicity study in mice to avoid potential damage to the pregnant uterus by the injection needle. Single-dose toxicity studies with pemetrexed have been performed in mice rats and dogs by the intravenous route of administration. Pemetrexed demonstrated low acute toxicity in mice at the dose of 4722 mg/m2, and in male rats, the MLD was 7922 mg/m2. Dogs' MLD was not determined. The toxicologic profile of pemetrexed following repeat dosing in dogs and mice is consistent with the known antiproliferative activities of folate antimetabolites. Lesions of mucositis, enteropathy, lymphoid and bone marrow hypocellularity, and effects on spermatogenesis are commonly encountered with folate antimetabolites and other oncolytic agents. The major pathologic effects associated with pemetrexed administration occurred in the intestinal tract and lymphoid tissues; the bone marrow was only minimally affected in dogs and mice given repeated doses up to 6 weeks. However, hematotoxicity was the dose-limiting effect in dogs treated for longer than 6 weeks. Clinical manifestations of toxicity were delayed approximately l week from the time of dose administration, with individual animal variability in response to the compound. Modest signs of toxicity were generally reversible with supportive care and interruption of pemetrexed treatment. Supportive care included parenteral fluid therapy, nutritional supplementation, and antibiotics, when clinically appropriate. Dogs were more sensitive to the toxic effects of pemetrexed than mice. This finding was expected, as mice have a "self-rescue" mechanism in a circulating thymidine moiety that can serve as a replacement source in folate-antagonized cells. Additionally, dogs are generally more predictive of systemic toxicity in man than are mice. Mice tolerated daily doses of 26.2 mg/kg (78.6 mg/m2) for 6 weeks and 700 mg/kg once weekly for 6 months without any compound- related deaths or clinical signs of toxicity. Most dogs (5 of 6) completed 6 weeks of daily doses of 0.11 mg/kg (2.2 mg/m2) with minimal clinicopathologic effects. The 1 dog that failed to complete the treatment period had become progressively anorectic, which accentuated the inherent toxicity of the folate antagonism. Higher daily doses were not tolerated for more than 3 weeks. Prominent toxicity was generally more evident in the daily dose schedule, even though the weekly dose was a much larger total dose of pemetrexed. The maximum tolerated dose (MTD) for mice given pemetrexed once weekly for 6 weeks was 314.8 mg/kg (944.4 mg/m2). The minimally toxic dose for dogs following four doses of pemetrexed given once per week was 25 mg/kg (500 mg/m2). Four doses of pemetrexed (25 mg/kg) given once per week caused slight-to-moderate decreases in neutrophils, lymphocytes, platelets, and reticulocytes. Primary histopathologic observation was minimal-to-slight enteropathy throughout the gastrointestinal tract. All changes except for the decreased platelet count fully or partially reversed within the 3- week recovery period. A 6-month repeat dose study in beagle dog was designed to evaluate the chronic toxicity of pemetrexed at doses of 0, 10, or 25 mg/kg (0, 200, or 500 mg/m2) given intravenously once per week, which bridges directly to the 1-month study described above. However, after approximately 3 months, the dosing frequency was changed to once every 3 weeks for the dogs in the 10-mg/kg group and dosing was discontinued for the 25-mg/kg group due to hematotoxicity. Therefore, hematotoxicity was the dose-limiting effect in this study, and weekly administration of 10 or 25 mg/kg exceeded a tolerated dose. Hematotoxicity was reversible as demonstrated during a 3-month drug holiday in the dogs that had been given 25 mg/kg. Further, even when the10-mg/kg group reached critically low platelet and neutrophil levels, a 3-week period without treatment was sufficient for hematology parameters to completely recover. An additional chronic study was conducted in which dogs were given pemetrexed intravenously at doses of 0, 10, or 25 mg/kg (0, 200, or 500 mg/m2) once every 3 weeks for 9 months. The observed effects were similar to those in the 6-month repeat-dose study in dogs, however, the hematotoxicity was not as severe due to the change in dosing regimen from once a week in the 6- month study to once every 3 weeks in the 9-month study. Additional changes observed in the 9- month study included decreased testes weight with degeneration/necrosis of the seminiferous epithelium and minimal-to-slight renal tubular karyomegaly and degeneration with no organ weight or clinical pathology correlates. This was observed in male dogs only. The effects on the testes, although not seen in previous studies (possibly due to the age of the dogs), were not unexpected based on the effects in the mouse and the cytotoxic nature of pemetrexed. Pemetrexed was positive in an in vivo mouse micronucleus assay. This finding was not unexpected with a compound that causes accumulation of deoxyuridine monophosphate through the inhibition of thymidylate synthase. Therefore, pemetrexed may be a potential clastogenic hazard for man. Administration of pemetrexed to pregnant mice resulted in decreased fetal weight at doses >=0.6 mg/m2, incomplete ossification of some skeletal structures at doses >=3 mg/m2, and cleft palate at 15 mg/m2. These observations were not unexpected findings for this class of compound (folic acid antimetabolite) and were consistent with previously reported findings with folic acid antagonists and folic acid deficiency. Administration of pemetrexed at doses of 0.3 to 30 mg/m2 resulted in male reproductive toxicity characterized by slightly reduced fertility rates and testicular atrophy and epididymal hypospermia. Two studies were conducted to evaluate potential rescue agents (leucovorin and thymidine) for treatment of severe toxicity due to pemetrexed administration. 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