Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H­pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C₂₀H₁₉N₅Na₂O₆•7H₂O and a molecular weight of 597.49. The structural formula is as follows:

ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

Last updated on RxList: 10/27/2008

Non-Small Cell Lung Cancer — Combination with Cisplatin

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

Non-Small Cell Lung Cancer — Single-Agent

ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. ALIMTA is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

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.

Combination Use with Cisplatin

Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma

The recommended dose of ALIMTA is 500 mg/m² administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information.

Single-Agent Use

Non-Small Cell Lung Cancer

The recommended dose of ALIMTA is 500 mg/m² administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

Premedication Regimen

Vitamin Supplementation

To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B₁₂ during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B₁₂ injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B₁₂ was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see WARNINGS AND PRECAUTIONS].

Corticosteroid

Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see WARNINGS AND PRECAUTIONS].

Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations

Monitoring

Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥ 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].

Dose Reduction Recommendations

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥ Grade 3, treatment should be withheld until resolution to less than or equal to the patient's be resumed according to guidelines in Table 2.pre-therapy value.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicities^a,b

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

Discontinuation Recommendation

ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients

In clinical studies, patients with creatinine clearance ≥ 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]. 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:

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

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 References].

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

1. Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.
2. Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount.
3. Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
5. An appropriate quantity of the reconstituted ALIMTA solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 ml. ALIMTA is administered as an intravenous infusion over 10 minutes.
6. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature [see USP Controlled Room Temperature] and lighting. When prepared as directed, reconstitution and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard any unused portion.

Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not and diluents has not been studied, and therefore is not recommended. ALIMTA is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.

Dosage Forms And Strengths

ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

ALIMTA, pemetrexed for injection is available in sterile single-use vials containing 100 mg pemetrexed.

NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.

ALIMTA, pemetrexed for injection is available in sterile single-use vials containing 500 mg pemetrexed.

NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.

Storage and Handling

ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Roo m Temperature]. When prepared as directed, reconstituted and infusion solutions of

ALIMT A contain no antimicrobial preservatives. Discard unused portion.

ALIMTA is not light sensitive.

Eli Lilly and Company Indianapolis, IN 46285, USA. www.ALIMTA.com. FDA rev date: 9/26/2008

Last updated on RxList: 10/27/2008

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥ 20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥ 20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) — Combination with Cisplatin

Table 4 provides the frequency and severity of adverse reactions that have been reported in > 5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B₁₂.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLC^a

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 Lung Cancer (NSCLC) — Single-Agent

Table 5 provides the frequency and severity of adverse reactions that have been reported in > 5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B₁₂ supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 5: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLC^a

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in < 5% of patients that received ALIMTA treatment but > 5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA.

Incidence 1% to 5%

Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection

Dermatology/Skin — erythema multiforme

Neurology — motor neuropathy, sensory neuropathy

Renal — increased creatinine

Incidence Less than 1%

Cardiovascular — supraventricular arrhythmias

Malignant Pleural Mesothelioma (MPM)

Table 6 provides the frequency and severity of adverse reactions that have been reported in > 5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B₁₂.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPM^a

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%

Body as a Whole — febrile neutropenia, infection, pyrexia

Dermatology/Skin — urticaria

General Disorders — chest pain

Metabolism and Nutrition — increased AST, increased ALT, increased GGT

Renal — renal failure

Incidence Less than 1%

Cardiovascular — arrhythmia

Neurology — motor neuropathy

Effects of Vitamin Supplementations

Table 7 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B₁₂from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 7: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence)

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Phase 2 Studies

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single-agent ALIMTA studies (N=164) and the Phase 3 single-agent ALIMTA study described above, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine transaminase elevation (15.2% versus 1.9%, respectively). These differences were likely due to differences in the patient population, since the Phase 2 studies included chemonaive and heavily pretreated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal — colitis

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory— interstitial pneumonitis.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Ibuprofen

Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥ 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) [see CLINICAL PHARMACOLOGY].

Other NSAIDs

Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.

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

Nephrotoxic Drugs

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

Last updated on RxList: 10/27/2008

Included as part of the PRECAUTIONS section.

Premedication Regimen

Need for Folate and Vitamin B₁₂ Supplementation

Patients treated with ALIMTA must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce

treatment-related hematologic and GI toxicity [see DOSAGE AND ADMINISTRATION] . In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B₁₂ was administered.

Corticosteroid Supplementation

Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see DOSAGE AND ADMINISTRATION].

Bone Marrow Suppression

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see ADVERSE REACTIONS]; 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].

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] .

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B₁₂ died of drug-related toxicity following administration of ALIMTA alone.

Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see DRUG INTERACTIONS].

Required Laboratory Monitoring

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 [see DOSAGE AND ADMINISTRATION] .

Pregnancy Category D

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. [see Pregnancy]

Third Space Fluid

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.

Patient counseling Information

See FDA-Approved Patient Labeling

Need for Folic Acid and Vitamin B₁₂

Patients treated with AL IMTA must be instructed to take folic acid and vitamin B₁₂ as a prophy lactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see DOSAGE AND ADMINISTRATION].

Low Blood Cell C ounts

Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

Gastrointestinal Effects

Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

Concomitant Medications

Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see DRUG INTERACTIONS].

FDA Approved Patient Labeling

Patients should be instructed to read the patient package insert carefully.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Use In Specific Populations

Pregnancy

Teratogenic Effects — Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m² basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

Nursing Mothers

It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use

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

Geriatric Use

ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see DOSAGE AND ADMINISTRATION].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥ 65 years and Grade 3/4 neutropenia was greater as compared to patients < 65 years (19.9% versus 12.2%). For patients < 65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥ 65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent to treat population.

In the previously treated non-small cell lung cancer trial, 29.7% patients treated with ALIMTA were ≥ 65 years and Grade 3/4 hypertension was greater as compared to patients < 65 years. For patients < 65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥ 65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent to treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ≥ 65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients < 65 years. For patients < 65 years, the HR for overall survival was 0.71(95% CI: 0.53, 0.96) and for patients ≥ 65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent to treat population.

Patients with Hepatic Impairment

There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see CLINICAL PHARMACOLOGY].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see DOSAGE AND ADMINISTRATION].

Patients with Renal Impairment

ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

Gender

In the previously untreated non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10 and for females the HR was 0.86 (95% CI: 0.70, 1.06 in the intent to treat population.

In the previously treated non-small cell lung cancer trial, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent to treat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent to treat population.

Race

In the previously untreated non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent to treat population.

In the previously treated non-small cell lung cancer trial, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent to treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent to treat population.

Last updated on RxList: 10/27/2008

There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥ 3 days, CTC Grade 4 neutropenia lasting ≥ 3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m², intravenously once, followed by leucovorin, 50 mg/m², intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Last updated on RxList: 10/27/2008

Mechanism of Action

ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier, membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Pharmacodynamics

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.

Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and vitamin B₁₂ supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. Thelevels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

Pharmacokinetics

Absorption

The pharmacokinetics of ALIMTA administered as a single-agent in doses ranging from 0.2 to 838 mg/m² infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.

Distribution

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

Metabolism and Excretion

Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).

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

Effect of Age

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

Effect of Gender

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

Effect of 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.

Effect of Hepatic Insufficiency

There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted [see DOSAGE AND ADMINISTRATION and Use in Specific Populations] .

Effect of Renal Insufficiency

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

Pediatric

Pediatric patients were not included in clinical trials.

Effect of Ibuprofen

Ibuprofen doses of 400 mg four times a day reduce pemetrexed's patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see DRUG INTERACTIONS].

Effect of Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.

Effect of Cisplatin

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Effect of Vitamins

Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Clinical Studies

Non-Small Cell Lung Cancer (NSCLC) — Combination with Cisplatin

A multi-center, randomized, open-label study in 1725 chemonaive patients with stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² with cisplatin administered intravenously at a dose of 75 mg/m² after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m² on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m² after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B₁₂, and dexamethasone [see DOSAGE AND ADMINISTRATION].

Patient demographics of the intent to treat (ITT) population are shown in Table 8. The demographics and disease characteristics were well balanced.

Table 8: Summary of Patient Characteristics in Study of NSCLC — Combination with Cisplatin

Patients received a median of 5 cycles of treatment in both study arms. Patients treated with ALIMTA plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the ALIMTA plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.

Table 9: Efficacy of ALIMTA plus Cisplatin versus Gemcitabine plus Cisplatin in First-line NSCLC — ITT Population

Figure 1: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC — ITT Population

A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 10. This difference in treatment effect for ALIMTA based on histology was also observed in the single-agent, second-line study [see Clinical Studies].

Table 10: Overall Survival of ALIMTA plus Cisplatin versus Gemcitabine plus Cisplatin in NSCLC — Histologic Subgroups, ITT Population

Figure 2: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC — Nonsquamous NSCLC and Squamous Cell Carcinoma

Non-Small Cell Lung Cancer — Single-Agent Use

A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² and docetaxel was administered at 75 mg/m² as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and vitamin B₁₂. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 11.

Table 11: Summary of Patient Characteristics in NSCLC Study

The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 12). The study did not show an overall survival superiority of ALIMTA.

Table 12: Efficacy of ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer — ITT Population

A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 13. This difference in treatment effect for ALIMTA based on histology was also observed in the first-line combination study [see Clinical Studies].

Table 13: Overall Survival of ALIMTA versus Docetaxel in NSCLC — Histologic Subgroups, ITT Population

Malignant Pleural Mesothelioma

A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m² beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B₁₂ supplementation.

The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B₁₂ supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended [see DOSAGE AND ADMINISTRATION]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 14.

Table 14: Summary of Patient Characteristics in MPM Study

Table 15 summarizes the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.

Table 15: Efficacy of ALIMTA plus Cisplatin versus Cisplatin in Malignant Pleural Mesothelioma

Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.

Figure 3: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients.

Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are jnot universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response ra te for ALIMTA plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the ALIMTA plus cisplat in arm compared to the control arm.

Patients who received full supplementation with folic acid and vitamin B₁₂ during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received fo lic acid and vitamin B₁₂ during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.

REFERENCES

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Ale rt 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Dr ugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharma cists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last updated on RxList: 10/27/2008

ALIMTA®
(uh-LIM-tuh) (pemetrexed for injection)

Read the Patient Information that comes with ALIMTA before you start treatment and each time you get treated with ALIMTA. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about ALIMTA.

What is ALIMTA?

ALIMTA is a treatment for:

• Malignant pleural mesothelioma. This cancer affects the inside lining of the chest cavity. ALIMTA is given with cisplatin, another anti-cancer medicine (chemotherapy).
• Non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. If this is the first time you have been treated for your lung cancer, ALIMTA may be given with another anti-cancer drug called cisplatin. If you are being treated because your cancer has come back or you had trouble tolerating a prior treatment, ALIMTA may be given alone. Your doctor will speak to you about whether ALIMTA is appropriate for your specific type of non-small cell lung cancer.

To lower your chances of side effects of ALIMTA, you must also take folic acid and vitamin B₁₂ prior to and during your treatment with ALIMTA. Your doctor will prescribe a medicine called a "corticosteroid" to take for 3 days during your treatment with ALIMTA. Corticosteroid medicines lower your chances of getting skin reactions with ALIMTA. ALIMTA has not been studied in children.

What should I tell my doctor before taking ALIMTA?

Tell your doctor about all of your medical conditions, including if you:

• are pregnant or planning to become pregnant. ALIMTA may harm your unborn baby.
• are breastfeeding. It is not known if ALIMTA passes into breast milk. You should stop breastfeeding once you start treatment with ALIMTA.
• are taking other medicines, including prescription and nonprescription medicines, vitamins, and herbal supplements. ALIMTA and other medicines may affect each other causing serious side effects. Especially, tell your doctor if you are taking medicines called "nonsteroidal anti-inflammatory drugs" (NSAIDs) for pain or swelling. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

How is ALIMTA given?

• ALIMTA is slowly infused (injected) into a vein. The injection or infusion will last about 10 minutes. You will usually receive ALIMTA once every 21 days (3 weeks).
• If you are being treated with ALIMTA and cisplatin for the initial treatment of either mesothelioma or non-small cell lung cancer, ALIMTA will be given first as a 10 minute infusion into your vein and cisplatin (another anti-cancer drug) will also be given through your vein starting about 30 minutes after ALIMTA and ending about 2 hours later.
• If you are being treated because your non-small cell lung cancer has returned, you may receive ALIMTA alone, given as a 10 minute infusion into your vein.
• Your doctor will prescribe a medicine called a "corticosteroid" to take for 3 days during your treatment with ALIMTA. Corticosteroid medicines lower your chances for getting skin reactions with ALIMTA.
• It is very important to take folic acid and vitamin B₁₂ during your treatment with ALIMTA to lower your chances of harmful side effects. You must start taking 350-1000 micrograms of folic acid every day for at least 5 days out of the 7 days before your first dose of ALIMTA. You must keep taking folic acid every day during the time you are getting treatment with ALIMTA, and for 21 days after your last treatment. You can get folic acid vitamins over-the-counter. Folic acid is also found in many multivitamin pills. Ask your doctor or pharmacist for help if you are not sure how to choose a folic acid product. Your doctor will give you vitamin B₁₂ injections while you are getting treatment with ALIMTA. You will get your first vitamin B₁₂ injection during the week before your first dose of ALIMTA, and then about every 9 weeks during treatment.
• You will have regular blood tests before and during your treatment with ALIMTA. Your doctor may adjust your dose of ALIMTA or delay treatment based on the results of your blood tests and on your general condition.

What should I avoid while taking ALIMTA?

• Women who can become pregnant should not become pregnant during treatment with ALIMTA. ALIMTA may harm the unborn baby.
• Ask your doctor before taking medicines called NSAIDs. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

What are the possible side effects of ALIMTA?

Most patients taking ALIMTA will have side effects. Sometimes it is not always possible to tell whether ALIMTA, another medicine, or the cancer itself is causing these side effects. Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. These symptoms could mean you have an infection. The most common side effects of ALIMTA when given alone or in combination with cisplatin are:

• Stomach upset, including nausea, vomiting, and diarrhea. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms.
• Low blood cell counts:
  • Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appear pale, and become short of breath.
  • Low white blood cells. Low white blood cells may give you a greater chance for infection. If you have a fever (temperature above 100.4°F) or other signs of infection,
  • Low platelets. Low platelets give you a greater chance for bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with ALIMTA.
• Tiredness. You may feel tired or weak for a few days after your ALIMTA treatments. If you have severe weakness or tiredness, call your doctor.
• Mouth, throat, or lip sores (stomatitis, pharyngitis). You may get redness or sores in your mouth, throat, or on your lips. These symptoms may happen a few days after ALIMTA treatment. Talk with your doctor about proper mouth and throat care.
• Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.
• Rash.You may get a rash or itching during treatment. These usually appear between treatments with ALIMTA and usually go away before the next treatment. Call your doctor if you get a severe rash or itching.

Talk with your doctor, nurse or pharmacist about any side effect that bothers you or that doesn't go away.

These are not all the side effects of ALIMTA. For more information, ask your doctor, nurse or pharmacist.

General information about ALIMTA

Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. ALIMTA was prescribed for your medical condition.

This leaflet summarizes the most important information about ALIMTA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ALIMTA that is written for health professionals. You can also call 1-800-LILLY-RX (1-800-545-5979) or visit www.ALIMTA.com. Patient information revised September 26, 2008

Last updated on RxList: 10/27/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PEMETREXED - INJECTION

(peh-meh-TREX-ed)

COMMON BRAND NAME(S): Alimta

USES: Pemetrexed is used to treat certain types of cancer (e.g., lung cancer, mesothelioma). It is a chemotherapy drug that is used alone or in combination with other medications to slow or stop cancer cell growth.

HOW TO USE: This medication comes with a Patient Information Leaflet available from your pharmacist. Read it carefully before you start using pemetrexed. If you have any questions regarding the information, consult your doctor or pharmacist.

This medication is given by injection into a vein (IV) by a healthcare professional, usually over 10 minutes, once every 3 weeks. The dosage is based on your medical condition, body size, and response to therapy.

This medication should be mixed and diluted in the correct IV fluids. The mixed medication should be clear and colorless or yellow to yellow-green in color. Before using, check this medication visually for particles and discoloration. If either is present, do not use the liquid. If you have questions regarding the use of this medication, consult your pharmacist.

To lower your chance of side effects, it is very important that you take folic acid vitamins and receive vitamin B12 shots before and during treatment with pemetrexed. Folic acid vitamins are available over-the-counter without a prescription, and folic acid can be found in many multivitamin products. Make sure your vitamin contains between 350 to 1000 micrograms (0.35 to 1 milligram) of folic acid. Take folic acid daily for at least 5 out of the 7 days before your first dose of pemetrexed, during treatment, and for 3 weeks after your last treatment. Consult your doctor or pharmacist if you need help choosing a folic acid vitamin. Your doctor will give you a vitamin B12 shot into the muscle, usually 1 week before your first dose of pemetrexed and then once every 9 weeks during your treatment. Consult your doctor or pharmacist for more details.

To reduce your chance of having a skin reaction while using pemetrexed, your doctor will prescribe a corticosteroid medicine (e.g., dexamethasone) to take for a short period around the time of each treatment. Consult your doctor or pharmacist for more details.

If this medication touches your skin, wash the skin immediately and completely with soap and water.

SIDE EFFECTS: Nausea, vomiting, loss of appetite, constipation, diarrhea, mouth sores, headache, body aches/pains, dizziness, and tiredness may occur. Nausea and vomiting can be severe. In some cases, drug therapy may be needed to prevent or relieve nausea and vomiting. Not eating before your treatment may help relieve vomiting. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/pounding heartbeat, change in the amount of urine, dark urine, yellowing eyes/skin, severe stomach/abdominal pain, pain/redness/swelling of arms or legs, sore throat, painful/difficult swallowing, mental/mood changes, depression, numbness or tingling of the hands/feet, easy bruising/bleeding.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, new or worsening shortness of breath.

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills or persistent sore throat.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

Pemetrexed can commonly cause a rash that is usually not serious and that can be prevented by taking corticosteroid medication (see How to Use section). However, if you do develop a rash, you may not be able to tell it apart from a rare rash that could be a sign of a severe reaction. Therefore, seek immediate medical attention if you develop a rash.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking pemetrexed, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: decreased bone marrow function/blood cell disorders (e.g., anemia, leukopenia, thrombocytopenia), kidney problems, liver problems.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine.

Use caution with sharp objects like safety razors or nail cutters, and avoid activities such as contact sports to lower the chance of getting cut, bruised or injured.

Wash your hands well to prevent the spread of infections.

This drug may make you dizzy; use caution while engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This medication is not recommended for use during pregnancy. It may cause harm to an unborn baby. Consult your doctor for more details and to discuss reliable forms of birth control. It is recommended that men and women use two effective forms of birth control (e.g., condoms, birth control pills) while taking this medication and for some period afterwards.

It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: probenecid, nonsteroidal anti-inflammatory drugs (NSAIDs such as aspirin, ibuprofen, naproxen).

Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually these dosages are 81-325 milligrams per day), should be continued. Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts, kidney and liver function tests) should be performed to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best benefits, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Store unmixed medication vials at room temperature at 77 degrees F (25 degrees C). Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Once the medication is mixed in solution, use it within 24 hours.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.