Trial Design

About GEMZAR
GEMZAR is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

See the GEMZAR (gemcitabine HCl for injection) Prescribing Information and Important Safety Information.

Indications for ALIMTA

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 indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

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.

Limitations of Use
ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

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.

Important Safety Information for ALIMTA

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

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

Warnings and Precautions
Patients must be instructed to take folic acid and vitamin B₁₂ with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. 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.

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). 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 toxicities.

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm³ and the platelet count is ≥100,000 cells/mm³ and creatinine clearance is ≥45 mL/min.

Pregnancy Category D — ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

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.

Drug Interactions
Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations
It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

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

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines
Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA.

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. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) for ALIMTA in 1st-line NSCLC
The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

Abbreviated Adverse Reactions (% incidence) for ALIMTA in Maintenance NSCLC
The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for ALIMTA in 2nd-line NSCLC
The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

Abbreviated Adverse Reactions (% incidence) for ALIMTA in MPM
The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, for the treatment of patients with malignant pleural mesothelioma (MPM) were neutropenia (23 vs 3); leukopenia (15 vs 1); thrombocytopenia (5 vs 0); anemia (4 vs 0); nausea (12 vs 6); vomiting (11 vs 4); fatigue (10 vs 9); creatinine elevation (1 vs 1); and creatinine clearance decrease (1 vs 2). Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, were neutropenia (56 vs 13); leukopenia (53 vs 17); anemia (26 vs 10); thrombocytopenia (23 vs 9); nausea (82 vs 77); vomiting (57 vs 50); fatigue (48 vs 42); and stomatitis/pharyngitis (23 vs 6).

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information.

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Indication for GEMZAR

GEMZAR is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

Important Safety Information for GEMZAR

Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

Contraindication
Known hypersensitivity to GEMZAR.

Warnings
Infusion times of GEMZAR longer than 60 minutes and more frequent than weekly dosing have been shown to increase toxicity.

Pulmonary toxicity has been reported. In cases of severe lung toxicity, GEMZAR therapy should be discontinued immediately and appropriate supportive care measures instituted.

Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of GEMZAR. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs.

GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman.

Precautions
Use caution in patients with pre-existing renal impairment or hepatic insufficiency. Administration of GEMZAR may exacerbate underlying hepatic insufficiency.

The optimum regimen for safe administration of GEMZAR with therapeutic doses of radiation has not yet been determined in all tumor types. GEMZAR has radiosensitizing activity and radiation recall reactions have been reported.

It is not known whether GEMZAR or its metabolites are excreted in human milk.

The effectiveness of GEMZAR in pediatric patients has not been demonstrated.

The toxicities of GEMZAR observed in pediatric patients were similar to those reported in adults.

GEMZAR clearance is affected by age as well as gender.

Patients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

Monitoring and Dosage Modifications
Dosage adjustments for hematologic toxicity may be required.

Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin.

Patients should be assessed with a CBC, including differential and platelet count, prior to each dose of GEMZAR. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Hepatic and renal function (including transaminases and serum creatinine) should be evaluated prior to therapy with GEMZAR and periodically thereafter.

Abbreviated Adverse Events (% incidence) for GEMZAR in 1st-line NSCLC
The most severe adverse events (Grades 3/4) with GEMZAR plus cisplatin for the first-line treatment of patients with NSCLC in comparative trials of a 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and a 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were neutropenia (57 vs 4, 64 vs 76); thrombocytopenia (50 vs 4, 55 vs 13); leukopenia (46 vs 3, 29 vs 43); anemia (25 vs 7, 22 vs 15); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); nausea/vomiting 21d (39 vs 26); neuromotor 28d (12 vs 3); hypomagnesemia 28d (7 vs 2); neurohearing 28d (6 vs 6); creatinine elevation 28d (5 vs 3); and dyspnea (7 vs 5, 1 vs 0). The most common adverse events (all Grades) of the 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and the 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were anemia (89 vs 67, 88 vs 77); leukopenia (82 vs 25, 86 vs 87); neutropenia (79 vs 20, 88 vs 87); thrombocytopenia (85 vs 13, 81 vs 45); lymphocytopenia 28d (75 vs 51); hematuria (15 vs 13, 22 vs 10); creatinine 28d (38 vs 31); hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); neuromotor 28d (35 vs 15); constipation (28 vs 21, 17 vs 15); neurohearing 28d (25 vs 21); paresthesias 21d (38 vs 16); and infection (18 vs 12, 28 vs 21).

For safety and dosing guidelines, see complete Warnings, Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information.

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