Indications and Important Safety Information for ALIMTA

Indications

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

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 and Important Safety Information for GEMZAR^® (gemcitabine HCl for injection)

Indication

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

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

Contraindication

Known hypersensitivity to GEMZAR.

Warnings and Precautions

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

Infusions of GEMZAR longer than 60 minutes or dosing more frequently than once weekly have been shown to increase toxicity.

GEMZAR can suppress bone marrow function, as manifested by leukopenia, thrombocytopenia, and anemia. Patients should be monitored for myelosuppression during therapy including a complete blood count with differential prior to each dose.

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

Monitor renal and hepatic function prior to initiation of GEMZAR therapy and periodically thereafter. Use GEMZAR with caution in patients with renal impairment or hepatic impairment. 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 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 in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs. Discontinue GEMZAR for HUS, or severe renal or hepatic toxicity.

GEMZAR can cause fetal harm. Advise women of potential risk to the fetus.

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

Abbreviated Adverse Reactions (% incidence)

The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) 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); lymphocytopenia 28d (43 vs 17); anemia (25 vs 7, 22 vs 15); nausea/vomiting 21d (39 vs 26); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); alopecia 21d (13 vs 51); neuromotor 28d (12 vs 3); dyspnea (7 vs 5, 1 vs 0); hypomagnesemia 28d (7 vs 2); neurohearing 28d (6 vs 6); creatinine elevation 28d (5 vs 3); and infection (5 vs 1, 4 vs 8).

The most common adverse reactions (all grades, with incidence of 20% or greater) 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); neutropenia (79 vs 20, 88 vs 87); leukopenia (82 vs 25, 86 vs 87); thrombocytopenia (85 vs 13, 81 vs 45); lymphocytopenia 28d (75 vs 51); RBC transfusion (39 vs 13, 29 vs 21); platelet transfusions (21 vs 1, 3 vs 8); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); creatinine elevation (38 vs 31, 2 vs 2); paresthesias 21d (38 vs 16); neuromotor 28d (35 vs 15); hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); infection (18 vs 12, 28 vs 21); neurohearing 28d (25 vs 21); diarrhea (24 vs 13, 14 vs 13); proteinuria (23 vs 18, 12 vs 5); neurosensory 28d (23 vs 18); hematuria (15 vs 13, 22 vs 10); hepatic transaminase 28d (22 vs 10); and stomatitis (14 vs 5, 20 vs 18).

Use in Specific Populations

GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, GEMZAR is expected to result in adverse reproductive effects. It is not known whether GEMZAR is excreted in human milk.

The safety and efficacy of GEMZAR in pediatric patients has not been established.

Use caution in patients with preexisting renal impairment or hepatic insufficiency. Administration of GEMZAR may exacerbate underlying hepatic insufficiency.

GEMZAR clearance is affected by age as well as gender.

Dose Modifications and Administration Guidelines

GEMZAR is for intravenous use only. Dosage adjustments for hematologic toxicity may be required. Dose modifications may be considered for severe nonhematologic toxicity. Modify or suspend therapy according to the Dosage and Administration guidelines in the full Prescribing Information.

Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin. See the manufacturers’ prescribing information for more information on any drug indicated in combination with GEMZAR.

Please see the full Prescribing Information for Patient Counseling Information on low blood cell counts and the use of GEMZAR in pregnant and nursing women.

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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