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GEMCITABINE for injection USP, for intravenous
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use gemcitabine safely and effectively. See full prescribing information for gemcitabine.
GEMCITABINE for injection USP, for intravenous use
Initial U.S. Approval: 1996
RECENT MAJOR CHANGES
Dosage and Administration:
Dose Modifications for Non-Hematologic Adverse Reactions (2.5) 06/2014
Warnings and Precautions: Posterior Reversible Encephalopathy Syndrome (5.9) 06/2014
INDICATIONS AND USAGE
Gemcitabine for injection is a nucleoside metabolic inhibitor indicated:
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in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy (1.1)
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in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated (1.2)
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in combination with cisplatin for the treatment of non-small cell lung cancer (1.3)
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as a single agent for the treatment of pancreatic cancer (1.4)
DOSAGE AND ADMINISTRATION
Gemcitabine for injection is for intravenous use only.
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Ovarian Cancer: 1,000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1)
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Breast Cancer: 1,250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2)
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Non-Small Cell Lung Cancer: 1,000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1,250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3)
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Pancreatic Cancer: 1,000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle (2.4)
DOSAGE FORMS AND STRENGTHS
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200 mg/single-use vial (3)
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1 g/single-use vial (3)
CONTRAINDICATIONS
Patients with a known hypersensitivity to gemcitabine (4)
WARNINGS AND PRECAUTIONS
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Schedule-dependent toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. (5.1)
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Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2, 5.7)
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Pulmonary Toxicity and Respiratory Failure: Discontinue gemcitabine immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity. (5.3)
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Hemolytic-Uremic Syndrome (HUS): Monitor renal function prior to initiation and during therapy. Discontinue gemcitabine for HUS or severe renal impairment. (5.4)
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Hepatic Toxicity: Monitor hepatic function prior to initiation and during therapy. Discontinue gemcitabine for severe hepatic toxicity. (5.5)
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Embryofetal Toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)
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Exacerbation of Radiation Therapy Toxicity: May cause severe and life- threatening toxicity when administered during or within 7 days of radiation therapy. (5.7)
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Capillary Leak Syndrome: Discontinue gemcitabine. (5.8)
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Posterior reversible encephalopathy syndrome (PRES): Discontinue gemcitabine. (5.9)
ADVERSE REACTIONS
The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 5/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Ovarian Cancer
Gemcitabine for injection, USP in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.
1.2 Breast Cancer
Gemcitabine for injection, USP in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.
1.3 Non-Small Cell Lung Cancer
Gemcitabine for injection, USP 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.
1.4 Pancreatic Cancer
Gemcitabine for injection, USP is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine for injection is indicated for patients previously treated with 5-FU.
2 DOSAGE AND ADMINISTRATION
2.1 Ovarian Cancer
Recommended Dose and Schedule
The recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine for injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.
Dose Modifications
Recommended gemcitabine for injection, USP dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
2.2 Breast Cancer
Recommended Dose and Schedule
The recommended dose of gemcitabine for injection, USP is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before gemcitabine for injection administration.
Dose Modifications
Recommended dose modifications for gemcitabine for injection, USP for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
2.3 Non-Small Cell Lung Cancer
Recommended Dose and Schedule
Every 4-week schedule
The recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection, USP.
Every 3-week schedule
The recommended dose of gemcitabine for injection, USP is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection, USP.
Dose Modifications
Recommended dose modifications for gemcitabine for injection, USP myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine for injection, USP recommendations for non-hematologic adverse reactions.
2.4 Pancreatic Cancer
Recommended Dose and Schedule
The recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows:
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Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one week rest.
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After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.
Dose Modifications
Recommended dose modifications for gemcitabine for injection, USP for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Patients receiving gemcitabine for injection, USP should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.
2.5 Dose Modifications for Non-Hematologic Adverse Reactions
Permanently discontinue gemcitabine for injection, USP for any of the following:
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Unexplained dyspnea or other evidence of severe pulmonary toxicity
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Severe hepatic toxicity
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Hemolytic-uremic syndrome
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Capillary leak syndrome
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Posterior reversible encephalopathy syndrome
Withhold gemcitabine for injection, USP or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.
2.6 Preparation and Administration Precautions
Exercise caution and wear gloves when preparing gemcitabine for injection, USP solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine for injection, USP contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine for injection, USP go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
2.7 Preparation for Intravenous Infusion Administration
Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.
Add 5 mL to the 200 mg vial or 25 mL to the 1 g vial. These dilutions each yield a gemcitabine for injection, USP concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine for injection, USP. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.
Reconstituted gemcitabine for injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for injection solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not refrigerate as crystallization can occur.
No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
3 DOSAGE ORMS AND STRENGTHS
Gemcitabine for injection, USP is a white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine.
4 CONTRAINDICATIONS
Gemcitabine for injection, USP is contraindicated in patients with a known hypersensitivity to gemcitabine.
5 WARNINGS AND PRECAUTIONS
5.1 Schedule-dependent Toxicity
In clinical trials eva luating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)].
5.2 Myelosuppression
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with gemcitabine as a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent gemcitabine. The frequencies of Grade 3 to 4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving gemcitabine in combination with another drug.
5.3 Pulmonary Toxicity and Respiratory Failure
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine. Discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].
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