gemcitabine (as gemcitamine HCl) 200 MG Injection

Details

Generic Name: GEMCITABINE HYDROCHLORIDE

Brand Name: GEMCITABINE Hydrochloride

Substance Name(s):
GEMCITABINE HYDROCHLORIDE

DRUG INTERACTIONS

7 No drug interaction studies have been conducted.

OVERDOSAGE

10 Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

DESCRIPTION

11 Gemcitabine for Injection, USP is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine hydrochloride, USP is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer). The structural formula is as follows: The molecular formula for gemcitabine hydrochloride, USP is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66. Gemcitabine hydrochloride, USP is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. Gemcitabine for Injection, USP is supplied in a sterile form for intravenous use only. Vials of Gemcitabine for Injection, USP contain either 200 mg, 1 g, or 2 g of gemcitabine hydrochloride, USP (expressed as free base) formulated with mannitol (200 mg, 1 g, or 2 g respectively) and sodium acetate (12.5 mg, 62.5 mg, or 125 mg respectively) as a sterile lyophilized powder. Sodium hydroxide may have been added for pH adjustment. . Image from Drug Label Content

CLINICAL STUDIES

14 14.1 Ovarian Cancer The safety and efficacy of Gemcitabine for Injection, USP was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemcitabine for Injection, USP 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemcitabine for Injection, USP infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS). Patient characteristics are shown in Table 11. The addition of Gemcitabine for Injection, USP to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received Gemcitabine for Injection, USP for treatment of disease progression. There was no significant difference in overall survival between the treatment arms. Table 11: Randomized Trial of Gemcitabine for Injection, USP plus Carboplatin versus Carboplatin in Ovarian Cancer – Baseline Demographics and Clinical Characteristics Gemcitabine for Injection, USP /Carboplatin Carboplatin Number of randomized patients 178 178 Median age, years 59 58 Range 36 to 78 21 to 81 Baseline ECOG performance status 0 to 1a 94% 95% Disease Status Evaluable 8% 3% Bidimensionally measurable 92% 96% Platinum-free intervalb 6 to 12 months 40% 40% >12 months 59% 60% First-line therapy Platinum-taxane combination 70% 71% Platinum-non-taxane combination 29% 28% Platinum monotherapy 1% 1% a 5 patients on Gemcitabine for Injection, USP plus carboplatin arm and 4 patients on carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status. b 2 on Gemcitabine for Injection, USP plus carboplatin arm and 1 on carboplatin arm had platinum-free interval <6 months. Table 12: Randomized Trial of Gemcitabine for Injection, USP plus Carboplatin versus Carboplatin in Ovarian Cancer – Efficacy Outcomes Gemcitabine for Injection, USP/Carboplatin Carboplatin (N=178) (N=178) Progression-free Survival Median (95% CIa) months 8.6 (8.0, 9.7) 5.8 (5.2, 7.1) Hazard Ratio (95% CI) 0.72 (0.57, 0.90) p-valueb p=0.0038 Overall Survival Median (95% CI) months 18.0 (16.2, 20.3) 17.3 (15.2, 19.3) Hazard Ratio (95% CI) 0.98 (0.78, 1.24) p-valueb p=0.8977 Investigator Reviewed Overall Response Rate 47.2% 30.9% p-valuec p=0.0016 CRd 14.6% 6.2% PR plus PRNMe 32.6% 24.7% Independently Reviewed Overall Response Ratef 46.3% 35.6% p-valuec p=0.11 CRd 9.1% 4.0% PR plus PRNMe 37.2% 31.7% a CI=confidence interval. b Log Rank, unadjusted. c Chi square. d Complete response. ePR plus PRNM=Partial response plus partial response, non-measurable disease. f Independently reviewed cohort – Gemcitabine for Injection, USP/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam. Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine for Injection, USP plus Carboplatin versus Carboplatin in Ovarian Cancer (N=356) 86578cbe-figure-02 14.2 Breast Cancer The safety and efficacy of Gemcitabine for Injection, USP were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to Gemcitabine for Injection, USP on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression. A total of 529 patients were enrolled; 267 were randomized to Gemcitabine for Injection, USP and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 and Figure 2. The addition of Gemcitabine for Injection, USP to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival. Table 13: Randomized Trial of Gemcitabine for Injection, USP plus Paclitaxel versus Paclitaxel in Breast Cancer Gemcitabine for Injection, USP/Paclitaxel Paclitaxel Number of patients 267 262 Demographic/Entry Characteristics Median age (years) 53 52 Range 26 to 83 26 to 75 Metastatic disease 97% 97% Baseline KPSa ≥90 70% 74% Number of tumor sites 1 to 2 57% 59% ≥3 43% 41% Visceral disease 73% 73% Prior anthracycline 97% 96% Efficacy Outcomes Time to Documented Disease Progressionb Median in months 5.2 2.9 (95% CI) (4.2, 5.6) (2.6, 3.7) Hazard Ratio (95% CI) 0.650 (0.524, 0.805) p-value p<0.0001 Overall Survivalc Median Survival in months 18.6 15.8 (95% CI) (16.5, 20.7) (14.1, 17.3) Hazard Ratio (95% CI) 0.86 (0.71, 1.04) p-value Not Significant Overall Response Rate 40.8% 22.1% (95% CI) (34.9, 46.7) (17.1, 27.2) p-value p<0.0001 a Karnofsky Performance Status. b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm. c Based on the ITT population. Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine for Injection, USP plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529) 86578cbe-figure-03 14.3 Non-Small Cell Lung Cancer (NSCLC) The safety and efficacy of Gemcitabine for Injection, USP was evaluated in two randomized, multicenter trials. 28-Day Schedule A multinational, randomized trial compared Gemcitabine for Injection, USP plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive Gemcitabine for Injection, USP 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the Gemcitabine for Injection, USP plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival. 21-Day Schedule A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21 -day cycle. There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see Table 14). The median survival was 8.7 months for the Gemcitabine for Injection, USP plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemcitabine for Injection, USP plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemcitabine for Injection, USP plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided). Figure 3: Kaplan-Meier Survival Curve in Gemcitabine for Injection, USP plus Cisplatin versus Cisplatin in Patients with NSCLC Study (N=522) Table 14: Randomized Trials of Gemcitabine for Injection, USP plus Cisplatin in Patients with NSCLC Trial 28-day Schedulea 21-day Scheduleb Treatment Arm Gemcitabine for Injection, USP plus Cisplatin Cisplatin Gemcitabine for Injection, USP plus Cisplatin Etoposide plus Cisplatin Number of patients 260 262 69 66 Demographic/Entry Characteristics Male 70% 71% 93% 92% Median age, years 62 63 58 60 Range 36 to 88 35 to 79 33 to 76 35 to 75 Stage IIIA 7% 7% N/Ac N/Ac Stage IIIB 26% 23% 48% 52% Stage IV 67% 70% 52% 49% Baseline KPSd 70 to 80 41% 44% 45% 52% Baseline KPSd 90 to 100 57% 55% 55% 49% Efficacy Outcomes Survival Median in months 9.0 7.6 8.7 7.0 (95% CIe) months 8.2, 11.0 6.6, 8.8 7.8, 10.1 6.0, 9.7 p-valuef p=0.008 p=0.18 Time to Disease Progression Median in months 5.2 3.7 5.0 4.1 (95% CIe) months 4.2, 5.7 3.0, 4.3 4.2, 6.4 2.4, 4.5 p-valuef p=0.009 p=0.015 Tumor Response 26% 10% 33% 14% p-valuef p<0.0001 p=0.01 a 28-day schedule – Gemcitabine for Injection, USP plus cisplatin: Gemcitabine for Injection, USP 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days. b 21-day schedule – Gemcitabine for Injection, USP plus cisplatin: Gemcitabine for Injection, USP 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days. c N/A Not applicable. d Karnofsky Performance Status. e CI=confidence intervals. f p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses. 86578cbe-figure-04 14.4 Pancreatic Cancer The safety and efficacy of Gemcitabine for Injection, USP was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive Gemcitabine for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemcitabine for Injection, USP 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles. The primary efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred: The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.OR The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for overall survival in Figure 4. Patients treated with Gemcitabine for Injection, USP had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm. Table 15: Randomized Trial of Gemcitabine for Injection, USP versus 5-Fluorouracil in Pancreatic Cancer Gemcitabine for Injection, USP 5-FU Number of patients 63 63 Demographic/Entry Characteristics Male 54% 54% Median age 62 years 61 years Range 37 to 79 36 to 77 Stage IV disease 71% 76% Baseline KPSa ≤70 70% 68% Efficacy Outcomes Clinical benefit response 22.2% 4.8% p-valueb p=0.004 Survival Median 5.7 months 4.2 months (95% CI) (4.7, 6.9) (3.1, 5.1) p-valueb p=0.0009 Time to Disease Progression Median 2.1 months 0.9 months (95% CI) (1.9, 3.4) (0.9, 1.1) p-valueb p=0.0013 a Karnofsky Performance Status. b p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test. Figure 4: Kaplan-Meier Survival Curve 1

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Gemcitabine for Injection, USP is a white to off-white lyophilized powder and is supplied as follows: NDC Gemcitabine for Injection, USP Package Factor 45963-612-57 200 mg Single-Dose Vial 1 vial per carton 45963-619-59 1 g Single-Dose Vial 1 vial per carton 45963-620-60 2 g Single-Dose Vial 1 vial per carton Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. 16.2 Storage and Handling Unopened vials of Gemcitabine for Injection, USP are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature] [see Dosage and Administration (2.6 and 2.7)].

DOSAGE FORMS AND STRENGTHS

3 Gemcitabine for Injection, USP is a white to off-white lyophilized powder available in sterile single-dose vials containing 200 mg, 1 g, or 2 g gemcitabine. 200 mg/single-dose vial for injection (3) 1 g/single-dose vial for injection (3) 2 g/single-dose vial for injection (3)

INDICATIONS AND USAGE

1 Gemcitabine for Injection, USP is a nucleoside metabolic inhibitor indicated: 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) 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) in combination with cisplatin for the treatment of non-small cell lung cancer. (1.3) as a single agent for the treatment of pancreatic cancer. (1.4) 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, USP is indicated for patients previously treated with 5-FU.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Schedule-dependent toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly. (5.1) Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2, 5.7) Pulmonary Toxicity and Respiratory Failure: Discontinue Gemcitabine for Injection, USP immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity. (5.3) Hemolytic-Uremic Syndrome (HUS): Monitor renal function prior to initiation and during therapy. Discontinue Gemcitabine for Injection, USP for HUS or severe renal impairment. (5.4) Hepatic Toxicity: Monitor hepatic function prior to initiation and during therapy. Discontinue Gemcitabine for Injection, USP for severe hepatic toxicity. (5.5) Embryofetal Toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days of radiation therapy. (5.7) Capillary Leak Syndrome: Discontinue Gemcitabine for Injection, USP. (5.8) Posterior reversible encephalopathy syndrome (PRES): Discontinue Gemcitabine for Injection, USP. (5.9) 5.1 Schedule-dependent Toxicity In clinical trials evaluating the maximum tolerated dose of Gemcitabine for Injection USP, 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 for Injection, USP 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 for Injection, USP as a single agent and the risks are increased when Gemcitabine for Injection, USP is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent Gemcitabine for Injection, USP. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving Gemcitabine for Injection, USP 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 for Injection, USP. Discontinue Gemcitabine for Injection, USP 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)]. 5.4 Hemolytic Uremic Syndrome Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with Gemcitabine for Injection, USP. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Assess renal function prior to initiation of Gemcitabine for Injection, USP and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Permanently discontinue Gemcitabine for Injection, USP in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy. 5.5 Hepatic Toxicity Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemcitabine for Injection, USP alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of Gemcitabine for Injection, USP in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of Gemcitabine for Injection, USP and periodically during treatment. Discontinue Gemcitabine for Injection, USP in patients that develop severe liver injury. 5.6 Embryofetal Toxicity Gemcitabine for Injection, USP can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemcitabine for Injection USP, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.7 Exacerbation of Radiation Therapy Toxicity Gemcitabine for Injection, USP is not indicated for use in combination with radiation therapy. Concurrent (given together or ≤7 days apart) – Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemcitabine for Injection, USP was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation. Non-concurrent (given >7 days apart) – Excessive toxicity has not been observed when Gemcitabine for Injection, USP is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemcitabine for Injection, USP after prior radiation. 5.8 Capillary Leak Syndrome Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemcitabine for Injection, USP as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemcitabine for Injection, USP if CLS develops during therapy. 5.9 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabine for Injection, USP as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue Gemcitabine for Injection, USP if PRES develops during therapy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients of the risks of low blood cell counts and the potential need for blood transfusions and increased susceptibility to infections. Instruct patients to immediately contact their healthcare provider for development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or shortness of breath [see Warnings and Precautions (5.2)]. Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough [see Warnings and Precautions (5.3)]. Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding [see Warnings and Precautions (5.4)]. Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant [see Warnings and Precautions (5.5)]. Made in Italy Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Revised – July 2016

DOSAGE AND ADMINISTRATION

2 Gemcitabine for Injection, USP is for intravenous use only. Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.1) Breast Cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.2) Non-Small Cell Lung Cancer: 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. (2.3) Pancreatic Cancer: 1000 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) 2.1 Ovarian Cancer Recommended Dose and Schedule The recommended dose of Gemcitabine for Injection, USP is 1000 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, USP 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 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. Table 1: Dosage Reduction Guidelines for Gemcitabine for Injection, USP for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Absolute granulocyte count Platelet count % of full dose Day (x 106/L) (x 106/L) Day 1 ≥1500 and ≥100,000 100% <1500 or <100,000 Delay Treatment Cycle Day 8 ≥1500 and ≥100,000 100% 1000 to 1499 or 75,000 to 99,999 50% <1000 or 75,000 100% 1000 to 1199 or 50,000 to 75,000 75% 700 to 999 and ≥50,000 50% <700 or <50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule Every 4-week schedule The recommended dose of Gemcitabine for Injection, USP is 1000 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 1250 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 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one week rest. 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. Table 4: Recommended Dose Reductions for Gemcitabine for Injection, USP for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute granulocyte count Platelet count % of full dose (x 106/L) (x 106/L) ≥1000 And ≥100,000 100 500 to 999 Or 50,000 to 99,999 75 <500 Or <50,000 Hold 2.5 Dose Modifications for Non-Hematologic Adverse Reactions Permanently discontinue Gemcitabine for Injection, USP for any of the following: Unexplained dyspnea or other evidence of severe pulmonary toxicity Severe hepatic toxicity Hemolytic-uremic syndrome Capillary leak syndrome 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, USP is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for Injection, USP solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.