Brand Name
Gemcitabine
View Brand InformationFDA approval date: November 15, 2010
Classification: Nucleoside Metabolic Inhibitor
Form: Injection
What is Gemcitabine?
Gemcitabine for Injection 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.
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Brand Information
Gemcitabine (GEMCITABINE HYDROCHLORIDE)
1DOSAGE FORMS AND STRENGTHS
Injection: 200 mg/5.26 mL (38 mg/mL), 1 g/26.3 mL (38 mg/mL), and 2 g/52.6 mL (38 mg/mL) as a clear and colorless to light straw-colored solution in a single-dose vial.
2CONTRAINDICATIONS
Gemcitabine Injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis
3ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labelling:
- Hypersensitivity [see
- Schedule-Dependent Toxicity
- Myelosuppression
- Pulmonary Toxicity and Respiratory Failure
- Hemolytic-Uremic Syndrome
- Hepatic Toxicity
- Exacerbation of Radiation Therapy Toxicity
- Capillary Leak Syndrome
- Posterior Reversible Encephalopathy Syndrome
3.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Single Agent
The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m² to 1250 mg/m² intravenously over 30 minutes once weekly, in 979 patients with various malignancies. The most common (20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.
The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m² to 1250 mg/m² intravenously over 30 minutes once weekly, in 979 patients with various malignancies. The most common (20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.
Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single-agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6.
Table 5: Selected Adverse Reactions Occurring in >10% of Patients Receiving Single-Agent Gemcitabine
aGrade based on criteria form the world Health Organization (WHO)
b For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related
cN=699-974; all patients with laboratory or non-laboratory data.
b For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related
cN=699-974; all patients with laboratory or non-laboratory data.
Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabinea
aGrade based on criteria from WHO.
bRegardless of causality.
cN=699-974; all patients with laboratory or non-laboratory data.
cN=699-974; all patients with laboratory or non-laboratory data.
Additional adverse reactions include the following:
- Transfusion requirements: Red blood cell transfusions (19%); platelet transfusions (<1%)
- Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%).
- Flu-like Symptoms: Fever, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%).
- Infection: Sepsis (<1%).
- Extravasation: Injection-site reactions (4%).
- Allergic: Bronchospasm (<2%); anaphylactoid reactions.
Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine/carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy
Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 8.
The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm.
Table 7: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1
aGrade based on criteria from the World Health Organization (WHO).
bRegardless of causality.
bRegardless of causality.
Table 8: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1
a Grade based on National Cancer Institute CTC Version 2.0.
b Regardless of causality.
c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
b Regardless of causality.
c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).
The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), motor neuropathy (1.1% versus 0.6%), and rash/ desquamation (0.6% versus 0). Breast Cancer.
Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in
The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%).
The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.
Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2
a Grade based on National Cancer Institute CTC Version 2.0.
b Non-laboratory events were graded only if assessed to be possibly drug-related.
b Non-laboratory events were graded only if assessed to be possibly drug-related.
Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2
a Grade based on National Cancer Institute CTC Version 2.0.
b Regardless of causality.
b Regardless of causality.
Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).
Non-Small Cell Lung Cancer
Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see .
Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see .
Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus <1%), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine / cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.
Table 11: Selected Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]
Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3
a Grade based on National Cancer Institute CTC.
b Regardless of causality.
c N=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
d N=213-248; all cisplatin patients with laboratory or non-laboratory data.
e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
b Regardless of causality.
c N=217-253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
d N=213-248; all cisplatin patients with laboratory or non-laboratory data.
e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC
Patients in the gemcitabine cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.
Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4
Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4
a Grade based on criteria from WHO.
b Regardless of causality.
c N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
d N=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
e Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions.
b Regardless of causality.
c N=67-69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.
d N=57-63; all etoposide/cisplatin patients with laboratory or non-laboratory data.
e Percent of patients receiving transfusions. WHO Grading scale not applicable to proportion patients with transfusions.
3.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of gemcitabine. 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.
4OVERDOSAGE
There is no known antidote for overdoses of gemcitabine. 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. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.
5DESCRIPTION
Gemcitabine is a nucleoside metabolic inhibitor. The chemical name of gemcitabine HCl is 2´- deoxy-2´, 2´difluorocytidine monohydrochloride (β-isomer).
The structural formula is as follows:
Gemcitabine HCl is a white to off-white solid with a molecular formula of C
Gemcitabine Injection is a sterile solution in single-dose vials for intravenous use. Each vial contains 200 mg, 1 g, or 2 g of gemcitabine equivalent to 227.7 mg, 1.139 g,or 2.277 g of gemcitabine HCl. Each mL contains 38 mg of gemcitabine free base in Water for Injection, USP equivalent to 43.27 mg of gemcitabine HCl. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.
6REFERENCES
1 OSHA Hazardous Drugs. ”
7HOW SUPPLIED/STORAGE AND HANDLING
Gemcitabine Injection is available in sterile single-dose vials individually packaged in a carton as follows:
- 200 mg/5.26 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 72485-221-02
Store at 2° to 8°C (36° to 46°F). Do not freeze.
Gemcitabine Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹
8PATIENT COUNSELING INFORMATION
Myelosuppression
Advise patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider should any signs or symptoms of infection, including fever, or if bleeding, or signs of anemia, occur
Pulmonary Toxicity
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
Hemolytic Uremic Syndrome and Renal Failure
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
Hepatic Toxicity
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
Embryo-Fetal Toxicity
Advise females and males of reproductive potential that Gemcitabine Injection can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine Injection and for 3 months after the final dose [see .
Lactation
Advise women not to breastfeed during treatment with Gemcitabine Injection and for at least one week after the last dose [see .
Infertility
Advise males of reproductive potential of the potential for reduced fertility with Gemcitabine Injection [
Manufactured by
Shilpa Medicare Limited,
Jadcherla-509301, INDIA
Shilpa Medicare Limited,
Jadcherla-509301, INDIA
Distributed by:
Armas Pharmaceuticals, Inc.
Manalapan, NJ 07726 (USA)
Armas Pharmaceuticals, Inc.
Manalapan, NJ 07726 (USA)
Revised: 08/2019
9Packaging
