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These highlights do not include all the information needed to use GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION. GEMCITABINE for injection, for intravenous useInitial U.S. Approval: 1996 | GEMCITABINE HYDROCHLORIDE [Mylan Institutional LLC] | BioPortfolio

13:51 EST 27th January 2019 | BioPortfolio

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Gemcitabine 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.

Gemcitabine 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.

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

Gemcitabine 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 is indicated for patients previously treated with fluorouracil.

The recommended dosage of gemcitabine for injection is 1000 mg/m intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with carboplatin AUC 4 administered intravenously on Day 1 after gemcitabine for injection administration. Refer to carboplatin prescribing information for additional information.

Recommended gemcitabine for injection dosage modifications for myelosuppression are described in Tables 1 and 2 [ see Warnings and Precautions (5.2) ]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ].

Table 1: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day Absolute Neutrophil Count (x 106/L) Platelet Count (x 106/L) Dosage Modification
Day 1 Greater than or equal to 1500 and Greater than or equal to 100,000 None
Less than 1500 or Less than 100,000 Delay Treatment Cycle
Day 8 Greater than or equal to 1500 and Greater than or equal to 100,000 None
1000 to 1499 or 75,000 to 99,999 50% of full dose
Less than 1000 or Less than 75,000 Hold
Absolute neutrophil count less than 500 x 106/L for more than 5 days or
Absolute neutrophil count less than 100 x 106/L for more than 3 days or
Febrile neutropenia or
Platelets less than 25,000 x 106/L or
Cycle delay for more than one week due to toxicity
Table 2: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression in Previous Cycle in Ovarian Cancer
Occurrence
Myelosuppression During Treatment Cycle
Dosage Modification
Initial Occurrence
Permanently reduce gemcitabine for injection to 800 mg/mon Days 1 and 8
Subsequent Occurrence
If any of the above toxicities occur after the initial dose reduction
Permanently reduce gemcitabine for injection dose to 800 mg/m2 on Day 1 only

The recommended dosage of gemcitabine for injection is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m administered as a 3-hour intravenous infusion on Day 1 before gemcitabine for injection administration. Refer to paclitaxel prescribing information for additional information.

Recommended gemcitabine for injection dosage modifications for myelosuppression are described in Table 3 [ see Warnings and Precautions (5.2)]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ].

Table 3: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment Day Absolute Neutrophil Count (x 106/L) Platelet Count (x 106/L) Dosage Modification
Day 1 Greater than or equal to 1500 and Greater than or equal to 100,000 None
Less than 1500 or Less than 100,000 Hold
Day 8 Greater than or equal to 1200 and Greater than or equal to 75,000 None
1000 to 1199 or 50,000 to 75,000 75% of full dose
700 to 999 and Greater than or equal to 50,000 50% of full dose
Less than 700 or Less than 50,000 Hold

Recommended Dose and Schedule

28-day schedule

The recommended dosage of gemcitabine for injection is 1000 mg/m intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m administered intravenously on Day 1 after gemcitabine for injection administration.

21-day schedule

The recommended dosage of gemcitabine for injection is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m administered intravenously on Day 1 after gemcitabine for injection administration.

Refer to cisplatin prescribing information for additional information.

Dosage Modifications

Recommended dosage modifications for gemcitabine for injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2) ]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ].

Recommended Dose and Schedule

The recommended dosage of gemcitabine for injection is 1000 mg/m intravenously over 30 minutes. The recommended treatment schedule is as follows:

Dosage Modifications

Recommended dosage modifications for gemcitabine for injection for myelosuppression are described in Table 4 [ see Warnings and Precautions (5.2) ]. Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ].

Table 4: Recommended Dosage Modifications for Gemcitabine for Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
Absolute Neutrophil Count (x 106/L) Platelet Count (x 106/L) Dosage Modification
Greater than or equal to 1000 and Greater than or equal to 100,000 None
500 to 999 or 50,000 to 99,999 75% of full dose
Less than 500 or Less than 50,000 Hold

Permanently discontinue gemcitabine for injection for any of the following:

Withhold gemcitabine for injection or reduce dose by 50% for other Grade 3 or 4 non-hematological adverse reactions until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

Gemcitabine for Injection, USP is a sterile, white lyophilized powder or plug available in single-dose vials containing 200 mg or 1 g or 2 g gemcitabine.

Gemcitabine is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis [see Adverse Reactions (6.1)].

In clinical trials evaluating 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) ]. Refer to the recommended gemcitabine dosage [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

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 the 979 patients who received 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 [see Adverse Reactions (6.1)].

Prior to each dose of gemcitabine, obtain a complete blood count (CBC) with a differential and a platelet count. Modify the dosage as recommended [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

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 the discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine [see Adverse Reactions ( 6.1 , 6.2 )].

Permanently discontinue gemcitabine in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.

Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with gemcitabine. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS [ see Adverse Reactions (6.1) ].

Assess renal function prior to initiation of gemcitabine and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or renal failure (increased serum creatinine or BUN). Permanently discontinue gemcitabine in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or with other potentially hepatotoxic drugs [ see Adverse Reactions ( 6.1 , 6.2 )]. Administration of gemcitabine 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. Assess hepatic function prior to initiation of gemcitabine and periodically during treatment. Permanently discontinue gemcitabine in patients who develop severe hepatic toxicity.

Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine 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 and for 3 months following the final dose [see Use in Specific Populations (8.1, 8.3)].

Gemcitabine is not recommended 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 was administered at a dose of 1000 mg/m 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 is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive gemcitabine after prior radiation.

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. Permanently discontinue gemcitabine if CLS develops during therapy.

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents [see Adverse Reactions (6.2)]. 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). Permanently discontinue gemcitabine if PRES develops during therapy.

The following serious adverse reactions are discussed in greater detail in another section of the label

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/m to 1250 mg/m 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 events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of the 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.

Grade based on criteria from the WHO.

Regardless of causality.

N=699 to 974; all patients with laboratory or non-laboratory data.

Additional adverse reactions include the following:

Non-Small Cell Lung Cancer

Tables 7 and 8 presents 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 non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3) ].

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 with 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.

Grade based on National Cancer Institute Common Toxicity Criteria (CTC).

Non-laboratory events were graded only if assessed to be possibly drug-related.

N=217 to 253; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.

N=213 to 248; all cisplatin patients with laboratory or non-laboratory data.

Grade based on National Cancer Institute CTC.

Regardless of causality.

N=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data

N=213 to 248; all cisplatin patients with laboratory or non-laboratory data

Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.

Tables 9 and 10 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 non-small cell lung cancer (NSCLC) [ see Clinical Studies (14.3) ]. Additional clinically significant adverse reactions are provided following Table 10.

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.

Grade based on criteria from the WHO.

Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.

N=67 to 69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.

N=57 to 63; all etoposide/cisplatin patients with laboratory or non-laboratory data.

Flu-like syndrome and edema were not graded.

Grade based on criteria from the WHO.

Regardless of causality.

N=67 to 69; all gemcitabine/cisplatin patients with laboratory or non-laboratory data.

N=57 to 63; all etoposide/cisplatin patients with laboratory or non-laboratory data.

WHO grading scale not applicable to proportion of patients with transfusions.

Breast Cancer

Tables 11 and 12 presents 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 paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [s ee Clinical Studies (14.2) ]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 12.

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.

Grade based on National Cancer Institute CTC Version 2.0.

Non-laboratory events were graded only if assessed to be possibly drug-related.

Grade based on National Cancer Institute CTC Version 2.0.

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).

Ovarian Cancer

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 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 [ see Clinical Studies (14.1) ]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 14.

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.

Grade based on National Cancer Institute CTC Version 2.0.

Regardless of causality.

Grade based on National Cancer Institute CTC Version 2.0.

Regardless of causality.

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).

Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabinea
Adverse Reactionsb Gemcitabinec
All Grades (%) Grade 3 (%) Grade 4 (%)
Nausea and Vomiting 69 13 1
Fever 41 2 0
Rash 30 <1 0
Dyspnea 23 3 <1
Diarrhea 19 1 0
Hemorrhage 17 <1 <1
Infection 16 1 <1
Alopecia 15 <1 0
Stomatitis 11 <1 0
Somnolence 11 <1 <1
Paresthesias 10 <1 0
AnemiaNeutropeniaThrombocytopeniaIncreased ALTIncreased ASTIncreased Alkaline PhosphataseHyperbilirubinemiaProteinuriaHematuriaIncreased BUNIncreased Creatinine
Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabinea
Laboratory Abnormalityb Gemcitabinec
All Grades (%) Grade 3 (%) Grade 4 (%)
Hematologic
 
68 7 1
 
63 19 6
 
24 4 1
Hepatic
 
68 8 2
 
67 6 2
 
55 7 2
 
13 2 <1
Renal
 
45 <1 0
 
35 <1 0
 
16 0 0
 
8 <1 0
Table 7: 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 to 4)] in Study 3a
Adverse Reactionsb Gemcitabine/Cisplatinc Cisplatind
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Nausea 93 25 2 87 20 <1
Vomiting 78 11 12 71 10 9
Alopecia 53 1 0 33 0 0
Neuro Motor 35 12 0 15 3 0
Diarrhea 24 2 2 13 0 0
Neuro Sensory 23 1 0 18 1 0
Infection 18 3 2 12 1 0
Fever 16 0 0 5 0 0
Neuro Cortical 16 3 1 9 1 0
Neuro Mood 16 1 0 10 1 0
Local 15 0 0 6 0 0
Neuro Headache 14 0 0 7 0 0
Stomatitis 14 1 0 5 0 0
Hemorrhage 14 1 0 4 0 0
Hypotension 12 1 0 7 1 0
Rash 11 0 0 3 0 0
Anemia Thrombocytopenia Neutropenia Lymphopenia RBC Transfusionse Platelet Transfusionse Increased Transaminases Increased Alkaline Phosphatase Elevated creatinine Proteinuria Hematuria Hyperglycemia Hypomagnesemia Hypocalcemia
Table 8: 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 to 4)] in Study 3a
Laboratory Abnormalityb Gemcitabine/Cisplatin Cisplatin
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Hematologic
 
89 22 3 67 6 1
 
85 25 25 13 3 1
 
79 22 35 20 3 1
 
75 25 18 51 12 5
 
39 - - 13 - -
 
21 - - <1 - -
Hepatic
 
22 2 1 10 1 0
 
19 1 0 13 0 0
Renal
 
38 4 <1 31 2 <1
 
23 0 0 18 0 0
 
15 0 0 13 0 0
Other Laboratory
 
30 4 0 23 3 0
 
30 4 3 17 2 0
 
18 2 0 7 0 <1
Table 9: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4a
Adverse Reactionsb Gemcitabine/Cisplatinc Etoposide/Cisplatind
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Nausea and Vomiting 96 35 4 86 19 7
Alopecia 77 13 0 92 51 0
Paresthesias 38 0 0 16 2 0
Infection 28 3 1 21 8 0
Stomatitis 20 4 0 18 2 0
Diarrhea 14 1 1 13 0 2
Edemae 12 - - 2 - -
Rash 10 0 0 3 0 0
Hemorrhage 9 0 3 3 0 3
Fever 6 0 0 3 0 0
Somnolence 3 0 0 3 2 0
Flu-like syndromee 3 - - 0 - -
Dyspnea 1 0 1 3 0 0
Anemia Neutropenia Thrombocytopenia RBC Transfusionsc Platelet Transfusionse Increased Alkaline Phosphatase Increased ALT Increased AST Bilirubin Hematuria Proteinuria BUN Creatinine
Table 10: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4a
Laboratory Abnormalityb Gemcitabine/Cisplatinc Etoposide/Cisplatind
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Hematologic
 
88 22 0 77 13 2
 
88 36 28 87 20 56
 
81 39 16 45 8 5
 
29 - - 21 - -
 
3 - - 8 - -
Hepatic
 
16 0 0 11 0 0
 
6 0 0 12 0 0
 
3 0 0 11 0 0
 
0 0 0 0 0 0
Renal
 
22 0 0 10 0 0
 
12 0 0 5 0 0
 
6 0 0 4 0 0
 
2 0 0 2 0 0
Table 11: 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 to 4)] in Study 2a
Adverse Reactionsb Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Alopecia 90 14 4 92 19 3
Neuropathy-sensory 64 5 <1 58 3 0
Nausea 50 1 0 31 2 0
Fatigue 40 6 <1 28 1 <1
Vomiting 29 2 0 15 2 0
Diarrhea 20 3 0 13 2 0
Anorexia 17 0 0 12 <1 0
Neuropathy-motor 15 2 <1 10 <1 0
Stomatitis/pharyngitis 13 1 <1 8 <1 0
Fever 13 <1 0 3 0 0
Rash/desquamation 11 <1 <1 5 0 0
Febrile neutropenia 6 5 <1 2 1 0
Anemia Neutropenia Thrombocytopenia Increased ALT Increased AST
Table 12: 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 to 4)] in Study 2a
Laboratory Abnormalityb Gemcitabine/Paclitaxel (N=262) Paclitaxel (N=259)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Hematologic
 
69 6 1 51 3 <1
 
69 31 17 31 4 7
 
26 5 <1 7 <1 <1
Hepatobiliary
 
18 5 <1 6 <1 0
 
16 2 0 5 <1 0
Table 13: Adverse Reactions Occurring in >10% of Patients Receiving in 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 to 4)] in Study 1a
Adverse Reactionsb Gemcitabine/Carboplatin (N=175) Carboplatin (N=174)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Nausea 69 6 0 61 3 0
Alopecia 49 0 0 17 0 0
Vomiting 46 6 0 36 2 <1
Constipation 42 6 1 37 3 0
Fatigue 40 3 <1 32 5 0
Diarrhea 25 3 0 14 <1 0
Stomatitis/pharyngitis 22 <1 0 13 0 0
Neutropenia Anemia Thrombocytopenia RBC Transfusionsc Platelet Transfusionsc
Table 14: 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 to 4)] in Study 1a
Laboratory Abnormalityb Gemcitabine/Carboplatin (N=175) Carboplatin (N=174)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Hematologic
 
90 42 29 58 11 1
 
86 22 6 75 9 2
 
78 30 5 57 10 1
 
38 - - 15 - -
 
9 - - 3 - -

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.

Risk Summary

Based on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of gemcitabine in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies 2 to 4% and 15 to 20% respectively.

Data

Animal Data

Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [approximately 0.005 times the 1000 mg/m clinical dose based on body surface area (BSA)]. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m clinical dose based on BSA).

Risk Summary

There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants from gemcitabine, advise women not to breastfeed during treatment with gemcitabine and for at least one week following the last dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating gemcitabine [see Use in Specific Populations (8.1)].

Contraception

Gemcitabine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with gemcitabine and for 6 months after the final dose of gemcitabine.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with gemcitabine and for 3 months after the last dose of gemcitabine [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on animal studies, gemcitabine may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

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

The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum tolerated dose was 10 mg/m/min for 360 minutes weekly for three weeks followed by a one-week rest period.

The safety and activity of gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3 to 4 thrombocytopenia in older patients as compared to younger patients.

In a randomized trial in women with ovarian cancer (Study 1), 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3 to 4 neutropenia in women 65 years of age or older [see Dosage and Administration (2.1)].

Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients’ age [ see Clinical Pharmacology (12.3) ].

Gemcitabine clearance is decreased in females [see Clinical Pharmacology (12.3)]. In single agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3 to 4 neutropenia and thrombocytopenia [see Dosage and Administration (2.1 , 2.2 , 2.3, 2.4)].

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/m 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.

Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine hydrochloride is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer) with the following structural formula:

The empirical formula for gemcitabine hydrochloride is CHFNO • HCl. It has a molecular weight of 299.66 g/mol.

Gemcitabine Hydrochloride, USP is a white to off-white solid and is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

Gemcitabine for Injection, USP is a sterile, white lyophilized powder or plug and available as 200 mg, 1 g and 2 g single-dose vials for intravenous use only. Each 200 mg vial contains gemcitabine hydrochloride, USP equivalent to 200 mg gemcitabine, 200 mg mannitol and 12.5 mg sodium acetate. Each 1 g vial contains gemcitabine hydrochloride, USP equivalent to 1 g gemcitabine, 1 g mannitol and 62.5 mg sodium acetate. Each 2 g vial contains gemcitabine hydrochloride, USP equivalent to 2 g gemcitabine, 2 g mannitol and 125 mg sodium acetate. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.

The pharmacokinetics of gemcitabine were examined in 353 patients with various solid tumors. Pharmacokinetic parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total gemcitabine dose varied from 500 mg/mto 3600 mg/m.

Distribution

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m.

Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and sex. Gemcitabine plasma protein binding is negligible.

Elimination

Metabolism

The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.

Excretion

Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m of radiolabeled drug as a 30-minute infusion. Within one week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

Specific Populations

Geriatric Patients

Clearance of gemcitabine was affected by age. The lower clearance in geriatric patients results in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.

Half-life for patients receiving a <70 minute infusion.

Gemcitabine half-life for short infusions ranged from 42 to 94 minutes and for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.

Male and Female Patients

Females have lower clearance and longer half-lives than male patients as described in Table 15.

Patients with Renal Impairment

No clinical studies have been conducted with gemcitabine in patients with decreased renal function.

Patients with Hepatic Impairment

No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function.

Drug Interactions Studies

When gemcitabine (1250 mg/m on Days 1 and 8) and cisplatin (75 mg/m on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m and on Day 8 was 107 L/hr/m. Data from patients with NSCLC demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent; however, due to wide confidence intervals and small sample size, interpatient variability may be observed.

Data from metastatic breast cancer patients shows that gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine.

Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient
Age Clearance Men (L/hr/m2) Clearance Women (L/hr/m2) Half-Lifea Men (min) Half-Lifea Women (min)
29 92.2 69.4 42 49
45 75.7 57.0 48 57
65 55.1 41.5 61 73
79 40.7 30.7 79 94

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day [about 1/700 the 1000 mg/m clinical dose based on body surface area (BSA)] in male mice resulted in moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the 1000 mg/m clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m clinical dose based on BSA).

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in 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 1000 mg/m on Days 1 and 8 of a 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n=178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n=178). The major efficacy outcome measure was progression free survival (PFS).

A total of 356 patients were enrolled. Demographics and baseline characteristics are shown in Table 16.

Efficacy results are presented in Table 17 and Figure 1. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate. 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 treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

CI=confidence interval.

Log rank, unadjusted.

Chi square.

CR=Complete response.

PR with PRNM=Partial response with partial response, non-measurable disease.

Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.

Figure 1: Kaplan-Meier Curves for Progression Free Survival in Study 1

Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Median age, years5958Range36 to 7821 to 81Baseline ECOG performance status 0 to 1a94%95%Disease StatusEvaluable8%3%Bidimensionally measurable92%96%Platinum-free intervalb6 to 12 months40%40%>12 months59%60%First-line therapyPlatinum-taxane combination70%71%Platinum-non-taxane combination29%28%Platinum monotherapy1%1%
Table 16: Baseline Demographics and Clinical Characteristics for Study 1
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Parameter Gemcitabine/Carboplatin (N=178) Carboplatin (N=178) Progression-free Survival Median (95% CIa) in months8.6 (8.0, 9.7)5.8 (5.2, 7.1)Hazard Ratio (95% CI)0.72 (0.57, 0.90)p-valuebp=0.0038 Overall Survival Median (95% CI) in months18.0 (16.2, 20.3)17.3 (15.2, 19.3)Hazard Ratio (95% CI)0.98 (0.78, 1.24)p-valuebp=0.8977 Overall Response Rate by Investigator Review 47.2%30.9%p-valuecp=0.0016CRd14.6%6.2%PR with PRNMe32.6%24.7% Overall Response Ratef by Independent Review 46.3%35.6%p-valuecp=0.11CRd9.1%4.0%PR with PRNMe37.2%31.7%
Table 17: Efficacy Results in Study 1
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The efficacy of gemcitabine were evaluated in a multi-national, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either gemcitabine 1250 mg/m on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m on Day 1 of each 21-day cycle (n=262). The major efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms (Table 18).

Efficacy results are presented in Table 19 and Figure 2. The addition of gemcitabine 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.

These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.

Based on the ITT population.

Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2

Table 18: Baseline Demographics and Clinical Characteristics for Study 2
a Karnofsky Performance Status.
Gemcitabine/Paclitaxel
(N=267)
Paclitaxel
(N=262)
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 Parameter Gemcitabine/Paclitaxel (N=267) Paclitaxel (N=262) Time to Documented Disease ProgressionaMedian (95% CI) in months5.2 (4.2, 5.6)2.9 (2.6, 3.7)Hazard Ratio (95% CI)0.650 (0.59, 0.85)p-valuep<0.0001 Overall SurvivalbMedian (95% CI) in months18.6 (16.6, 20.7)15.8 (14.1, 17.4)Hazard Ratio (95% CI)0.86 (0.71, 1.04)p-valueNot Significant Overall Response Rate 40.8%22.1%(95% CI)(34.9, 46.7)(17.1, 27.2)p-valuep<0.0001
Table 19: Efficacy Results in Study 2
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The efficacy of gemcitabine was evaluated in two randomized, multicenter trials.

Study 3: 28-Day Schedule

A multinational, randomized trial (Study 3) compared gemcitabine with 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 either gemcitabine 1000 mg/m on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival.

A total of 522 patients were enrolled. Demographics and baseline characteristics (Table 20) 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 with cisplatin arm having adenocarcinoma.

Efficacy results are presented in Table 21 and Figure 3.

Study 4: 21-Day Schedule

A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive either gemcitabine 1250 mg/m on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m on Day 1 after gemcitabine administration or etoposide 100 mg/m intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m on Day 1 of each 21-day cycle. The major efficacy outcome measure was response rate.

A total of 135 patients were enrolled. Demographics and baseline characteristics are summarized in Table 20.

Efficacy results are presented in Table 21. There was no significant difference in survival between the two treatment arms. The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher’s Exact p=0.01, two-sided).

CI=confidence intervals.

p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses.

Figure 3: Kaplan-Meier Curves for Overall Survival in Study 3

Male Range
Table 20: Baseline Demographics and Clinical Characteristics for Studies 3 and 4
Trial 28-day Schedule (Study 3) 21-day Schedule (Study 4)
Gemcitabine/Cisplatin (N=260) Cisplatin (N=262) Gemcitabine/Cisplatin (N=69) Etoposide/Cisplatin (N=66)
 
70% 71% 93% 92%
Median age, years 62 63 58 60
 
36 to 88 35 to 79 33 to 76 35 to 75
Stage IIIA 7% 7% N/Aa N/Aa
Stage IIIB 26% 23% 48% 52%
Stage IV 67% 70% 52% 49%
Baseline KPSb 70 to 80 41% 44% 45% 52%
Baseline KPSb 90 to 100 57% 55% 55% 49%
Median (95% CIa) in monthsp-valuefMedian (95% CIa)in monthsp-valueb p-valueb
Table 21: Efficacy Results for Studies 3 and 4
Trial 28-day Schedule (Study 3) 21-day Schedule (Study 4)
Efficacy Parameter Gemcitabine/Cisplatin (N=260) Cisplatin (N=262) Gemcitabine/Cisplatin (N=69) Etoposide/Cisplatin (N=66)
Survival
 
9.0 (8.2, 11.0) 7.6 (6.6, 8.8) 8.7 (7.8, 10.1) 7.0 (6.0, 9.7)
 
p=0.008 p=0.18
Time to Disease Progression
 
5.2 (4.2, 5.7) 3.7 (3.0, 4.3) 5.0 (4.2, 6.4) 4.1 (2.4, 4.5)
 
p=0.009 p=0.05
Tumor Response 26% 10% 33% 14%
 
p<0.0001 p=0.01

The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) 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 (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles.

The major 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:

Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms (Table 22).

The efficacy results are shown in Table 23 and Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm.

Karnofsky Performance Status.

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 Curves for Overall Survival in Study 5

Table 22: Baseline Demographics and Clinical Characteristics for Study 5
Gemcitabine  (N=63) Fluorouracil (N=63)
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%
Table 23: Efficacy Results in Study 5
Efficacy Parameter Gemcitabine  (N=63) Fluorouracil (N=63)
Clinical benefit response 22.2% 4.8%
p-valuea p=0.004
Overall Survival
Median (95% CI) in months 5.7 (4.7, 6.9) 4.2 (3.1,5.1)
p-valuea p=0.0009
Time to Disease Progression
Median (95% CI) in months 2.1 (1.9,3.4) 0.9(0.9, 1.1)
p-valuea p=0.0013

1. OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

Gemcitabine for Injection, USP is a sterile white lyophilized powder or plug available in single-dose vials individually packaged in a carton containing 200 mg or 1 g or 2 g gemcitabine:

200 mg single-dose vial – NDC 67457-464-20

1 g single-dose vial – NDC 67457-462-01

2 g single-dose vial – NDC 67457-463-02

Gemcitabine for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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 [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise females and males of reproductive potential that gemcitabine can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with gemcitabine 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 and for 3 months after the final dose [see Warnings and Precaution (5.6), Use in Specific Populations (8.1 , 8.3)].

Lactation

Advise women not to breastfeed during treatment with gemcitabine and for at least one week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males of reproductive potential of the potential for reduced fertility with gemcitabine [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured by:

Mylan Laboratories Limited

Bangalore, India

JANUARY 2019

NDC 67457-464-20

Gemcitabine for Injection, USP

200 mg*/vial

Lyophilized

Must be diluted

Cytotoxic Agent

DO NOT REFRIGERATE

Sterile

For Intravenous Use Only

Mylan

Rx only

Single-Dose Vial

NDC 67457-462-01

Gemcitabine for Injection, USP

1 g*/vial

Lyophilized

Must be diluted

Cytotoxic Agent

DO NOT REFRIGERATE

Sterile

For Intravenous Use Only

Mylan

Rx only

Single-Dose Vial

NDC 67457-463-02

Gemcitabine for Injection, USP

2 g*/vial

Lyophilized

Must be diluted

Cytotoxic Agent

DO NOT REFRIGERATE

Sterile

For Intravenous Use Only

Mylan

Rx only

Single-Dose Vial

Manufacturer

Mylan Institutional LLC

Active Ingredients

Source

Drugs and Medications [242 Associated Drugs and Medications listed on BioPortfolio]

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These highlights do not include all the information needed to use gemcitabine for injection safely and effectively. See full prescribing information for gemcitabine for injection. Gemcitabine For Inje...

Gemcitabine [dr. reddy's laboratories limited ]

These highlights do not include all the information needed to used GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION. GEMCITABINE for inj...

Gemcitabine [hospira, inc.]

These highlights do not include all the information needed to use GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION. GEMCITABINE for inje...

Gemcitabine [hospira, inc.]

These highlights do not include all the information needed to use GEMCITABINE FOR INJECTION safely and effectively. See full prescribing information for GEMCITABINE FOR INJECTION.GEMCITABINE for injec...

Gemcitabine hydrochloride [bluepoint laboratories]

These highlights do not include all the information needed to use Gemcitabine for Injection safely and effectively. See full prescribing information for Gemcitabine for Injection. Gemcitabine for inje...

Clinical Trials [3162 Associated Clinical Trials listed on BioPortfolio]

Gemcitabine Hydrochloride With or Without GDC-0449 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from div...

Gemcitabine Hydrochloride, Dasatinib, and Erlotinib Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer That Cannot Be Removed by Surgery

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Cisplatin, Capecitabine, Gemcitabine Hydrochloride and Epirubicin Hydrochloride or Docetaxel in Treating Patients With Stage III or Stage IV Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy, such as cisplatin, capecitabine, gemcitabine hydrochloride, epirubicin hydrochloride, and docetaxel, work in different ways to stop the growth of tum...

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Gemcitabine Hydrochloride, Oxaliplatin, and Erlotinib Hydrochloride in Treating Patients With Advanced Biliary Tract Cancer, Pancreatic Cancer, Duodenal Cancer, or Ampullary Cancer

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PubMed Articles [317 Associated PubMed Articles listed on BioPortfolio]

Comparison of Gemcitabine monotherapy with Gemcitabine and Cisplatin combination in metastatic pancreatic cancer: a retrospective analysis.

Gemcitabine is among the standard first-line agents for the treatment of metastatic pancreatic cancer. However, as the median survival with gemcitabine monotherapy is 6 months, different combinations ...

USP9X inhibition improves gemcitabine sensitivity in pancreatic cancer by inhibiting autophagy.

Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms res...

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Berberine hydrochloride is one the effective compound among Rhizoma Coptidis, Cortex Phellodendri, and other plants. There are several clinical functions of berberine hydrochloride including anti-infl...

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway.

Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-re...

Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207.

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