GEMCITABINE Dailymed

Generic: gemcitabine is used for the treatment of Breast Neoplasms Carcinoma, Non-Small-Cell Lung Ovarian Neoplasms Pregnancy Carcinoma, Pancreatic Ductal

Go PRO for all pill images

Recent Major Changes Section

Warnings and Precautions,

Hemolytic Uremic Syndrome (5.4)

1 Indications And Usage

Gemcitabine 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. ( 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 Injection 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 Injection 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 Injection 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 (NSCLC).

1.4 Pancreatic Cancer

Gemcitabine Injection 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 Injection is indicated for patients previously treated with fluorouracil.

2 Dosage And Administration

Gemcitabine Injection is for intravenous infusion use only.

Ovarian cancer: 1000 mg/m ²over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.1)

Breast cancer: 1250 mg/m ²over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.2)

Non-small cell lung cancer: 1000 mg/m ²over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m ²over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.3)

Pancreatic cancer: 1000 mg/m ²over 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 dosage of Gemcitabine Injection is 1000 mg/m ²intravenously 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 Injection administration. Refer to the carboplatin prescribing information for additional information.

Dose Modifications

Recommended Gemcitabine Injection dose modifications for myelosuppression are described in Table 1and Table 2 [see Warnings and Precautions ( 5.2)]. Refer to the dose modification recommendations for non-hematologic adverse reactions [see Dosage and Administration ( 2.5)].

Table 1: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer

Treatment Day

Absolute neutrophil count (x 10 ⁶/L)

Platelet count (x 10 ⁶/L)

Dose modification

Day 1

Greater than or equal to 1500

Less than 1500

and

or

Greater than or equal to 100,000 Less than 100,000

None

Delay Treatment Cycle

Day 8

Greater than or equal to 1500

1000-1499 Less than 1000

and

or or

Greater than or equal to 100,000 75,000-99,999 Less than 75,000

None

50% of full dose Hold

Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer

Occurrence

Myelosuppression During Treatment Cycle

Dose Modification

Initial Occurrence

Absolute neutrophil count less than500 x 10 ⁶/L for more than 5 days or Absolute neutrophil count less than 100 x 10 ⁶/L for more than 3 days or Febrile neutropenia or Platelets less than 25,000x10 ⁶/L Cycle delay of more than one week due to toxicity

Permanently reduce Gemcitabine Injection dose to 800 mg/m ²on Days 1 and 8

Subsequent Occurrence

If any of the above toxicities occur after the initial dose reduction

Permanently reduce Gemcitabine Injection to 800 mg/m ²on Day 1 only

2.2 Breast Cancer

Recommended Dose and Schedule

The recommended dosage of Gemcitabine Injection is 1250 mg/m ²intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m ²administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine Injection administration. Refer to the paclitaxel prescribing information for additional information.

Dosage Modifications

Recommended Gemcitabine Injection dose 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 Injection for Myelosuppression on Day of Treatment in Breast Cancer

Treatment Day

Absolute neutrophil count (x 10 ⁶/L)

Platelet count (x 10 ⁶/L)

Dose 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 75,000

None

1000-1199

or

50,000-75,000

75% of full dose

700-999

and

Greater than or equal to 50,000

50% of full dose

Less than 700

or

Less than 50,000

Hold

2.3 Non-Small Cell Lung Cancer

Recommended Dose and Schedule

28-day schedule

The recommended dosage of Gemcitabine Injection is 1000 mg/m ²intravenously over 30 minutes on Days 1, 8, and 15 of each 28-day cycle in combination with cisplatin 100 mg/m ²administered intravenously on Day 1 after Gemcitabine Injection administration.

21-day schedule

The recommended dosage of Gemcitabine Injection is 1250 mg/m ²intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with cisplatin 100 mg/m ²therapy administered intravenously on Day 1 after Gemcitabine Injection administration.

Refer to the cisplatin prescribing information for additional information.

Dose Modifications

Table 4presents the recommended dose modifications for Gemcitabine Injection myelosuppression [see Warnings and Precautions ( 5.2)]. Refer to the dose modification recommendations for non-hematologic adverse reactions [see Dosage and Administration ( 2.5)].

2.4 Pancreatic Cancer

Recommended Dose and Schedule

The recommended dose of Gemcitabine Injection is 1000 mg/m ²over 30 minutes intravenously. The recommended treatment schedule is as follows:

Weeks 1-8: 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.

Dosage Modifications

Recommended dosage modifications for Gemcitabine 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)].

If myelosuppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.

Table 4: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer

Absolute neutrophil count (x 10 ⁶/L)

Platelet count (x 10 ⁶/L)

Dose modification

Greater than or equal to 1000

and

Greater than or equal to 100,000

None

500-999

or

50,000-99,999

75% of full dose

Less than 500

or

Less than 50,000

Hold

2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue Gemcitabine Injection for any of the following:

Unexplained dyspnea or other evidence of severe pulmonary toxicity [see Warnings and Precautions ( 5.3)]

Hemolytic uremic syndrome (HUS) or severe renal impairment [see Warnings and Precautions ( 5.4)]

Severe hepatic toxicity [see Warnings and Precautions ( 5.5)]

Capillary leak syndrome (CLS) [see Warnings and Precautions ( 5.8)]

Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions ( 5.9)]

Withhold Gemcitabine 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.

2.6 Preparation and Administration

Gemcitabine Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. ¹

Exercise caution and wear gloves when preparing Gemcitabine Injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine Injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.

Preparation

Inspect solution and discard vial if particulate matter or discoloration is observed.

Dilute Gemcitabine Injection with 0.9% Sodium Chloride Injection to a minimum final concentration of at least 0.1 mg/mL.

Mix diluted solution by gentle inversion. Do not shake.

After dilution with 0.9% Sodium Chloride Injection, inspect the diluted Gemcitabine injection solution visually for particulate matter and discoloration. Discard if particulate matter or discoloration is found.

Storage

After initial withdrawal with a needle, use the remaining portion in the vial or discard within 28 days.

Store diluted Gemcitabine Injection at controlled room temperature 20°C to 25°C (68°F to 77°F) Discard the diluted solution after 24 hours.

Administration

Inspect the diluted solution for particulate matter and discoloration prior to administration. Do not administer if particulate matter or discoloration is found.

The compatibility of Gemcitabine Injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

Table 1: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day	Absolute neutrophil count (x 10 ⁶/L)		Platelet count (x 10 ⁶/L)	Dose modification
Day 1	Greater than or equal to 1500 Less than 1500	and or	Greater than or equal to 100,000 Less than 100,000	None Delay Treatment Cycle
Day 8	Greater than or equal to 1500 1000-1499 Less than 1000	and or or	Greater than or equal to 100,000 75,000-99,999 Less than 75,000	None 50% of full dose Hold

Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer
Occurrence	Myelosuppression During Treatment Cycle	Dose Modification
Initial Occurrence	Absolute neutrophil count less than500 x 10 ⁶/L for more than 5 days or Absolute neutrophil count less than 100 x 10 ⁶/L for more than 3 days or Febrile neutropenia or Platelets less than 25,000x10 ⁶/L Cycle delay of more than one week due to toxicity	Permanently reduce Gemcitabine Injection dose to 800 mg/m ²on Days 1 and 8
Subsequent Occurrence	If any of the above toxicities occur after the initial dose reduction	Permanently reduce Gemcitabine Injection to 800 mg/m ²on Day 1 only

Table 3: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer
Treatment Day	Absolute neutrophil count (x 10 ⁶/L)		Platelet count (x 10 ⁶/L)	Dose 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 75,000	None
	1000-1199	or	50,000-75,000	75% of full dose
	700-999	and	Greater than or equal to 50,000	50% of full dose
	Less than 700	or	Less than 50,000	Hold

Table 4: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
Absolute neutrophil count (x 10 ⁶/L)		Platelet count (x 10 ⁶/L)	Dose modification
Greater than or equal to 1000	and	Greater than or equal to 100,000	None
500-999	or	50,000-99,999	75% of full dose
Less than 500	or	Less than 50,000	Hold

3 Dosage Forms And Strengths

Injection: 100mg/mL of gemcitabine as a clear, colorless to pale yellow solution available in sterile multiple-dose vials containing

200 mg/2 mL (100 mg/mL)

1 g/10 mL (100 mg/mL)

1.5 g/15 mL (100 mg/mL)

2 g/20 mL (100 mg/mL)

Gemcitabine Injection in multiple dose vials containing:

200 mg/2 mL (100 mg/mL) ( 3)

1 g/10 mL (100 mg/mL) ( 3)

1.5 g/15 mL (100 mg/mL) ( 3)

2 g/20 mL (100 mg/mL) ( 3)

4 Contraindications

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

Patients with a known hypersensitivity to gemcitabine. ( 4)

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 Injection for unexplained dyspnea or other evidence of severe pulmonary toxicity. ( 5.3)

Hemolytic-uremic syndrome (HUS):Monitor renal function prior to initiation and during therapy. Discontinue Gemcitabine Injection for HUS or severe renal impairment. ( 5.4)

Hepatoxicity:Monitor hepatic function prior to initiation and during therapy. Discontinue Gemcitabine Injection for severe hepatic toxicity. ( 5.5)

Embryo-Fetal toxicity:Can cause fetal harm. Advise females and males of reproductive potential to use effective contraception. ( 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 Injection. ( 5.8)

Posterior reversible encephalopathy syndrome (PRES):Discontinue Gemcitabine Injection. ( 5.9)

5.1 Schedule-dependent Toxicity

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 Injection dosing schedule [see Dosage and Administration ( 2.1, 2.2, 2.3, and 2.4)]. ]

5.2 Myelosuppression

Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with gemcitabine as a single agent and the risks are increased when gemcitabine is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of the 979 patients who received single-agent gemcitabine. The frequencies of Grade 3-4 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 Injection, obtain a complete blood count (CBC), with a differential and a platelet count. Modify the Gemcitabine Injection dosage as recommended [see Dosage and Administration ( 2.1, 2.2, 2.3, and 2.4)] .

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 [see Adverse Reactions ( 6.1, 6.2)] .

Permanently discontinue Gemcitabine Injection in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity.

5.4 Hemolytic Uremic Syndrome

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)] . Serious cases of thrombotic microangiopathy (TMA) other than HUS have been reported with gemcitabine [see Adverse Reactions ( 6.2)].

Assess renal function prior to initiation of Gemcitabine Injection 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 Injection 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 alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions ( 6.1and 6.2)] . Administration of gemcitabine in patients with concurrent hepatic 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 Injection and periodically during treatment. Permanently discontinue Gemcitabine Injection in patients that develop severe liver injury.

5.6 Embryofetal Toxicity

Based on animal data and its mechanism of action Gemcitabine Injection can cause fetal harm when administered to a pregnant woman. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. Advise pregnant women of the potential risk to a fetus. 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 and for 3 months following the final dose [see Use in Specific Populations ( 8.1), ( 8.3)] .

5.7 Exacerbation of Radiation Therapy Toxicity

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 ²to 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.

5.8 Capillary Leak Syndrome

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 Injection if CLS develops during therapy.

5.9 Posterior Reversible Encephalopathy Syndrome

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 Injection if PRES develops during therapy.

6 Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity [see Contraindications ( 4)]

Schedule-Dependent Toxicity [see Warnings and Precautions ( 5.1)]

Myelosuppression [see Warnings and Precautions ( 5.2)]

Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions ( 5.3)]

Hemolytic Uremic Syndrome [see Warnings and Precautions ( 5.4)]

Hepatic Toxicity [see Warnings and Precautions ( 5.5)]

Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions ( 5.7)]

Capillary Leak Syndrome [see Warnings and Precautions ( 5.8)]

Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions ( 5.9)]

The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, anemia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical 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 clinical practice.

Single-Agent

The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m ²to 1250 mg/m ²intravenously 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 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 5and 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 and laboratory abnormalities are provided following Table 6.

Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine ^a

Adverse Reactions ^b Gemcitabine ^c

All Grades (%) Grade 3 (%) Grade 4 (%)

^aGrade based on criteria from the World Health Organization (WHO).

^bFor approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.

^cN=699-974; all patients with laboratory or non-laboratory data.

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

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single-Agent Gemcitabine ^a

Laboratory Abnormality ^b Gemcitabine ^c

All Grades (%) Grade 3 (%) Grade 4 (%)

^aGrade based on criteria from the WHO.

^bRegardless of causality.

^cN=699-974 ; all patients with laboratory or non-laboratory data.

Hematologic

Anemia

68

7

1

Neutropenia

63

19

6

Thrombocytopenia

24

4

1

Hepatic

Increased ALT

68

8

2

Increased AST

67

6

2

Increased alkaline phosphatase

55

7

2

Hyperbilirubinemia

13

2

<1

Renal

Proteinuria

45

<1

0

Hematuria

35

<1

0

Increased BUN

16

0

0

Increased creatinine

8

<1

0

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.

Ovarian Cancer

Tables 7and 8present 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 plus 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 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 >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 ^a

^aGrade based on National Cancer Institute CTC Version 2.0.

^bRegardless of causality.

Adverse Reactions ^b

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

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)]

^aGrade based on National Cancer Institute CTC Version 2.0.

^bRegardless of causality.

^cPercent of patients receiving a transfusion. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

Laboratory Abnormality ^b

Gemcitabine/ Carboplatin (N=175)

Carboplatin (N=174)

All Grades

(%)

Grade 3

(%)

Grade 4

(%)

All Grades

(%)

Grade 3

(%)

Grade 4

(%)

Hematologic

Neutropenia

90

42

29

58

11

1

Anemia

86

22

6

75

9

2

Thrombocytopenia

78

30

5

57

10

1

RBC Transfusions ^c

38

-

-

15

-

-

Platelet Transfusions ^c

9

-

-

3

-

-

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis agents (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

Table 9and 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 plus 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 [see Clinical Studies ( 14.2)] . Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10.

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 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)]
^aGrade based on National Cancer Institute CTC Version 2.0.

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

Adverse Reactions ^b

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

Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 ^a
^aGrade based on National Cancer Institute CTC Version 2.0.

^bRegardless of causality.

Laboratory Laboratory Abnormality ^b

Gemcitabine/ Paclitaxel (N=262)

Paclitaxel (N=259)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematologic

Anemia

69

6

1

51

3

<1

Neutropenia

69

31

17

31

4

7

Thrombocytopenia

26

5

<1

7

<1

<1

Hepatobiliary

Increased ALT

18

5

<1

6

<1

0

Increased AST

16

2

0

5

<1

0

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:

Table 11and 12present 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 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.

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)] in Study 3 ^a

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

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

^cN=217-253; all gemcitabine/ cisplatin patients with laboratory or non-laboratory data

^dN=213-248; all cisplatin patients with laboratory or non-laboratory data.

Adverse Reactions ^b

Gemcitabine/ Cisplatin ^c

Cisplatin ^d

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

Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin 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

^aGrade based on National Cancer Institute CTC.

^bRegardless of causality.

^cN=217-253; all gemcitabine/ cisplatin patients with laboratory or non-laboratory.

^dN=213-248; all cisplatin patients with laboratory or non-laboratory data.

^ePercent of patients receiving a transfusion. Percent transfusions are not CTC-graded events.

Laboratory Abnormality ^b

Gemcitabine/ Cisplatin ^c

Cisplatin ^d

All Grades (%)

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematologic

Anemia

89

22

3

67

6

1

Thrombocytopenia

85

25

25

13

3

1

Neutropenia

79

22

35

20

3

1

Lymphopenia

75

25

18

51

12

5

RBC transfusions ^e

39

-

-

13

-

-

Platelet transfusions ^e

21

-

-

<1

-

-

Renal

Increased creatinine

38

4

<1

31

2

<1

Proteinuria

23

0

0

18

0

0

Hematuria

15

0

0

13

0

0

Other laboratory

Hyperglycemia

30

4

0

23

3

0

Hypomagnesemia

30

4

3

17

2

0

Hypocalcemia

18

2

0

7

0

<1

Hepatic

Increased transaminases

22

2

1

10

1

0

Increased alkaline Phosphatase

19

1

0

13

0

0

Tables 13 and 14present 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 [see Clinical Studies ( 14.3)] . Additional clinically significant adverse reactions are provided following Table 14.

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 ^a

^aGrade based on criteria from the World Health Organization (WHO).

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

^cN=67-69; all gemcitabine/ cisplatin patients with non-laboratory data.

^dN=57-63; all cisplatin plus etoposide patients with non-laboratory data.

^eFlu-like syndrome and edema were not graded.

Adverse Reactions ^d

Gemcitabine/ Cisplatin ^c

Etoposide/ Cisplatin ^d

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

Edema ^e

12

-

-

2

-

-

Rash

10

0

0

3

0

0

Hemorrhage

9

0

3

3

0

3

Fever

6

0

0

3

0

0

Flu-like syndrome ^e

3

-

-

0

-

-

Somnolence

3

0

0

3

2

0

Dyspnea

1

0

1

3

0

0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4 ^a
^aGrade based on criteria from the WHO.

^bRegardless of causality.

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

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

^eWHO grading scale not applicable to proportion of patients with transfusions.

Laboratory Abnormalities ^d

Gemcitabine/ Cisplatin ^c

Etoposide/ Cisplatin ^d

All Grades (%)

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematologic

Anemia

88

22

0

77

13

2

RBC Transfusions ^e

29

-

-

21

-

-

Neutropenia

88

36

28

87

20

56

Thrombocytopenia

81

39

16

45

8

5

Platelet Transfusions ^e

3

-

-

8

-

-

Hepatic

Increased ALT

6

0

0

12

0

0

Increased AST

3

0

0

11

0

0

Increased alkaline

16

0

0

11

0

0

phosphatase

Renal

Proteinuria

12

0

0

5

0

0

Hematuria

22

0

0

10

0

0

Increased BUN

6

0

0

4

0

0

Increased Creatinine

2

0

0

2

0

0

6.2 Post-Marketing 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.

Blood and Lymphatic System:TMA

Cardiovascular— congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias

Vascular Disorders— peripheral vasculitis, gangrene, and capillary leak syndrome

Skin— cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions

Hepatic— hepatic failure, hepatic veno-occlusive disease

Pulmonary— interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia

Nervous System— posterior reversible encephalopathy syndrome (PRES)

8 Use In Specific Populations

Lactation: Advise not to breastfeed. ( 8.2)

8.1 Pregnancy

Risk Summary

Based on animal data and its mechanism of action, Gemcitabine Injection 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 reproductive 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 in mice [approximately 0.005 times the 1000 mg/m ²clinical 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 ²clinical dose based on BSA)

8.2 Lactation

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, advise a women not to breastfeed during treatment with Gemcitabine Injection and for one week following the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Gemcitabine Injection 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 Injection and for 6 months after the final dose .

Males

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

Infertility

Males

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

8.4 Pediatric Use

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

The safety and pharmacokinetics of gemcitabine were evaluated in a trial of pediatric patients with refractory leukaemia. The maximum tolerated dose was 10 mg/m ²/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 ²/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.

8.5 Geriatric Use

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 3-4 thrombocytopenia in older patients 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 3-4 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)].

8.6 Gender

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 3-4 neutropenia and thrombocytopenia [see Dosage and Administration ( 2.1, 2.2, 2.3, 2.4) ].

10 Overdosage

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 ²was 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 should receive supportive therapy, as necessary.

11 Description

Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine Hydrochloride is 2’-deoxy-2’,2’-difluorocytidine monohydrochloride (β-isomer) with the following molecular structure:

Gemcitabine Hydrochloride is a white to off white crystalline powder. The empirical formula for gemcitabine hydrochloride is C ₉H ₁₁F ₂N ₃O ₄• HCl and the molecular weight is 299.66.

Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

Gemcitabine Injection is a sterile, clear colorless to pale yellow solution that is provided in 100mg/mL multiple-dose vials for intravenous use only. Gemcitabine Injection is available in four presentations: 200 mg/2 mL, 1 g/10 mL, 1.5 g/15 mL or 2 g/20 mL. Each mL contains 100 mg of gemcitabine free base (equivalent to 113.85 mg of gemcitabine hydrochloride), 250 mg PEG-300, 150 mg propylene glycol, and 16 mg sodium hydroxide in dehydrated alcohol. Sodium hydroxide and/or hydrochloric acid may have been added for pH adjustment.

12 Clinical Pharmacology

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

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 to 3600 mg/m ².

Distribution

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m ²following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m ².

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/m2 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 the elderly 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 15shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex.

Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient
^aHalf-life for patients receiving <70 minute infusion.

Age

Clearance Men (L/hr/m ²)

Clearance Women (L/hr/m ²)

Half-Life ^aMen (min)

Half-Life ^aWomen (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

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 sex, reflecting a greatly increased volume of distribution with longer infusions.

Male and Female Patients

Female patients have lower clearance and longer half-lives than male patientsas 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 Interaction Studies

When gemcitabine (1250 mg/m ²on Days 1 and 8) and cisplatin (75 mg/m ²on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day 1 was 128 L/hr/m ²and on Day 8 was 107 L/hr/m ². 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.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitromouse lymphoma (L5178Y) assay and was clastogenic in an in vivomouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day [about 1/700 the 1000 mg/m ²clinical 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 ²clinical 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 ²clinical dose based on BSA).

14 Clinical Studies

14.1 Ovarian Cancer

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 ²on Days 1 and 8 of each 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.

Table 16: Baseline Demographics and Clinical Characteristics for Study 1
^a5 patients on gemcitabine with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.

^b2 patients on gemcitabine with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months

Table 17: Efficacy Results in Study 1

Gemcitabine /Carboplatin (N=178)

Carboplatin (N=178)

Median age, years

59

58

Range

36 to 79

21 to 81

Baseline ECOG performance status 0-1 ^a

94%

95%

Disease Status

Evaluable

8%

3%

Bidimensionally measurable

92%

96%

Platinum-free interval ^b

6 -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%

^aCI=confidence interval.

^bLog rank, unadjusted.

^cChi square.

^dCR=Complete response.

^ePR plus PRNM=Partial response plus partial response, non-measurable disease.

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

Gemcitabine /Carboplatin (N=178)

Carboplatin (N=178)

Progression-free Survival

Median (95% CI ^a) months

8.6 (8.0, 9.7)

5.8 (5.2, 7.1)

Hazard Ratio (95% CI)

0.72 (0.57, 0.90)

p-value ^b

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-value ^b

p=0.8977

Overall Response Rate by investigator

47.2%

30.9%

p-value ^c

p=0.0016

CR ^d

14.6%

6.2%

PR plus PRNM ^e

32.6%

24.7%

Overall Response Rate ^fby independent review

46.3%

35.6%

p-value ^c

p=0.11

CR ^d

9.1%

4.0%

PR plus PRNM ^e

37.2%

31.7%

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Study 1.

14.2 Breast Cancer

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

Table 18: Baseline Demographics and Clinical Characteristics for Study 2

Gemcitabine/Paclitaxel (N=267)

Paclitaxel (N=262)

Median age (years)

53

52

Range

26 to 83

26 to 75

Metastatic Disease

97%

97%

Baseline KPS ^a≥90

70%

74%

Number Tumor Sites

1-2

57%

59%

≥3

43%

41%

Visceral Disease

73%

73%

Prior anthracycline

97%

96%

^aKarnofsky Performance Status

Table 19: Efficacy Results in Study 2
^aThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.

^bBased on the ITT population.

Gemcitabine/Paclitaxel, N=267

Paclitaxel, N=262

Efficacy Outcomes

Time to Documented Disease Progression ^a

Median (95% CI) in months

5.2 (4.2, 5.6)

2.9 (2.6, 3.7)

Hazard Ratio (95% CI)

0.650 (0.524, 0.805)

p-value

p<0.0001

Overall Survival ^b

Median Survival (95% CI) in months

18.6 (16.5, 20.7)

15.8 (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

Figure 2: Kaplan-Meier Curve of Time to Disease Progression in Study 2

14.3 Non-Small Cell Lung Cancer (NSCLC)

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 ²on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m ²on Day 1 after gemcitabine administration (n=260) or cisplatin 100 mg/m ²on 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 221 and Figure 3for overall survival.

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 ²on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m ²on Day 1 after gemcitabine administration or etoposide 100 mg/m ²intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m ²on 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).

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)

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/A ^a

N/A ^a

Stage IIIB

26%

23%

48%

52%

Stage IV

67%

70%

52%

49%

Baseline KPS ^b70 to 80

41%

44%

45%

52%

Baseline KPS ^b90 to 100

57%

55%

55%

49%

^aN/A Not Applicable

^bKarnofsky Performance Status.

Table 21: Efficacy Results for Studies 3 and 4
^aCI=confidence intervals.

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

Trial

28-day Schedule (Study 3)

21-day Schedule (Study 4)

Efficacy Parameter

Gemcitabine/ Cisplatin

Cisplatin

Gemcitabine/ Cisplatin

Etoposide/ Cisplatin

Survival

Median (95% CI ^a) in months

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-value ^b

p=0.008

p=0.18

Time to Disease Progression

Median (95% CI ^a) in months

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-value ^b

p=0.009

p=0.015

Tumor Response

26%

10%

33%

14%

p-value ^b

p<0.0001

p=0.01

Figure 3: Kaplan-Meier Survival Curves in Study 3

14.4 Pancreatic Cancer

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 ²intravenously 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 ²intravenously over 30 minutes once weekly (n=63). In the Study 6, all patients received gemcitabine 1000 mg/m ²intravenously 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:

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

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.

Study 5 enrolled 126. Demographics and baseline characteristics were similar between the arms (Table 22). The efficacy results are shown in Table 23and 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.

Table 22: Baseline Demographics and Clinical Characteristics for Study 5

Gemcitabine (N=63)

Fluorouracil (N=63)

Male

54%

54%

Median age, years

62

61

Range

37 to 79

36 to 77

Stage IV disease

71%

76%

Baseline KPS ^a≤70

70%

68%

^aKarnofsky Performance Status.

Table 23: Efficacy Results in Study 5
^ap-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.

Efficacy Parameter

Gemcitabine (N= 63)

Fluorouracil (N= 63)

Clinical benefit response

p-value ^a

22.2%

4.8%

p=0.004

Survival

  Median (95% CI) in months

5.7 (4.7, 6.9)

4.2 (3.1, 5.1)

  p-value ^a

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-value ^a

p=0.0013

Figure 4: Kaplan-Meier Survival Curve.

15 References

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

16 How Supplied/storage And Handling

Gemcitabine Injection is a clear colorless to pale yellow solution available in sterile multiple-dose vials containing:

Vial NDC number

200 mg/2 mL (100 mg/mL) 1 g/10 mL (100 mg/mL) 1.5 g/15 mL (100 mg/mL) 2 g/ 20 mL (100 mg/mL)

68001-342-34 68001-348-36 68001-350-68 68001-359-37

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° C and 30°C (59°F and 86°F).

After initial puncture, Gemcitabine Injection multiple-dose vials are stable for 28 days when stored at room temperature.

Gemcitabine is a cytotoxic drug. Follow applicable special handling and disposal procedures. ¹

17 Patient Counseling Information

Myelosuppression

Advise patients of the risk 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)].

Hepatotoxicity

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 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 of Gemcitabine Injection [see Warnings and Precautions ( 5.6)and Use in Specific Populations ( 8.1, 8.3) ].

Lactation

Advise women not to breastfeed during treatment with Gemcitabine Injection 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 Injection [see Use in Specific Populations ( 8.3), Nonclinical Toxicology ( 13.1)].

Manufactured By: Intas Pharmaceuticals Limited, Plot No.:457, 458, Village – Matoda, Bavla Road,

Ta.- Sanand, Dist. – Ahmedabad – 382 210. INDIA

For BluePoint Laboratories

Package Label.principal Display Panel

PACKAGE CARTON – 200 mg/2 mL

NDC 68001- 342-34

Gemcitabine Injection

200 mg/2 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Discard 28 days after initial puncture

CAUTION: Cytotoxic Agent

Rx only

Sterile       Multiple-Dose Vial

Package Label.principal Display Panel

PACKAGE CONTAINER – 200 mg/2 mL

NDC 68001-342-34      Rx only

Gemcitabine Injection

200 mg/2 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Multiple-Dose Vial      Sterile

Package Label.principal Display Panel

PACKAGE CARTON – 1 g/10 mL

NDC 68001- 348-36

Gemcitabine Injection

1 g/10 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Discard 28 days after initial puncture

CAUTION: Cytotoxic Agent

Rx only

Sterile       Multiple-Dose Vial

Package Label.principal Display Panel

PACKAGE CONTAINER – 1 g/10 mL

NDC 68001- 348-36      Rx only

Gemcitabine Injection

1 g/10 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Multiple-Dose Vial      Sterile

Package Label.principal Display Panel

PACKAGE CARTON – 1.5 g/15 mL

NDC 68001- 350-68

Gemcitabine Injection

1.5 g/15 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Discard 28 days after initial puncture

CAUTION: Cytotoxic Agent

Rx only

Sterile       Multiple-Dose Vial

Package Label.principal Display Panel

PACKAGE CONTAINER – 1.5 g/15 mL

NDC 68001-350-68      Rx only

Gemcitabine Injection

1.5 g/15 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Multiple-Dose Vial      Sterile

Package Label.principal Display Panel

PACKAGE CARTON – 2 g/20 mL

NDC 68001-359-37

Gemcitabine Injection

2 g/20 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Discard 28 days after initial puncture

CAUTION: Cytotoxic Agent

Rx only

Sterile       Multiple-Dose Vial

Package Label.principal Display Panel

PACKAGE CONTAINER – 2 g/20 mL

NDC 68001-359-37      Rx only

Gemcitabine Injection

2 g/20 mL (100 mg/mL)

For Intravenous Infusion Only

Must be Diluted Before Use

Multiple-Dose Vial      Sterile

Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine ^a
Adverse Reactions ^b	Gemcitabine ^c
^aGrade based on criteria from the World Health Organization (WHO).
^bFor approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
^cN=699-974; all patients with laboratory or non-laboratory data.
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

Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single-Agent Gemcitabine ^a
Laboratory Abnormality ^b	Gemcitabine ^c
^aGrade based on criteria from the WHO.
^bRegardless of causality.
^cN=699-974 ; all patients with laboratory or non-laboratory data.
Hematologic
Anemia	68	7	1
Neutropenia	63	19	6
Thrombocytopenia	24	4	1
Hepatic
Increased ALT	68	8	2
Increased AST	67	6	2
Increased alkaline phosphatase	55	7	2
Hyperbilirubinemia	13	2	<1
Renal
Proteinuria	45	<1	0
Hematuria	35	<1	0
Increased BUN	16	0	0
Increased creatinine	8	<1	0

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)]
^aGrade based on National Cancer Institute CTC Version 2.0.
^bNon-laboratory events were graded only if assessed to be possibly drug-related.
Adverse Reactions ^b	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

Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 ^a
^aGrade based on National Cancer Institute CTC Version 2.0.
^bRegardless of causality.
Laboratory Laboratory Abnormality ^b	Gemcitabine/ Paclitaxel (N=262)	Paclitaxel (N=259)
All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)

Hematologic
Anemia	69	6	1	51	3	<1
Neutropenia	69	31	17	31	4	7
Thrombocytopenia	26	5	<1	7	<1	<1
Hepatobiliary
Increased ALT	18	5	<1	6	<1	0
Increased AST	16	2	0	5	<1	0

Table 14: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4 ^a
^aGrade based on criteria from the WHO.
^bRegardless of causality.
^cN=67-69; all gemcitabine/ cisplatin patients with laboratory or non-laboratory data.
^dN=57-63; all cisplatin/ etoposide patients with laboratory or non-laboratory data.
^eWHO grading scale not applicable to proportion of patients with transfusions.
Laboratory Abnormalities ^d	Gemcitabine/ Cisplatin ^c	Etoposide/ Cisplatin ^d
All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)

Hematologic
Anemia	88	22	0	77	13	2
RBC Transfusions ^e	29	-	-	21	-	-
Neutropenia	88	36	28	87	20	56
Thrombocytopenia	81	39	16	45	8	5
Platelet Transfusions ^e	3	-	-	8	-	-
Hepatic
Increased ALT	6	0	0	12	0	0
Increased AST	3	0	0	11	0	0
Increased alkaline	16	0	0	11	0	0
phosphatase
Renal
Proteinuria	12	0	0	5	0	0
Hematuria	22	0	0	10	0	0
Increased BUN	6	0	0	4	0	0
Increased Creatinine	2	0	0	2	0	0

Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient
^aHalf-life for patients receiving <70 minute infusion.
Age	Clearance Men (L/hr/m ²)	Clearance Women (L/hr/m ²)	Half-Life ^aMen (min)	Half-Life ^aWomen (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

Table 16: Baseline Demographics and Clinical Characteristics for Study 1
^a5 patients on gemcitabine with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
^b2 patients on gemcitabine with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months
Table 17: Efficacy Results in Study 1
	Gemcitabine /Carboplatin (N=178)	Carboplatin (N=178)
Median age, years	59	58
Range	36 to 79	21 to 81
Baseline ECOG performance status 0-1 ^a	94%	95%
Disease Status
Evaluable	8%	3%
Bidimensionally measurable	92%	96%
Platinum-free interval ^b
6 -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%

Table 18: Baseline Demographics and Clinical Characteristics for Study 2
	Gemcitabine/Paclitaxel (N=267)	Paclitaxel (N=262)
Median age (years)	53	52
Range	26 to 83	26 to 75
Metastatic Disease	97%	97%
Baseline KPS ^a≥90	70%	74%
Number Tumor Sites
1-2	57%	59%
≥3	43%	41%
Visceral Disease	73%	73%
Prior anthracycline	97%	96%

Table 19: Efficacy Results in Study 2
^aThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
^bBased on the ITT population.
	Gemcitabine/Paclitaxel, N=267	Paclitaxel, N=262
Efficacy Outcomes
Time to Documented Disease Progression ^a
Median (95% CI) in months	5.2 (4.2, 5.6)	2.9 (2.6, 3.7)
Hazard Ratio (95% CI)	0.650 (0.524, 0.805)
p-value	p<0.0001
Overall Survival ^b
Median Survival (95% CI) in months	18.6 (16.5, 20.7)	15.8 (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

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)
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/A ^a	N/A ^a
Stage IIIB	26%	23%	48%	52%
Stage IV	67%	70%	52%	49%
Baseline KPS ^b70 to 80	41%	44%	45%	52%
Baseline KPS ^b90 to 100	57%	55%	55%	49%

Table 21: Efficacy Results for Studies 3 and 4
^aCI=confidence intervals.
^bp-value two-sided Fisher's Exact test for difference in binomial proportions; log rank test for time-to-event analyses.
Trial	28-day Schedule (Study 3)	21-day Schedule (Study 4)
Efficacy Parameter	Gemcitabine/ Cisplatin	Cisplatin	Gemcitabine/ Cisplatin	Etoposide/ Cisplatin
Survival
Median (95% CI ^a) in months	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-value ^b	p=0.008	p=0.18
Time to Disease Progression
Median (95% CI ^a) in months	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-value ^b	p=0.009	p=0.015
Tumor Response	26%	10%	33%	14%
p-value ^b	p<0.0001	p=0.01

Table 22: Baseline Demographics and Clinical Characteristics for Study 5
	Gemcitabine (N=63)	Fluorouracil (N=63)
Male	54%	54%
Median age, years	62	61
Range	37 to 79	36 to 77
Stage IV disease	71%	76%
Baseline KPS ^a≤70	70%	68%

Table 23: Efficacy Results in Study 5
^ap-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.
Efficacy Parameter	Gemcitabine (N= 63)	Fluorouracil (N= 63)
Clinical benefit response p-value ^a	22.2%	4.8%
p=0.004
Survival
Median (95% CI) in months	5.7 (4.7, 6.9)	4.2 (3.1, 5.1)
p-value ^a	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-value ^a	p=0.0013

Vial	NDC number
200 mg/2 mL (100 mg/mL) 1 g/10 mL (100 mg/mL) 1.5 g/15 mL (100 mg/mL) 2 g/ 20 mL (100 mg/mL)	68001-342-34 68001-348-36 68001-350-68 68001-359-37

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

PillSync may earn a commission via links on our site

Adverse Reactions ^b	Gemcitabine ^c
Adverse Reactions ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)
^aGrade based on criteria from the World Health Organization (WHO).
^bFor approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
^cN=699-974; all patients with laboratory or non-laboratory data.
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

^aGrade based on National Cancer Institute CTC Version 2.0.
^bRegardless of causality.
^cPercent of patients receiving a transfusion. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
Laboratory Abnormality ^b	Gemcitabine/ Carboplatin (N=175)			Carboplatin (N=174)
Laboratory Abnormality ^b	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)

Hematologic
Neutropenia	90	42	29	58	11	1
Anemia	86	22	6	75	9	2
Thrombocytopenia	78	30	5	57	10	1
RBC Transfusions ^c	38	-	-	15	-	-
Platelet Transfusions ^c	9	-	-	3	-	-

^aGrade based on National Cancer Institute Common Toxicity Criteria (CTC).
^bNon-laboratory events were graded only if assessed to be possibly drug-related.
^cN=217-253; all gemcitabine/ cisplatin patients with laboratory or non-laboratory data
^dN=213-248; all cisplatin patients with laboratory or non-laboratory data.
Adverse Reactions ^b	Gemcitabine/ Cisplatin ^c			Cisplatin ^d
Adverse Reactions ^b	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

^aCI=confidence interval.
^bLog rank, unadjusted.
^cChi square.
^dCR=Complete response.
^ePR plus PRNM=Partial response plus partial response, non-measurable disease.
^fIndependently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.
	Gemcitabine /Carboplatin (N=178)	Carboplatin (N=178)
Progression-free Survival
Median (95% CI ^a) months	8.6 (8.0, 9.7)	5.8 (5.2, 7.1)
Hazard Ratio (95% CI)	0.72 (0.57, 0.90)
p-value ^b	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-value ^b	p=0.8977

Overall Response Rate by investigator	47.2%	30.9%
p-value ^c	p=0.0016
CR ^d	14.6%	6.2%
PR plus PRNM ^e	32.6%	24.7%

Overall Response Rate ^fby independent review	46.3%	35.6%
p-value ^c	p=0.11
CR ^d	9.1%	4.0%
PR plus PRNM ^e	37.2%	31.7%

GEMCITABINE Dailymed

Drug Classes

Version History

Generic: gemcitabine is used for the treatment of Breast Neoplasms Carcinoma, Non-Small-Cell Lung Ovarian Neoplasms Pregnancy Carcinoma, Pancreatic Ductal

FDA Adverse Reactions

Recent Major Changes Section

1 Indications And Usage

1.1 Ovarian Cancer

1.2 Breast Cancer

1.3 Non-Small Cell Lung Cancer

1.4 Pancreatic Cancer

2 Dosage And Administration

2.1 Ovarian Cancer

2.2 Breast Cancer

2.3 Non-Small Cell Lung Cancer

2.4 Pancreatic Cancer

2.5 Dose Modifications for Non-Hematologic Adverse Reactions

2.6 Preparation and Administration

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Schedule-dependent Toxicity

5.2 Myelosuppression

5.3 Pulmonary Toxicity and Respiratory Failure

5.4 Hemolytic Uremic Syndrome

5.5 Hepatic Toxicity

5.6 Embryofetal Toxicity

5.7 Exacerbation of Radiation Therapy Toxicity

5.8 Capillary Leak Syndrome

5.9 Posterior Reversible Encephalopathy Syndrome

6 Adverse Reactions

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Gender

10 Overdosage

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1 Ovarian Cancer

14.2 Breast Cancer

14.3 Non-Small Cell Lung Cancer (NSCLC)

14.4 Pancreatic Cancer

15 References

16 How Supplied/storage And Handling

17 Patient Counseling Information

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel

Package Label.principal Display Panel