NDC 0143-9395 Gemcitabine

Gemcitabine

NDC Product Code 0143-9395

NDC 0143-9395-01

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-DOSE

NDC Product Information

Gemcitabine with NDC 0143-9395 is a a human prescription drug product labeled by Hikma Pharmaceuticals Usa Inc.. The generic name of Gemcitabine is gemcitabine. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1719000 and 1719003.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Gemcitabine Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM ACETATE (UNII: 4550K0SC9B)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • MANNITOL (UNII: 3OWL53L36A)
  • SODIUM ACETATE (UNII: 4550K0SC9B)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nucleic Acid Synthesis Inhibitors - [MoA] (Mechanism of Action)
  • Nucleoside Metabolic Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hikma Pharmaceuticals Usa Inc.
Labeler Code: 0143
FDA Application Number: ANDA206617 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-25-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Gemcitabine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Ovarian Cancer

Gemcitabine for 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 for 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 for injection 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 (NSCLC).

1.4 Pancreatic Cancer

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

2.5 Dosage Modifications For Non-Hematologic Adverse Reactions

  • Permanently discontinue gemcitabine for injection for any of the following:
  • Unexplained dyspnea or 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 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.

2.6 Preparation

  • Gemcitabine for injection vials contain no antimicrobial preservatives and are intended for single use only.
  • Gemcitabine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1Exercise caution and wear gloves when preparing gemcitabine for injection solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine for injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.
  • Reconstitute the 200 mg vial with 5 mL and the 1 g vial with 25 mL of 0.9% Sodium Chloride Injection, USP to yield a gemcitabine for injection concentration of 38 mg/mL. Reconstituted gemcitabine for injection is a clear, colorless to light straw-colored solution.
  • Visually inspect reconstituted product for particulate matter and discoloration. Discard if particulate matter or discoloration is observed.
  • Withdraw the calculated dose from the vial and discard any unused portion.
  • Prior to administration, dilute the reconstituted solution with 0.9% Sodium Chloride Injection, USP to a minimum final concentration of at least 0.1 mg/mL.
  • Store gemcitabine for injection solutions (reconstituted and diluted) at controlled room temperature of 20°C to 25°C (68°F to 77°F). Do not refrigerate as crystallization can occur. Discard gemcitabine for injection solutions if not used within 24 hours after reconstitution.
  • No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

3 Dosage Forms And Strengths

For injection: 200 mg gemcitabine or 1 g gemcitabine as a sterile white to off-white lyophilized powder in a single-dose vial for reconstitution.

4 Contraindications

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

5.1 Schedule-Dependent Toxicity

In clinical trials evaluating the maximum tolerated dose of gemcitabine for injection, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine for injection is influenced by the length of the infusion [see Clinical Pharmacology (12.3)]. Refer to the recommended gemcitabine for injection dosage [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

5.2 Myelosuppression

Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with gemcitabine for injection as a single agent and the risks are increased when gemcitabine for injection 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 for injection. 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 for injection in combination with another drug [see Adverse Reactions (6.1)].
Prior to each dose of gemcitabine for injection, 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)].

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 the discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine for injection [see Adverse Reactions (6.1, 6.2)].
Permanently discontinue gemcitabine for injection in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe 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 for injection. 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 other than HUS have been reported with gemcitabine for injection [see Adverse Reactions (6.2)].Assess renal function prior to initiation of gemcitabine for 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 for injection in patients with HUS or severe renal impairment. Renal failure may not be reversible even with the discontinuation of therapy.

5.5 Hepatic Toxicity

Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine for injection alone or with other potentially hepatotoxic drugs [see Adverse Reactions (6.1, 6.2)]. Administration of gemcitabine for injection in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of gemcitabine for injection and periodically during treatment. Permanently discontinue gemcitabine for injection in patients who develop severe hepatic toxicity.

5.6 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, gemcitabine for 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 for 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 for injection 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 for injection is not recommended for use in combination with radiation therapy.

5.8 Capillary Leak Syndrome

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

5.9 Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine for injection 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 for 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)]

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 practice.

6.2 Postmarketing Experience

  • The following adverse reactions have been identified during postapproval use of gemcitabine for injection. 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: Thrombotic microangiopathy (TMA)
  • Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias
  • Vascular: Peripheral vasculitis, gangrene, 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)

8.4 Pediatric Use

The safety and effectiveness of gemcitabine for injection 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/m2/min for 360 minutes weekly for three weeks followed by a one-week rest period.
The safety and activity of gemcitabine for injection 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/m2/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 for injection, 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 for injection 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 for injection 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 for injection clearance is decreased in females [see Clinical Pharmacology (12.3)]. In single agent studies of gemcitabine for injection, 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)].

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/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study. In the event of suspected overdose, monitor with appropriate blood counts and provide supportive therapy, as necessary.

11 Description

Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine hydrochloride is 2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β-isomer) with the following structural formula:
The molecular formula for gemcitabine hydrochloride is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66 g/mol.
Gemcitabine hydrochloride 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 to off-white lyophilized powder and available as 200 mg and 1 g single-dose vials for intravenous use only. Each 200 mg vial contains 200 mg gemcitabine (equivalent to 227.7 mg gemcitabine hydrochloride), 200 mg mannitol and 12.5 mg sodium acetate. Each 1 g vial contains 1 g gemcitabine (equivalent to 1.139 g gemcitabine hydrochloride), 1 g mannitol, and 62.5 mg sodium acetate. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

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 for injection dose varied from 500 mg/m2 to 3600 mg/m2.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine for injection 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/m2 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/m2 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/m2 clinical dose based on BSA).

14.1 Ovarian Cancer

The efficacy of gemcitabine for injection 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 for injection 1000 mg/m2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine for injection 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 for injection 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 injection 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
a 5 patients on gemcitabine for injection with carboplatin arm and 4 patients on carboplatin arm had no baseline Eastern Cooperative Oncology Group (ECOG) performance status.
b 2 patients on gemcitabine for injection with carboplatin arm and 1 patient on carboplatin arm had platinum-free interval <6 months.
Gemcitabine for Injection/Carboplatin(N=178)Carboplatin(N=178)Median age, years
59
58
     Range
36 to 78
21 to 81
Baseline ECOG performance status 0 to 1a94%
95%
Disease Status
     Evaluable
8%
3%
     Bidimensionally measurable
92%
96%
Platinum-free intervalb     6 to 12 months
40%
40%
     >12 months
59%
60%
First-line therapy
     Platinum-taxane combination
70%
71%
     Platinum-non-taxane combination
29%
28%
     Platinum monotherapy
1%
1%
Table 17: Efficacy Results in Study 1
a CI=confidence interval.
b Log rank, unadjusted.
c Chi square.
d CR=Complete response.
e PR with PRNM=Partial response with partial response, non-measurable disease.
f Independently reviewed cohort - gemcitabine for injection/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.
Efficacy ParameterGemcitabine for Injection/Carboplatin(N=178)Carboplatin(N=178)Progression-Free Survival     Median (95% CIa) in months
8.6 (8, 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 months
18 (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 Review47.2%
30.9%
     p-valuecp=0.0016
     CRd14.6%
6.2%
     PR with PRNMe32.6%
24.7%
Overall Response Rate by Independent Reviewf46.3%
35.6%
     p-valuecp=0.11
     CRd9.1%
4%
     PR with PRNMe37.2%
31.7%
Figure 1: Kaplan-Meier Curves for Progression-Free Survival in Study 1

14.2 Breast Cancer

The efficacy of gemcitabine for injection was evaluated in a multinational, 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 for injection 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m2 administered on Day 1 before gemcitabine for injection administration (n=267) or paclitaxel 175 mg/m2 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 for injection 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
a Karnofsky Performance Status.
Gemcitabine for Injection/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%
Table 19: Efficacy Results in Study 2
a These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
b Based on the ITT population.
Efficacy ParameterGemcitabine for Injection/Paclitaxel(N=267)Paclitaxel(N=262)Time to Documented Disease ProgressionaMedian (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 Survivalb     Median (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 Rate40.8%
22.1%
      (95% CI)
(34.9, 46.7)
(17.1, 27.2)
     p-value
p<0.0001
Figure 2: Kaplan-Meier Curves for Time to Documented Disease Progression in Study 2

14.3 Non-Small Cell Lung Cancer

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

14.4 Pancreatic Cancer

  • The efficacy of gemcitabine for injection 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 for injection 1000 mg/m2 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/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine for injection 1000 mg/m2 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:
  • The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy.OR
  • The patient was stable on all of the aforementioned parameters and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.
  • 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 for injection 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
  • A Karnofsky Performance Status.
  • Gemcitabine for Injection(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 KPSa ≤70
  • 70%
  • 68%
  • Table 23: Efficacy Results in Study 5
  • A 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.
  • Efficacy ParameterGemcitabine for Injection(N=63)Fluorouracil(N=63)Clinical Benefit Response22.2%
  • 4.8%
  • P-valueap=0.004
  • Overall Survival     Median (95% CI) in months
  • 5.7 (4.7, 6.9)
  • 4.2 (3.1, 5.1)
  • P-valueap=0.0009
  • Time to Disease Progression     Median (95% CI) in months
  • 2.1 (1.9, 3.4)
  • 0.9 (0.9, 1.1)
  • P-valueap=0.0013
  • Figure 4: Kaplan-Meier Curves for Overall Survival in Study 5

15 References

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

16 How Supplied/Storage And Handling

  • Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder available in single-dose vials individually packaged in a carton containing 200 mg or 1 g gemcitabine:200 mg vial: NDC 0143-9394-011 g vial: NDC 0143-9395-01Gemcitabine for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

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NDC 0143-9394-01         Rx onlyGemcitabinefor Injection, USP200 mg per vialFor Intravenous use ONLYDiscard unused portionSterile Single-Dose VialNDC 0143-9394-01         Rx onlyGemcitabinefor Injection, USP200 mg per vialFor Intravenous use ONLYDiscard unused portionSterile Single-Dose Vial

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