NDC 67457-617 Gemcitabine

Gemcitabine Hydrochloride

NDC Product Code 67457-617

NDC 67457-617-30

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 26.3 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Gemcitabine with NDC 67457-617 is a a human prescription drug product labeled by Mylan Institutional Llc. The generic name of Gemcitabine is gemcitabine hydrochloride. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Mylan Institutional Llc

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

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.

  • GEMCITABINE HYDROCHLORIDE 1 g/26.3mL

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.

  • WATER (UNII: 059QF0KO0R)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • WATER (UNII: 059QF0KO0R)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

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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: Mylan Institutional Llc
Labeler Code: 67457
FDA Application Number: ANDA205242 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: 12-18-2017 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: 12-31-2021 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".

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Information for Patients

Gemcitabine Injection

Gemcitabine Injection is pronounced as (jem sit' a been)

Why is gemcitabine injection medication prescribed?
Gemcitabine is used in combination with other chemotherapy drugs to treat cancer of the ovaries (cancer that begins in the female reproductive organs where eggs are forme...
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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 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.

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 5-FU.

2.1 Ovarian Cancer

Recommended Dose and ScheduleThe recommended dose of gemcitabine injection is 1,000 mg/m2 as an intravenous infusion over30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.Dose ModificationsRecommended gemcitabine injection dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Table 1: Dosage Reduction Guidelines for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian CancerTreatmentDayAbsolute granulocyte count(x 106/L)Platelet count(x 106/L)% of full doseDay 1≥1,500and≥100,000100%<1,500or<100,000Delay Treatment CycleDay 8≥1,500and≥100,000100%1,000 to 1,499or75,000 to 99,99950%<1,000or<75,000HoldTable 2: Gemcitabine Injection Dose Modification for Myelosuppression in Previous Cycle in Ovarian CancerOccurrenceMyelosuppression During Treatment CycleDose ModificationInitial OccurrenceAbsolute granulocyte count less than 500 x 106/L for more than 5 daysAbsolute granulocyte count less than 100 x 106/L for more than 3 daysFebrile neutropeniaPlatelets less than 25,000 x 106/LCycle delay of more than one week due to toxicityPermanently reduce gemcitabineinjection to 800 mg/m2 on Days 1and 8Subsequent OccurrenceIf any of the above toxicities occur after the initial dose reductionPermanently reduce gemcitabineinjection dose to 800 mg/m2 onDay 1 only

2.2 Breast Cancer

Recommended Dose and ScheduleThe recommended dose of gemcitabine injection is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine injection administration.Dose ModificationsRecommended dose modifications for gemcitabine injection for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Table 3: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast CancerTreatment DayAbsolute granulocytecount (x 106/L)Platelet count(x 106/L)% of full doseDay 1≥1,500and≥100,000100%less than 1,500orless than 100,000HoldDay 8≥1,200and>75,000100%1,000 to 1,199or50,000 to 75,00075%700 to 999and≥50,00050%<700or<50,000Hold

2.3 Non-Small Cell Lung Cancer

Recommended Dose and ScheduleEvery 4-week scheduleThe recommended dose of gemcitabine injection is 1,000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection.Every 3-week scheduleThe recommended dose of gemcitabine injection is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine injection.Dose ModificationsRecommended dose modifications for gemcitabine injection myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine injection recommendations for non-hematologic adverse reactions.

2.4 Pancreatic Cancer

  • Recommended Dose and ScheduleThe recommended dose of gemcitabine injection is 1,000 mg/m2 over 30 minutes intravenously.The recommended treatment schedule is as follows: •Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest. •After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.Dose ModificationsRecommended dose modifications for gemcitabine injection for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Patients receiving gemcitabine injection should be monitored prior to each dose with a completeblood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.Table 4: Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung CancerAbsolute granulocyte count (x 106/L)Platelet count(x 106/L)% of full dose≥1,000And≥100,000100%500 to 999Or50,000 to 99,99975%<500Or<50,000Hold

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 •Severe hepatic toxicity •Hemolytic-uremic syndrome •Capillary leak syndrome •Posterior reversible encephalopathy syndromeWithhold gemcitabine injection or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation And Administration Precautions

Exercise caution and wear gloves when preparing gemcitabine solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks includingOSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

2.7 Preparation For Intravenous Infusion Administration

Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.Each vial contains a gemcitabine concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of gemcitabine, respectively. Prior to administration, the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.Reconstituted gemcitabine injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags andadministration sets.

3 Dosage Forms And Strengths

  • Gemcitabine Injection is a clear and colorless to light straw-colored solution available in sterilesingle-dose vials containing: •200 mg/5.26 mL (38 mg/mL) •1 g/26.3 mL (38 mg/mL) •2 g/52.6 mL (38 mg/mL)

4 Contraindications

Gemcitabine injection is contraindicated in patients with a known hypersensitivity to gemcitabine.

5.1 Schedule-Dependent Toxicity

In clinical trials evaluating the maximum tolerated dose of gemcitabine injection, prolongation ofthe infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increasedincidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine injection is influenced by the length of the infusion [see ClinicalPharmacology (12.3)].

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 to 4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent gemcitabine. The frequencies of Grade 3 to 4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8% to 28%, and 5% to 55%, respectively, in patients receiving gemcitabine in combination with another drug.

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 injection. Discontinue gemcitabine injection in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].

5.4 Hemolytic Uremic Syndrome

Hemolytic-uremic syndrome (HUS), including fatalities from renal failure or the requirement fordialysis, can occur in patients treated with gemcitabine. In clinical trials, HUS was reported in 6 of 2,429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Assess renal function prior to initiation of gemcitabine injection and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) andUse inSpecific Populations (8.6)]. 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 (6.1 and 6.2)]. Administration of gemcitabine injection in patients with concurrent liver metastases or apre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of theunderlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior toinitiation of gemcitabine injection and periodically during treatment. Discontinue gemcitabine injection in patients that develop severe liver injury.

5.6 Embryo Fetal Toxicity

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

5.7 Exacerbation Of Radiation Therapy Toxicity

Gemcitabine is not indicated for use in combination with radiation therapy.Concurrent (given together or ≤7 days apart)- Life-threatening mucositis, especially esophagitisand pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1,000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.Non-concurrent (given >7 days apart) - Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who received gemcitabine after prior radiation.

5.8 Capillary Leak Syndrome

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receivinggemcitabine as a single-agent or in combination with other chemotherapeutic agents. Discontinuegemcitabine 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. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and discontinue gemcitabine if PRES develops during therapy.

6 Adverse Reactions

  • The following serious adverse reactions are discussed in greater detail in another section of thelabel •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)] •Embryofetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1), andNonclinical Toxicology (13.1)] •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 clinical practice.Single-Agent UseThe data described below reflect exposure to gemcitabine as a single-agent administered at dosesbetween 800 mg/m2 to 1,250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased ALT, increased 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, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in less than 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.Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent gemcitabine across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table.Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent GemcitabineaAll PatientsbAll GradesGrade 3Grade 4LaboratorycHematologicAnemia6871Neutropenia63196Thrombocytopenia2441HepaticIncreased ALT6882Increased AST6762Increased Alkaline Phosphatase5572Hyperbilirubinemia132<1RenalProteinuria45<10Hematuria35<10Increased BUN1600Increased Creatinine8<10Non-laboratorydNausea and Vomiting69131Fever4120Rash30<10Dyspnea233<1Diarrhea1910Hemorrhage17<1<1Infection161<1Alopecia15<10Stomatitis11<10Somnolence11<1<1Paresthesias10<10a Grade based on criteria from the World Health Organization (WHO).b N=699 to 974; all patients with laboratory or non-laboratory data.c Regardless of causality.d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. •Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%) •Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms. •Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm. •Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients discontinued gemcitabine due to edema. •Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued gemcitabine due to flu-like symptoms. •Infection — Sepsis (<1%). •Extravasation — Injection-site reactions (4%). •Allergic — Bronchospasm (<2%); anaphylactoid reactions [see Contraindications (4)]. Non-Small Cell Lung CancerTable 6 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in a randomized trial of gemcitabine plus cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)].Patients randomized to gemcitabine plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin 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 plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine plus 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 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial ofGemcitabine plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]aGemcitabine plus CisplatinbCisplatincAll GradesGrade 3Grade 4All GradesGrade 3Grade 4LaboratorydHematologicAnemia892236761RBC Transfusione3913Neutropenia7922352031Thrombocytopenia8525251331Platelet Transfusionse21<1Lymphopenia75251851125HepaticIncreased Transaminase22211010Increased Alkaline Phosphatase19101300RenalProteinuria23001800Hematuria15001300Elevated creatinine384<1312<1Other LaboratoryHyperglycemia30402330Hypomagnesemia30431720Hypocalcemia182070<1Non-laboratoryfNausea932528720<1Vomiting78111271109Alopecia53103300Neuro Motor351201530Diarrhea24221300Neuro Sensory23101810Infection18321210Fever1600500Neuro Cortical1631910Neuro Mood16101010Local1500600Neuro Headache1400700Stomatitis1410500Hemorrhage1410400Hypotension1210710Rash1100300a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading.b N=217 to 253; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1,000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days.c N=213 to 248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.d Regardless of causality.e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.f Non-laboratory events were graded only if assessed to be possibly drug-related.Table 7 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus cisplatin arm, reported in arandomized trial of gemcitabine plus cisplatin (n=69) administered in 21-day cycles as compared toetoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced ormetastatic NSCLC [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions isprovided following the table.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 treatment-related adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients 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 gemcitabine/cisplatin arm.Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemcitabine plus Cisplatin versus Etoposide plus Cisplatin in Patients with NSCLCaGemcitabine plus CisplatinbEtoposide plus CisplatincAll GradesGrade 3Grade 4All GradesGrade 3Grade 4LaboratorydHematologicAnemia8822077132RBC Transfusione29--21--Neutropenia883628872056Thrombocytopenia8139164585Platelet Transfusionse3--8--HepaticIncreased ALT6001200Increased AST3001100Increased Alkaline Phosphatase16001100Bilirubin000000RenalProteinuria1200500Hematuria22001000BUN600400Creatinine1200200Non-laboratoryfNausea and Vomiting9635486197Fever600300Rash1000300Dyspnea101300Diarrhea14111302Hemorrhage903303Infection28312180Alopecia7713092510Stomatitis20401820Somnolence300320Paresthesias38001620Flu-like syndromeg3--0--Edemag12--2--a Grade based on criteria from the World Health Organization (WHO).b N=67 to 69; all gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1,250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.c N=57 to 63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.d Regardless of causality.e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events.f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.g Flu-like syndrome and edema were not graded.Breast CancerTable 8 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus paclitaxel arm, reported in arandomized trial of gemcitabine plus paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containingchemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [seeClinical Studies (14.2)].The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial ofGemcitabine plus Paclitaxel versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]Gemcitabine plus Paclitaxel(N=262)Paclitaxel(N=259)All GradesGrade 3Grade 4All GradesGrade 3Grade 4LaboratorybHematologicAnemia6961513<1Neutropenia6931173147Thrombocytopenia265<17<1<1HepatobiliaryIncreased ALT185<16<10Increased AST16205<10Non-laboratorycAlopecia9014492193Neuropathy-sensory645<15830Nausea50103120Fatigue406<1281<1Vomiting29201520Diarrhea20301320Anorexia170012<10Neuropathy-motor152<110<10Stomatitis/pharyngitis131<18<10Fever13<10300Rash/desquamation11<1<1500Febrile neutropenia65<1210a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.b Regardless of causality.c Non-laboratory events were graded only if assessed to be possibly drug-related.Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine plus paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).Ovarian CancerTable 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine plus carboplatin arm, reported in a randomized trial 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 less than 10% of patients, are provided following Table 9.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 treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for gemcitabine occurred in 10.4% of patients and gemcitabine dose was omitted in 13.7% of patients in the gemcitabine/carboplatin arm.Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancera Occurring at Higher Incidence inGemcitabine-Treated Patients [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 to 4)]Gemcitabine plus Carboplatin (N=175)Carboplatin (N=174)All GradesGrade 3Grade 4All GradesGrade 3Grade 4LaboratorybHematologicNeutropenia90422958111Anemia862267592Thrombocytopenia7830557101RBC Transfusionsc3815Platelet Transfusionsc93Non-laboratorybNausea69606130Alopecia49001700Vomiting4660362<1Constipation42613730Fatigue403<13250Diarrhea253014<10Stomatitis/pharyngitis22<101300a Grade based on Common Toxicity Criteria (CTC) Version 2.0.b Regardless of causality.c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine plus 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).

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.Cardiovascular - Congestive heart failure, myocardial infarction, arrhythmias, supraventriculararrhythmias.Vascular Disorders - Peripheral vasculitis, gangrene and capillary leak syndrome [see Warningsand Precautions (5.8)].Skin - Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skineruptions.Hepatic - Hepatic failure, hepatic veno-occlusive disease.Pulmonary - Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS)Nervous System — Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)]

7 Drug Interactions

No specific drug interaction studies have been conducted.

8.1 Pregnancy

Risk SummaryBased on animal data and its mechanism of action, gemcitabine can cause fetal harm when administered to a pregnant woman. Gemcitabine injection is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits [see Data]. Advise pregnant women of the potential risk to a fetusIn the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataGemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) atdoses of 1.5 mg/kg/day in mice (about 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.

8.2 Lactation

There are no data on the presence of gemcitabine in human milk, or the effects of gemcitabine onthe breastfed infant or milk production. Because of the potential for serious adverse reactions in nursing infants from gemcitabine injection, advise a lactating woman not to breastfeed during treatment with gemcitabine injection and for one week after the final dose.

8.3 Females And Males Of Reproductive Potential

ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with gemcitabine injection and for 6 months after the final dose [see Use in Specific Populations (8.1)].MalesAdvise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of gemcitabine injection [see Nonclinical Toxicology (13.1)].InfertilityMalesBased on animal studies, gemcitabine injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of gemcitabine has not been established in pediatric patients. The safety and pharmacokinetics of gemcitabine was 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 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 bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

8.5 Geriatric Use

In clinical studies of gemcitabine, enrolling 979 patients with various cancers who received gemcitabine as a single-agent, 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, 175 women received gemcitabine plus 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. Gemcitabine clearance is affected by age, however there are no recommended dose adjustments based on patients' age [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

8.8 Gender

Gemcitabine clearance is affected by gender [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.

10 Overdosage

Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5,700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-escalation study.

11 Description

Gemcitabine is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl, USP is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).The structural formula is as follows:The empirical formula for Gemcitabine HCl, USP is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66.Gemcitabine HCl, USP is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. The clinical formulation is supplied as a sterile solution for intravenous single vial use only. Vials of gemcitabine injection contain either 200 mg, 1 g, or 2 g of gemcitabine HCl, USP (expressed as free base). Each mL contains equivalent of 38 mg of gemcitabine in Water for Injection, USP. 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 the 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

Absorption and DistributionThe 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 3,600 mg/m2.The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.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 gender. Gemcitabineplasma protein binding is negligible.MetabolismGemcitabine disposition was studied in 5 patients who received a single 1,000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) 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.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.EliminationClearance of gemcitabine was affected by age and gender. The lower clearance in women and 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 10 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.Table 10: Gemcitabine Clearance and Half-Life for the “Typical” PatientAgeClearanceMen(L/hr/m2)ClearanceWomen(L/hr/m2)Half-LifeaMen(min)Half-LifeaWomen(min)2992.269.442494575.75748576555.141.561737940.730.77994a Half-life for patients receiving <70 minute infusion.Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.Drug InteractionsWhen gemcitabine (1,250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on average, 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. Data from NSCLC patients 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.

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 vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with 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 1/200the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/dayadministered intravenously (about 1/1,300 the human dose on a mg/m2 basis).

14.1 Ovarian Cancer

The safety and efficacy of gemcitabine was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1,000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine infusion on Day 1 of each cycle (n = 178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n = 178). The primary efficacy outcome measure was progression free survival (PFS).Patient characteristics are shown in Table 11. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.Table 11: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Baseline Demographics and Clinical CharacteristicsGemcitabine/CarboplatinCarboplatinNumber of randomized patients178178Median age, years5958Range36 to 7821 to 81Baseline ECOG performance status 0 to 1a94%95%Disease StatusEvaluableBidimensionally measurable8%92%3%96%Platinum-free intervalb6 to 12 months>12 months40%59%40%60%First-line therapyPlatinum-taxane combinationPlatinum-non-taxane combinationPlatinum monotherapy70%29%1%71%28%1%a 5 patients on the gemcitabine plus carboplatin arm and 4 patients on the carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status.b 2 on the gemcitabine plus carboplatin arm and 1 on the carboplatin arm had a platinum-free interval of less than 6 months.Table 12: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy OutcomesGemcitabine/Carboplatin(N=178)Carboplatin(N=178) Progression free SurvivalMedian (95% CI a) monthsHazard Ratio (95% CI)8.6 (8, 9.7)5.8 (5.2, 7.1)0.72 (0.57, 0.90)p=valuebOverall SurvivalMedian (95% CI) monthsHazard Ratio (95% CI)p=valuebInvestigator ReviewedOverall Response Ratep=0.003818 (16.2, 20.3)17.3 (15.2, 19.3)0.98 (0.78, 1.24)p=0.897747.2%30.9%p=valuecp=0.0016CRdPR+PRNMe14.6%32.6%6.2%24.7%Independently ReviewedOverall Response Ratef46.3%35.6%p=valuecp=0.11CRdPR+PRNMe9.1%37.2%4%31.7%a CI=confidence interval.b Log rank, unadjusted.c Chi square.d CR=Complete responsee PR plus PRNM=Partial response plus partial response, non-measurable diseasef Independently reviewed cohort - gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer (N=356)

14.2 Breast Cancer

The safety and efficacy of gemcitabine were evaluated in a multinational, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated.Patients were randomized to receive gemcitabine 1,250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to gemcitabine on Day 1 of each cycle (n = 267). Single-agent paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n = 262). The primary efficacy outcome measure was time to documented disease progression.A total of 529 patients were enrolled; 267 were randomized to gemcitabine and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are presented in Table 13 and Figure 2. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.Table 13: Randomized Trial of Gemcitabine plus Paclitaxel versus Paclitaxel in Breast CancerGemcitabine/PaclitaxelPaclitaxelNumber of patients267262Demographic/Entry CharacteristicsMedian age, yearsRange5326 to 835226 to 75Metastatic disease97%97%Baseline KPSa≥9070%74%Number of tumor sites1 to 2≥357%43%59%41%Visceral disease73%73%Prior anthracycline97%96%Efficacy OutcomesTime to Documented Disease ProgressionbMedian in months (95% CI)5.2(4.2, 5.6)2.9(2.6, 3.7)Hazard Ratio (95% CI)0.650 (0.524, 0.805)p-valuep<0.0001Overall SurvivalcMedian Survival in months (95% CI)18.6(16.5, 20.7)15.8(14.1, 17.3)Hazard Ratio (95% CI)0.86 (0.71, 1.04)p-valueNot significantOverall Response Ratec (95% CI)40.8% (34.9, 46.7)22.1% (17.1, 27.2)p-valuep<0.0001a Karnofsky Performance Status.b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.c Based on the ITT population.Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529)

14.3 Non-Small Cell Lung Cancer (Nsclc)

The safety and efficacy of gemcitabine was evaluated in two randomized, multicenter trials.28-Day ScheduleA multinational, randomized trial compared gemcitabine plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive gemcitabine 1,000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.21-Day ScheduleA randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1,250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle. There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see Table 14). The median survival was 8.7 months for the gemcitabine plus cisplatin arm versus 7 months for the etoposide plus cisplatin arm. Median time to disease progression for the gemcitabine plus cisplatin arm was 5 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided).Figure 3: Kaplan-Meier Survival Curve in Gemcitabine plus Cisplatin versus Cisplatin NSCLC Study (N=522)Table 14: Randomized Trials of Gemcitabine plus Cisplatin in Patients with NSCLCTrial28-day Schedulea21-day SchedulebTreatment ArmGemcitabine plusCisplatinCisplatinGemcitabine plusCisplatinEtoposide plus CisplatinNumber of patients2602626966Demographic/EntryCharacteristicsMaleMedian age, yearsRange70%6236 to 8871%6335 to 7993%5833 to 7692%6035 to 75Stage IIIAStage IIIBStage IV7%26%67%7%23%70%N/Ac48%52%N/Ac52%49%Baseline KPSd 70 to 80Baseline KPSd 90 to 10041%57%44%55%45%55%52%49%Efficacy OutcomesSurvivalMedian, months(95% CIe) months98.2, 117.66.6, 8.88.77.8, 10.176, 9.7p-valuefp=0.008p=0.18Time to DiseaseProgressionMedian in months(95% CIe) months5.24.2, 5.73.73, 4.354.2, 6.44.12.4, 4.5p-valuefp=0.009p=0.015Tumor Response26%10%33%14%p-valuefp<0.0001p=0.01a 28-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1,000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days.b 21-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1,250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days.c N/A Not applicable.d Karnofsky Performance Status.e CI=confidence intervals.f p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to- event analyses.

14.4 Pancreatic Cancer

  • The safety and efficacy of gemcitabine was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive gemcitabine 1,000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received gemcitabine 1,000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles. The primary efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to have had a clinical benefit response if either of the following occurred: •The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status(Karnofsky Performance Status) for a period of at least 4 consecutive weeks, withoutshowing any sustained worsening in any of the other parameters. Sustained worsening wasdefined as 4 consecutive weeks with either any increase in pain intensity or analgesicconsumption or a 20-point decrease in performance status occurring during the first 12weeks of therapy.OR •The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.  The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for overall survival in Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm.Table 15: Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic CancerGemcitabine5-FUNumber of patients6363Demographic/Entry CharacteristicsMaleMedian ageRangeStage IV diseaseBaseline KPSa≤7054%62 years37 to 7971%70%54%61 years36 to 7776%68%Efficacy OutcomesClinical benefit responsep-valueb22.2%4.8%p=0.004SurvivalMedian(95% CI)p-valueb5.7 months(4.7, 6.9)4.2 months(3.1, 5.1)p=0.0009Time to Disease ProgressionMedian(95% CI)p-valueb2.1 months(1.9, 3.4)0.9 months(0.9, 1.1)p=0.0013a Karnofsky Performance Status.b p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.Figure 4: Kaplan-Meier Survival Curve

16.1 How Supplied

  • Gemcitabine Injection is a clear and colorless to light straw-colored solution available in sterile single-dose vials individually packaged in a carton as follows: •200 mg/5.26 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-616-10 1 g/26.3 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-617-30 •1 g/26.3 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-617-30 2 g/52.6 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-618-10 •2 g/52.6 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-618-10

16.2 Storage And Handling

Unopened vials of gemcitabine injection are stable until the expiration date indicated on the package when stored at 2° to 8°C (36° to 46°F). Do not freeze [see Dosage and Administration (2.6 and2.7)].

17 Patient Counseling Information

  • •Advise patients of the risk of low blood cell counts and the potential need for blood transfusionsand increased susceptibility to infections. Instruct patients to immediately contact their healthcareprovider for development of signs or symptoms of infection, fever, prolonged or unexpectedbleeding, bruising, or shortness of breath [see Warnings and Precautions (5.2)]. •Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instructpatients to immediately contact their healthcare provider for development of shortness of breath,wheezing, or cough [see Warnings and Precautions (5.3)]. •Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instructpatients to immediately contact their healthcare provider for changes in the color or volume ofurine output or for increased bruising or bleeding [see Warnings and Precautions (5.4)]. •Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients toimmediately contact their healthcare provider for signs of jaundice or for pain/tenderness in theright upper abdominal quadrant [see Warnings and Precautions (5.5)].Manufactured for:Mylan Institutional LLCRockford, IL 61103 U.S.A.Manufactured by:Mylan Laboratories LimitedBangalore, IndiaAPRIL 2018

Package/Label Display Panel

NDC 67457-616-10Gemcitabine Injection200 mg/5.26 mL(38 mg/mL)For Intravenous Infusion OnlyMust Be Diluted Before UseCAUTION: CYTOTOXIC AGENTDiscard Unused PortionSterileMylanRx onlySingle-Use Vial

NDC 67457-617-30Gemcitabine Injection1 g/26.3 mL(38 mg/mL)For Intravenous Infusion OnlyCAUTION: CYTOTOXIC AGENTDiscard Unused PortionSterileMylanRx onlySingle-Use Vial

NDC 67457-618-10Gemcitabine Injection2 g/52.6 mL(38 mg/mL)For Intravenous Infusion OnlyCAUTION: CYTOTOXIC AGENTDiscard Unused PortionSterileMylanRx onlySingle-Use Vial

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