Advanced Breast Cancer: Learn about treatment options.

Generic Name: Gemcitabine Hydrochloride
Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2′-Deoxy-2′,2′-difluoro-cytidine monohydrochloride
Molecular Formula: C9H11F2N3O4•ClH
CAS Number: 122111-03-9

Introduction

Antimetabolite antineoplastic agent; a synthetic pyrimidine nucleoside.1 2 4

Uses for Gemzar

Breast Cancer

Used in combination with paclitaxel as first-line therapy for metastatic breast cancer in patients who did not respond to previous anthracycline-containing chemotherapy or in whom such chemotherapy was contraindicated.a

Non-small Cell Lung Cancer

Used for initial treatment in patients with inoperable, locally advanced (stage IIIA or IIIB) or metastatic (stage IV) non-small cell lung cancer in combination with cisplatin.1 5 27 28 54 58 68

Used as monotherapy for advanced non-small cell lung cancer36 37 38 49 50 51 54 in patients with relapsed or refractory advanced non-small cell lung cancer who previously were treated with platinum-containing chemotherapy regimens41 or in those who have not received prior chemotherapy.36 37 38 50 51

Slideshow: Flashback: FDA Drug Approvals 2013

Use of chemotherapy generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond.52 Individualize decision to use chemotherapy according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.52 54 55

Pancreatic Cancer

Used as first-line therapy1 10 57 for the palliative treatment of locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas.1 5

Also used as second-line therapy in patients previously treated with fluorouracil.1 11

Bladder Cancer

Used alone22 23 24 or in combination therapy5 (i.e., cisplatin)59 59 60 for the treatment of advanced or metastatic bladder cancer.

Objective responses to gemcitabine have been observed in patients with metastatic bladder cancer that did not respond to previous treatment with cisplatin-based regimens, including some patients with hepatic metastases.24 25

Ovarian Cancer

Currently being investigated for use in the treatment of advanced epithelial ovarian cancer.5 62 63 64 65 66

Biliary Tract Cancer

Use in combination with cisplatin is recommended (accepted) for the treatment of unresectable locally advanced or metastatic biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), including unresectable recurrent disease following surgical resection, in patients with good performance status (ECOG performance status of 0 or 1).76 78 82

Gemzar Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

  • Perform CBC, including differential and platelets, prior to each dose of gemcitabine.1 Modify or temporarily withhold dosage if myelosuppression is detected, according to the degree of hematologic toxicity.1 When used in combination with other antineoplastic agents, dosage modification of the concomitant agent also may be required for hematologic and/or nonhematologic toxicity.

Administration

IV Administration

Administer by IV infusion.1 11 57

The drug is for IV use only.a

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vials containing 200 mg or 1 g of gemcitabine by adding 5 or 25 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide a solution containing 38 mg/mL (accounts for the displacement volume of lyophilized powder).1 3 21 Shake to dissolve.1

Total volume upon reconstitution for vials labeled as containing 200 mg or 1 g is about 5.26 or 26.3 mL, respectively.1 3

Smaller volumes should not be used for reconstitution; concentrations >38 mg/mL may exceed the solubility of the drug and result in incomplete dissolution.1 3

Discard any unused portion after preparation of the appropriate dose.1

Dilution

Reconstituted solutions can be infused IV without further dilution or as solutions that have been further diluted in 0.9% sodium chloride injection to concentrations as low as 0.1 mg/mL.1

Rate of Administration

Infuse over a period of 30 minutes.1

Prolonged IV infusion (>60 minutes) is associated with a prolonged half-life and increased toxicity, including clinically important myelosuppression.1 15 (See Elimination under Pharmacokinetics.) Infusion time should not exceed 60 minutes.1

Dosage

Available as gemcitabine hydrochloride; dosage expressed in terms of gemcitabine.1

Individualize dosage based on body surface area and patient tolerance and response.1

Adults

Breast Cancer
IV

1.25 g/m2 given on days 1 and 8 of a 21-day cycle; administer in combination with paclitaxel 175 mg/m2, given on day 1, as a 3-hour infusion before administration of gemcitabine.a

Patients should have an absolute granulocyte count of ≥1500/mm3 and platelet count of ≥100,000/mm3 prior to each cycle.a Adjust dosage according to granulocyte and platelet counts obtained on day 8 of therapy (see Table 1).a

Table 1. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Paclitaxel in Breast Cancer

Absolute Granulocyte Count (per mm3)

Platelets (per mm3)

Gemcitabine Dosage in Next Cycle (expressed as % of full dose)

≥1200

and

>75,000

100%

1000–1199

or

50,000–75,000

75%

700–999

and

≥50,000

50%

<700

or

<50,000

Withhold dose

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.a

Non-small Cell Lung Cancer
Combination Therapy with Cisplatin

Optimum dosage regimen has not been established.1

IV

1 g/m2 administered on days 1, 8, and 15 of each 28-day cycle (4-week schedule) or 1.25 g/m2 administered on days 1 and 8 of each 21-day cycle (3-week schedule).1 27 28 Administer cisplatin 100 mg/m2 on day 1 following completion of the gemcitabine infusion.1

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.a

See Table 2 for gemcitabine dosage modification for hematologic toxicity.

Table 2. Dosage Modification for Hematologic Toxicity for Gemcitabine Given in Combination with Cisplatin in Non-small Cell Lung Cancer

Absolute Granulocyte Count (per mm3)

Platelets (per mm3)

Gemcitabine Dose Modification (expressed as % of full dose)

≥1000

and

≥100,000

100%1

500–999

or

50,000–99,000

75%1 3

<500

or

<50,000

Withhold dose until counts exceed these levels

Monotherapy
IV

1 or 1.25 g/m2 once weekly for 3 weeks followed by 1 week of rest.36 37 38 41 42 44 50 51

Pancreatic Cancer
Initial Dosing Cycle
IV

1 g/m2 once weekly;1 11 57 repeat at weekly intervals as tolerated for up to 7 weeks, followed by a week of rest from treatment.1 If necessary, reduce or withhold dosage according to the degree of hematologic toxicity. (See Table 3 for dosage modification for hematologic toxicity.)1

Table 3. Dosage Modification for Hematologic Toxicity for Gemcitabine in Pancreatic Cancer

Absolute granulocyte count (per mm3)

Platelets (per mm3)

Gemcitabine Dose Modification (expressed as % of full dose)

≥1000

and

≥100,000

100%1

500–999

or

50,000–99,000

75%1 3

<500

or

<50,000

Withhold dose until counts exceed these levels

Subsequent Dosing Cycles
IV

1 g/m2 once weekly for 3 consecutive weeks, followed by a week of rest from treatment.1

Dosage may be increased to 1.25 g/m2 weekly for 3 consecutive weeks, followed by a week of rest, in patients who successfully complete the initial 7-week or subsequent 3-week cycle of therapy at the full weekly dosage, provided nadirs of the absolute granulocyte and platelet counts are >1500 and 100,000/mm3, respectively, and WHO nonhematologic toxicity > grade 1 is not present.1 11 Dosage can be further increased to 1.5 g/m2 weekly given in 3-week cycles if previous 3-week course is tolerated (i.e., hematologic parameters are met and no evidence of WHO nonhematologic toxicity >1).1

If necessary, reduce or withhold dosage according to the degree of hematologic toxicity.1 (See Table 3.)

In clinical trials, patients received an average of 3 cycles of therapy.3

Biliary Tract Cancer
IV

Gemcitabine 1 g/m2 (as 30-minute infusion) has been given on days 1 and 8 of each 21-day cycle; administered in combination with cisplatin (25 mg/m2 as 1-hour infusion on days 1 and 8 prior to gemcitabine).76 78 Treatment continued for 24 weeks (8 cycles) in the absence of disease progression or unacceptable toxicity.76 78

Prescribing Limits

Do not administer more frequently than once weekly, since risk of toxicity is increased with such dosing.1 16 Infusion time should not exceed 60 minutes.1 (See Rate of Administration under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.1

Renal Impairment

No specific recommendations for dosage adjustment; use with caution.1

Geriatric Patients

Decreased clearance.1 No dosage adjustments in patients >65 years of age except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).1

Female Patients

Decreased clearance.1 No dosage adjustments except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).1

Cautions for Gemzar

Contraindications

  • Known hypersensitivity to gemcitabine or any ingredient in the formulation.a

Warnings/Precautions

Warnings

IV Administration

IV infusion over >60 minutes and administration more frequent than once weekly may be associated with increased toxicity (e.g., myelosuppression).1 (See Rate of Administration under Dosage and Administration.)

Hematologic Effects

Myelosuppression, including leukopenia, anemia, and thrombocytopenia, (usually dose-limiting) may require blood transfusions.a Perform a CBC, including differential and platelets, prior to each dose; modify dosage accordingly.1

Pulmonary Effects

Severe adverse pulmonary effects, sometimes fatal (e.g., pulmonary edema, interstitial pneumonitis, pulmonary fibrosis, ARDS), have been reported.1 70 71 Onset of pulmonary symptoms has occurred up to 2 weeks following administration of the last dose; rarely, respiratory failure and death have occurred despite discontinuance of therapy.1

Dyspnea, occasionally accompanied by bronchospasm, has been reported.1 Possible dose-limiting pulmonary toxicity (e.g., esophagitis, pulmonary fibrosis, and pneumonitis) in patients receiving concurrent thoracic radiation therapy for non-small cell lung cancer.72

Discontinue therapy immediately and institute appropriate supportive care (e.g., diuretics, corticosteroids) promptly in patients who develop severe adverse pulmonary effects.1 70 71

Renal Effects

Risk of hemolytic-uremic syndrome and/or renal failure; rarely fatal or requires dialysis despite discontinuance of therapy.1 Discontinue therapy immediately and consider a diagnosis of hemolytic-uremic syndrome in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, reticulocytosis, and/or severe thrombocytopenia with or without evidence of renal failure (e.g., elevation of Scr or BUN).1 70

Hepatic Effects

Severe hepatotoxicity, including hepatic failure and death, has been reported rarely.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;a embryotoxic and fetotoxic in animals.a If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.a

Sensitivity Reactions

Anaphylactoid reactions reported rarely.a

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under close supervision of qualified clinician experienced in cancer chemotherapy.a Adverse effects generally are reversible and do not require discontinuance of therapy; however, dosage adjustments may be required.a

Assess renal and hepatic function prior to and periodically during therapy.a

Specific Populations

Pregnancy

Category D.a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether gemcitabine is distributed into human milk.a Discontinue nursing because of potential risk to nursing infants.a

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 3

Geriatric Use

Decreased clearance and increased half life.1 a Possible increased incidence of severe (grade 3/4) thrombocytopenia.a

Hepatic Impairment

Use with caution; assess hepatic function prior to and periodically during therapy.a

Renal Impairment

Use with caution; assess renal function prior to and periodically during therapy.a

Women

Decreased clearance.1 Women tolerate the drug more poorly than men, are less likely to progress to subsequent cycles, and are more likely to experience hematologic toxicity (i.e., neutropenia, thrombocytopenia).1 3

Common Adverse Effects

Myelosuppression, transient elevations of serum AST and ALT, proteinuria, hematuria, nausea, vomiting, pain, constipation, fever, fatigue, rash, dyspnea, diarrhea, edema, flu-like symptoms, infection, alopecia, stomatitis, somnolence, paresthesias, and injection site reactions.a

Gemzar Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained up to 30 minutes after discontinuance of the infusion.a

Distribution

Extent

Volume of distribution increases with length of infusion.a Not extensively distributed into tissues following IV infusion over <70 minutes (volume of distribution 50 L/m2).a Following long infusion times, volume of distribution is 370 L/m2, indicating slow equilibration into tissues.a

Plasma Protein Binding

Negligible.a

Special Populations

Volume of distribution is affected by gender.a

Elimination

Metabolism

Converted intracellularly to active metabolites (gemcitabine diphosphate and gemcitabine triphosphate).1 2 4 19 58

Elimination Route

Excreted principally in urine as unchanged drug (<10%) and as inactive metabolite.a

Half-life

Increases with age.a

42, 48, 61, and 79 minutes for men 29, 45, 65, and 79 years of age, respectively.a

49, 57, 73, and 94 minutes for women 29, 45, 65, and 79 years of age, respectively.a

32–94 minutes following short infusions; 245–638 minutes following long infusions.a

Special Populations

Clearance is reduced and half-life increased in women and geriatric patients.1

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C); do not refrigerate since crystallization may occur.a

Solutions are stable for 24 hours at 20–25°C.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Amifostine

Amikacin sulfate

Aminophylline

Ampicillin sodium

Ampicillin sodium–sulbactam sodium

Anidulafungin

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefazolin sodium

Cefotetan disodium

Cefoxitin sodium

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Chlorpromazine HCl

Ciprofloxacin

Cisplatin

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dactinomycin

Daunorubicin HCl

Dexamethasone sodium phosphate

Dexrazoxane

Diphenhydramine HCl

Dobutamine HCl

Docetaxel

Dopamine HCl

Doripenem

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Etoposide

Etoposide phosphate

Famotidine

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Leucovorin calcium

Linezolid

Lorazepam

Mannitol

Meperidine HCl

Mesna

Metoclopramide HCl

Metronidazole

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Oxaliplatin

Paclitaxel

Palonosetron HCl

Potassium chloride

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Streptozocin

Teniposide

Thiotepa

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Topotecan HCl

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Acyclovir sodium

Amphotericin B

Cefotaxime sodium

Furosemide

Ganciclovir sodium

Imipenem–cilastatin sodium

Irinotecan HCI

Methotrexate sodium

Methylprednisolone sodium succinate

Mitomycin

Pemetrexed disodium

Piperacillin sodium–tazobactam sodium

Prochlorperazine edisylate

Actions

  • Cell-cycle specific, acting principally in the S phase of the cell cycle; the drug also may cause cellular arrest at the G1—S border.1

  • Combined actions of diphosphate and triphosphate metabolites lead to inhibition of DNA synthesis.1 2 4 19 20 58

  • Gemcitabine diphosphate interferes with subsequent de novo nucleotide production1 2 4 58 by inhibiting ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis.1 2 4 58

  • Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA.1 2 4 58 Following incorporation of gemcitabine triphosphate into the DNA chain, a single additional nucleotide, a normal base pair, is added and DNA synthesis is terminated, resulting in apoptosis (programmed cell death).1 2 4 58

  • DNA polymerase ε is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand,1 2 3 4 58 which results in a prolonged intracellular half-life of gemcitabine compared with other nucleoside analogs such as cytarabine and is thought to contribute to gemcitabine’s expanded spectrum of antineoplastic activity relative to such agents.4 58

Advice to Patients

  • Risk of myelosuppression.a .

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.a

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.a

  • Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Gemcitabine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

200 mg (of gemcitabine)

Gemzar

Lilly

1 g (of gemcitabine)

Gemzar

Lilly

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gemcitabine HCl 1GM Solution (SANDOZ): 1/$759.98 or 3/$2,159.90

Gemcitabine HCl 2GM Solution (HOSPIRA): 1/$1,239.99 or 3/$1,970.97

Gemcitabine HCl 200MG Solution (SANDOZ): 1/$149.98 or 3/$429.97

Gemzar 1GM Solution (LILLY): 1/$850.02 or 3/$2,395.88

Gemzar 200MG Solution (LILLY): 1/$174.98 or 3/$515.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Eli Lilly and Company. Gemzar (gemcitabine) prescribing information. Indianapolis, IN: 2003 Jan 6.

2. Eli Lilly and Company. Treatment IND of Gemzar (gemcitabine) for patients with pancreatic cancer. Protocol No. B9E-MC-JHEW (c). Indianapolis, IN: Eli Lilly and Company; 1995 Feb 2.

3. Eli Lilly and Company, Indianapolis, IN: Personal communication.

4. Eli Lilly and Company. Gemzar (gemcitabine hydrochloride) product information. Indianapolis, IN: 1995 Apr 27.

5. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther. 2000; 42:83-92. [PubMed 10994034]

6. Pancreatic cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jul 3.

7. Brennan MF, Kinsella TJ, Casper ES. Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:849-82.

8. Weiss GR, Burris HA III, Eckardt JR et al. New anticancer agents. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:132-67.

9. Vaughn DJ, Treat J. Cancers of the large bowel and hepatobiliary tract. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy. Annual 16. New York: Elsevier; 1996:495-10.

10. Carmichael J, Fink U, Russell RC et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996; 73:101-5. [PubMed 8554969]

11. Rothenberg ML, Moore MJ, Cripps MC et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996; 7:347-53. [PubMed 8805925]

12. Moore M, Andersen J, Burris H et al. A randomized trial of gemcitabine (GEM) versus 5FU as first-line therapy in advanced pancreatic cancer. Proc Annu Meet Soc Clin Oncol. 1995; 14:A473.

13. Andersen JS, Burris HA, Casper E et al. Development of a new system for assessing clinical benefit for patients with advanced pancreatic cancer. Proc Annu Meet Am Soc Clin Oncol. 1994; 13:A1600.

14. Lawrence TS, Chang EY, Hahn TM et al. Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys. 1996; 34:867-72. [PubMed 8598364]

15. Pollera CF, Ceribelli A, Crecco M et al. Prolonged infusion of gemcitabine: a preliminary report of a Phase I study. Ann Oncol. 1992; 3(Suppl 5):52.

16. Hansen HH, Lund B. Gemcitabine (2,2-difluorodeoxycytidine): a novel antineoplastic agent with activity in both lung and ovarian cancer. Ann Oncol. 1992; 3(Suppl 1):161.

17. Abbruzzese JL, Gravel D, Tarassoff P et al. Pharmacologically directed strategy for dose intensification of gemcitabine: a Phase I trial. Proc Annu Meet Am Assoc Cancer Res. 1993; 34:A2233.

18. Brown T, O’Rourke T, Burris H et al. A phase I trial of gemcitabine (LY188011) administered IV every two weeks. Proc Annu Meet Am Soc Clin Oncol. 1991; 10:A328.

19. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anti-Cancer Drugs. 1995; 6(Suppl 6):7-13. [PubMed 8718419]

20. Plunkett W, Huang P, Yi-Zheng X et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995; 22(Suppl 11):3-10.

21. O’Brien TE. Gemcitabine concentration lower than cited in package insert. Am J Health-Syst Pharm. 1996; 53:2882.

22. De Lena M, Gridelli C, Lorusso V et al. Gemcitabine activity (objective responses and symptom improvement) in resistant stage IV bladder cancer. Proc Am Soc Clin Oncol. 1996; 15:246.

23. Stadler WM, Kuzel T, Roth B et al. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997; 15:3394-8. [IDIS 396655] [PubMed 9363871]

24. Pollera CF, Ceribelli A, Crecco M et al. Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol. 1994; 5:182-4. [PubMed 8186164]

25. Roth BJ. Chemotherapy for advanced bladder cancer. Semin Oncol. 1996; 23:633-44. [PubMed 8893874]

26. Moore MJ, Tannock IF, Ernst DS et al. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol. 1997; 15:3441-5. [IDIS 397896] [PubMed 9396395]

27. Sandler AB, Nemunaitis J, Denham C et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2000; 18:122-30. [IDIS 438909] [PubMed 10623702]

28. Cardenal F, Lopez-Cabrerizo MP, Anton A et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999; 17:12-8. [IDIS 419947] [PubMed 10458212]

29. Crino L, Scagliotti G, Marangolo M et al. Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 1997; 15:297-303. [IDIS 379623] [PubMed 8996156]

30. Anton A, Carrato A, Gonzalez Larriba JL et al. Phase II activity of gemcitabine in combination with cisplatin in advanced non-small cell lung cancer (NSCLC). Ann Oncol. 1996; 7(Suppl 5):A457P.

31. Shepherd F, Cormier Y, Evans W et al. A phase II study of gemcitabine and cisplatin weekly x 3 every 4 weeks in patients with non-small cell lung cancer (NSCLC). Proc Annu Meet Am Soc Clin Oncol. 1996; 15:A1135.

32. Abratt RP, Bezwoda WR, Goedhals L et al. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol. 1997; 15:744-9. [IDIS 381290] [PubMed 9053500]

33. Sandler AB, Ansari R, McClean J et al. A Hoosier Oncology Group phase II study of gemcitabine plus cisplatin in non-small cell lung cancer (NSCLC). Proc Annu Meet Am Soc Clin Oncol. 1995; 14:A1089.

34. Steward WP, Dunlop DJ, Dabouis G et al. Phase I/II study of gemcitabine and cisplatin in the treatment of advanced non-small cell lung cancer: preliminary results. Semin Oncol. 1996; 23(5 Suppl 10):43-7. [PubMed 8893881]

35. Weick JK, Crowley J, Natale RB et al. A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1991; 9:1157-62. [PubMed 1646292]

36. Gatzemeier U, Shepherd FA, Le Chevalier T et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre, extended phase II study. Eur J Cancer. 1996; 32A:243-8. [PubMed 8664035]

37. Abratt RP, Bezwoda WR, Folkson G et al. Efficacy and safety profile of gemcitabine in non-small cell lung cancer: a phase II study. J Clin Oncol. 1994; 12:1535-40. [IDIS 334284] [PubMed 8040664]

38. Anderson H, Lund B, Bach F et al. Single-agent activity of weekly gemcitabine in advanced non-small cell lung cancer: a phase II study. J Clin Oncol. 1994; 12:1821-6. [IDIS 335229] [PubMed 8083706]

39. Perng RP, Chen YM, Ming-Liu J et al. Gemcitabine versus the combination of cisplatin and etoposide in patients with inoperable non-small-cell lung cancer in a phase II randomized study. J Clin Oncol. 1997; 15:2097-102. [IDIS 387805] [PubMed 9164223]

40. Manegold C, Bergman B, Chemaissani A et al. Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomized phase II study in locally advanced or metastatic non-small-cell lung cancer. Ann Oncol. 1997; 8:525-9. [PubMed 9261520]

41. Crino L, Mosconi AM, Scagliotti GV et al. Gemcitabine as second-line treatment for relapsing or refractory advanced non-small cell lung cancer: a phase II trial. Semin Oncol. 1998; 25(4 Suppl 9):23-6. [PubMed 9728581]

42. Le Chevalier T. Single-agent activity of gemcitabine in advanced non-small cell lung cancer. Semin Oncol. 1996; 23(5 Suppl 10):36-42. [PubMed 8893880]

43. Shepherd F, Iglesias JL. Single agent gemcitabine: a new alternative for the treatment of elderly patients with advanced non-small cell lung cancer (NSCLC). Ann Oncol. 1996; 7(Suppl 5):A201P.

44. Thatcher N, Anderson H, Betticher DC et al. Symptomatic benefit from gemcitabine and other chemotherapy in advanced non-small cell lung cancer: changes in performance status and tumour-related symptoms. Anti-Cancer Drugs. 1995; 6(Suppl 6):39-48. [PubMed 8718424]

45. Hui YF, Reitz J. Gemcitabine: a cytidine analogue active against solid tumors. Am J Health-Syst Pharm. 1996; 54:162-70.

46. Fossella FV, Lippman SM, Shin DM et al. Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer. J Clin Oncol. 1997; 15:310-6. [IDIS 379625] [PubMed 8996158]

47. Kassem B, Miketic LM, Landreneau RJ et al. Phase I study of gemcitabine, given weekly as short infusion. Proc Annu Meet Am Soc Clin Oncol. 1995; 14:A1190.

48. Anderson H, Thatcher N, Walling J et al. A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. Br J Cancer. 1996; 74:460-2. [PubMed 8695365]

49. Ramanathan RK, Belani CP. Chemotherapy for advanced non-small cell lung cancer: past, present, and future. Semin Oncol. 1997; 24:440-54. [PubMed 9280224]

50. Halme M, Jekunen A, Tamminen K et al. Phase II study of weekly gemcitabine in advanced non-small cell lung cancer. Respir Med. 1997; 91:423-6. [PubMed 9327044]

51. Yokoyama A, Nakai Y, Yoneda S et al. Activity of gemcitabine in the treatment of patients with non-small cell lung cancer: a multicenter phase II study. Anticancer Drugs. 1997; 8:574-81. [PubMed 9300571]

52. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. J Clin Oncol. 1997; 15:2996-3018. [IDIS 391214] [PubMed 9256144]

53. Castellano D, Lianes P, Paz-Ares L et al. A phase II study of a novel gemcitabine plus cisplatin regimen administered every three weeks for advanced non-small-cell lung cancer. Ann Oncol. 1998; 9:457-9. [PubMed 9636840]

54. Non-small cell lung cancer. From CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

55. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995; 311:899-909. [PubMed 7580546]

56. Martin C, Ardizzoni A, Rosso R. Gemcitabine: safety profile and efficacy in non-small cell lung cancer unaffected by age. Aging Clin Exp Res. 1997; 9:297-303.

57. Burris III HA, Moore MJ, Anderson J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997; 15:2403-13. [IDIS 388900] [PubMed 9196156]

58. Noble S, Goa KL. Gemcitabine: a review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs. 1997; 54:447-72. [PubMed 9279506]

59. von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000; 18:3068-77. [PubMed 11001674]

60. Reviewers’ comments (personal observations) on bladder cancer.

61. Bladder cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

62. Lund B, Hansen OP, Theilade K et al. Phase II study of gemcitabine (2’,2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst. 1994; 86:1530-3. [IDIS 336649] [PubMed 7932808]

63. Shapiro JD, Millward MJ, Rischin D et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol. 1996; 63:89-93. [PubMed 8898175]

64. Friedlander M, Millward MJ, Bell D et al. A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol. 1998; 9:1343-5. [PubMed 9932166]

65. von Minckwitz G, Bauknecht T, Visseren-Grul CM et al. Phase II study of gemcitabine in ovarian cancer. Ann Oncol. 1999; 10:853-5. [PubMed 10470434]

66. Ovarian epithelial cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jul.

67. Vansteenkiste JF, Bomans P, Verbeken EK et al. Fatal pulmonary veno-occlusive disease possibly related to gemcitabine. Lung Cancer. 2001; 31:85-5.

68. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346:92-8. [IDIS 478960] [PubMed 11784875]

69. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet. 2001; 357:1478-84. [IDIS 463814] [PubMed 11377599]

70. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Gemzar (gemcitabine HCl) injection [June 23, 2000: Eli Lilly]. From FDA web site.

71. Pavlakis N, Bell DR, Millward MJ et al. Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer. 1997; 80:286-91. [IDIS 391351] [PubMed 9217042]

72. Blackstock AW, Lesser GJ, Fletcher-Steede J et al. Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2001; 51:1281-9. [PubMed 11728688]

73. Pfisterer J, Plante M, Vergote I et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006; 24:4699-707. [PubMed 16966687]

74. Albain KS, Nag SM, Calderillo-Ruiz G et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008; 26:3950-7. [PubMed 18711184]

75. . Drugs for breast cancer. Treat Guidel Med Lett. 2005; 3:1-6. [PubMed 15597095]

76. Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362:1273-81. [PubMed 20375404]

77. Furuse J, Takada T, Miyazaki M et al. Guidelines for chemotherapy of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg. 2008; 15:55-62. [PubMed 18274844]

78. Gemcitabine with or without cisplatin in treating patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors. From ClinicalTrials.gov registry (). Accessed 2011 Feb 24.

79. Glimelius B, Hoffman K, Sjödén PO et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996; 7:593-600. [PubMed 8879373]

80. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer. 2007; 96:896-902. [PubMed 17325704]

81. Ishii H, Furuse J, Yonemoto N et al. Chemotherapy in the treatment of advanced gallbladder cancer. Oncology. 2004; 66:138-42. [PubMed 15138366]

82. AHFS Final Determination: Gemcitabine and cisplatin in unresectable biliary tract cancer. Published 2012 Feb.

a. Eli Lilly and Company. Gemzar (gemcitabine) prescribing information. Indianapolis, IN: 2004 May 19.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:553-7.

Hide
(web2)