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Gemcitabine

Pronunciation

Pronunciation

(jem SITE a been)

Index Terms

  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine Hydrochlorothiazide
  • Gemcitabine HCl
  • Gemcitabine Hydrochloride
  • LY-188011

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 200 mg/5.26 mL (5.26 mL); 1 g/26.3 mL (26.3 mL); 2 g/52.6 mL (52.6 mL)

Solution, Intravenous [preservative free]:

Generic: 200 mg/5.26 mL (5.26 mL); 1 g/26.3 mL (26.3 mL); 2 g/52.6 mL (52.6 mL)

Solution Reconstituted, Intravenous:

Gemzar: 200 mg (1 ea); 1 g (1 ea)

Generic: 200 mg (1 ea); 1 g (1 ea); 2 g (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 200 mg (1 ea); 1 g (1 ea)

Brand Names: U.S.

  • Gemzar

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

A pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, cell cycle-specific for the S-phase of the cycle (also blocks cellular progression at G1/S-phase). Gemcitabine is phosphorylated intracellularly by deoxycytidine kinase to gemcitabine monophosphate, which is further phosphorylated to active metabolites gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase; gemcitabine triphosphate incorporates into DNA and inhibits DNA polymerase.

Distribution

Widely distributed into tissues; present in ascitic fluid; Vd: Infusions <70 minutes: 50 L/m2; Long infusion times (70-285 minutes): 370 L/m2

Metabolism

Metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites

Excretion

Urine (92% to 98%; primarily as inactive uracil metabolite); feces (<1%)

Time to Peak

30 minutes after completion of infusion

Half-Life Elimination

Gemcitabine: Infusion time ≤70 minutes: 42 to 94 minutes; infusion time 3 to 4 hours: 4 to 10.5 hours (affected by age and gender)

Metabolite (gemcitabine triphosphate), terminal phase: 1.7 to 19.4 hours

Protein Binding

Negligible

Special Populations: Elderly

The lower clearance in elderly patients results in higher concentrations of gemcitabine for any given dose.

Special Populations: Gender

The lower clearance in women results in higher concentrations of gemcitabine for any given dose.

Use: Labeled Indications

Breast cancer: First-line treatment of metastatic breast cancer (in combination with paclitaxel) after failure of adjuvant chemotherapy which contained an anthracycline (unless contraindicated)

Non-small cell lung cancer (NSCLC): First-line treatment of inoperable, locally-advanced (stage IIIA or IIIB) or metastatic (stage IV) NSCLC (in combination with cisplatin)

Ovarian cancer: Treatment of advanced ovarian cancer (in combination with carboplatin) that has relapsed at least 6 months following completion of platinum-based chemotherapy

Pancreatic cancer: First-line treatment of locally-advanced (nonresectable stage II or III) or metastatic (stage IV) pancreatic adenocarcinoma

Use: Unlabeled

Treatment of bladder cancer, cervical cancer (recurrent or persistent), Ewing sarcoma (refractory), head and neck cancer (nasopharyngeal), hepatobiliary cancers (advanced), Hodgkin lymphoma (relapsed), non-Hodgkin lymphomas (refractory), malignant pleural mesothelioma, osteosarcoma (refractory), renal cell cancer (metastatic), small cell lung cancer (refractory or relapsed), soft tissue sarcoma (advanced), testicular cancer (refractory germ cell tumors), thymic malignancies, uterine sarcoma, and unknown-primary adenocarcinoma

Contraindications

Hypersensitivity to gemcitabine or any component of the formulation

Dosing: Adult

Note: Prolongation of the infusion duration >60 minutes and administration more frequently than once weekly have been shown to increase toxicity.

Breast cancer, metastatic: IV: 1250 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with paclitaxel) or (off-label dosing; as a single agent) 800 mg/m2 over 30 minutes days 1, 8, and 15 of a 28-day treatment cycle (Carmichael, 1995)

Non-small cell lung cancer, locally advanced or metastatic: IV: 1000 mg/m2 over 30 minutes days 1, 8, and 15; repeat cycle every 28 days (in combination with cisplatin) or 1250 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) or (off-label dosing/combination) 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with carboplatin) for up to 4 cycles (Grønberg, 2009) or (off-label combination) 1000 mg/m2 over 30 minutes days 1, 8, and 15; repeat cycle every 28 days (in combination with carboplatin) for up to 4 cycles (Danson, 2003) or (off-label combination) 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) for 8 cycles (Pujol, 2005) or (off-label combination) 1000 mg/m2 days 1, 8, and 15; repeat cycle every 28 days (in combination with vinorelbine) for 6 cycles (Greco, 2007)

Ovarian cancer, advanced: IV: 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with carboplatin) or (off-label dosing; as a single agent) 1000 mg/m2 over 30-60 minutes days 1 and 8; repeat cycle every 21 days (Mutch, 2007)

Pancreatic cancer, locally advanced or metastatic: IV: Initial: 1000 mg/m2 over 30 minutes once weekly for 7 weeks followed by 1 week rest; then once weekly for 3 weeks out of every 4 weeks or (off-label combinations) 1000 mg/m2 over 30 minutes weekly for up to 7 weeks followed by 1 week rest; then weekly for 3 weeks out of every 4 weeks (in combination with erlotinib) (Moore, 2007) or 1000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (in combination with capecitabine) (Cunningham, 2009) or 1000 mg/m2 over 30 minutes days 1 and 15 every 28 days (in combination with cisplatin) (Heinemann, 2006) or 1000 mg/m2 infused at 10 mg/m2/minute every 14 days (in combination with oxaliplatin) (Louvet, 2005) or 1000 mg/m2 days 1, 8, and 15 every 28 days (in combination with paclitaxel [protein bound]) (Von Hoff, 2013)

Bladder cancer (off-label use):

Advanced or metastatic: IV: 1000 mg/m2 over 30-60 minutes days 1, 8, and 15; repeat cycle every 28 days (in combination with cisplatin) (von der Maase, 2000) or 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with carboplatin) until disease progression or unacceptable toxicity (De Santis, 2012)

Transitional cell carcinoma: Intravesicular instillation: 2000 mg (in 100 mL NS; retain for 1 hour) twice weekly for 3 weeks; repeat cycle every 4 weeks for at least 2 cycles (Dalbagni, 2006)

Cervical cancer, recurrent or persistent (off-label use): IV: 1000 mg/m2 days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) (Monk, 2009) or 1250 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) (Burnett, 2000) or 800 mg/m2 over 30 minutes days 1, 8, and 15; repeat cycle every 28 days (as a single-agent) (Schilder, 2005) or 800 mg/m2 days 1 and 8; repeat cycle every 28 days (in combination with cisplatin) (Brewer, 2006)

Head and neck cancer, nasopharyngeal (off-label use): IV: 1000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (Zhang, 2008) or 1000 mg/m2 over 30 minutes days 1 and 8 every 21 days (in combination with vinorelbine) (Chen, 2012)

Hepatobiliary cancer, advanced (off-label use): IV: 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) (Valle, 2010) or 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with capecitabine) (Knox, 2005) or 1000 mg/m2 infused at 10 mg/m2/minute every 2 weeks (in combination with oxaliplatin) (Andre, 2004)

Hodgkin lymphoma, relapsed (off-label use): IV: 1000 mg/m2 (800 mg/m2 for post-transplant patients) over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with vinorelbine and doxorubicin liposomal) (Bartlett, 2007) or 800 mg/m2 days 1 and 4; repeat cycle every 21 days (in combination with ifosfamide, mesna, vinorelbine, and prednisolone) (Santoro, 2007)

Malignant pleural mesothelioma (off-label use; in combination with cisplatin): IV: 1000 mg/m2 over 30 minutes days 1, 8 and 15 every 28 days for up to 6 cycles (Nowak, 2002) or 1250 mg/m2 over 30 minutes days 1 and 8 every 21 days for up to 6 cycles (van Haarst, 2002)

Non-Hodgkin lymphoma, refractory (off-label use): IV: 1000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin and dexamethasone) (Crump, 2004) or 1000 mg/m2 every 15-21 days (in combination with oxaliplatin and rituximab) (Lopez, 2008)

Sarcoma (off-label uses): IV:

Ewing’s sarcoma, refractory: 675 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Navid, 2008)

Osteosarcoma, refractory: 675 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Navid, 2008) or 1000 mg/m2 weekly for 7 weeks followed by 1 week rest; then weekly for 3 weeks out of every 4 weeks (Merimsky, 2000)

Soft tissue sarcoma, advanced: 800 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with vinorelbine) (Dileo, 2007) or 675 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Leu, 2004) or 900 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Maki, 2007)

Small cell lung cancer, refractory or relapsed (off-label use): IV: 1000-1250 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (as a single agent) (Masters, 2003)

Testicular cancer, refractory germ cell (off-label use): IV: 1000-1250 mg/m2 over 30 minutes days 1 and 8 every 21 days (in combination with oxaliplatin) (DeGiorgi, 2006; Kohllmannsberger, 2004; Pectasides, 2004) or 1000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days for up to 6 cycles (in combination with paclitaxel) (Hinton, 2002) or 800 mg/m2 over 30 minutes days 1 and 8 every 21 days (in combination with oxaliplatin and paclitaxel) (Bokemeyer, 2008)

Unknown-primary, adenocarcinoma (off-label use): IV: 1250 mg/m2 days 1 and 8 every 21 days (in combination with cisplatin) (Culine, 2003) or 1000 mg/m2 over 30 minutes days 1 and 8 every 21 days for up to 6 cycles (in combination with docetaxel) (Pouessel, 2004)

Uterine cancer (off-label use): IV: 900 mg/m2 over 90 minutes days 1 and 8 every 21 days (in combination with docetaxel) (Hensley, 2008) or 1000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (Look, 2004)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Prolongation of the infusion duration >60 minutes and administration more frequently than once weekly have been shown to increase toxicity. Refer to specific references for ages of populations studied:

Germ cell tumor, refractory (off-label use): IV: 1000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (in combination with paclitaxel) for up to 6 cycles (Hinton, 2002)

Hodgkin lymphoma, relapsed (off-label use): IV: 1000 mg/m2 over 100 minutes days 1 and 8; repeat cycle every 21 days (in combination with vinorelbine) (Cole; 2009) or 800 mg/m2 days 1 and 4; repeat cycle every 21 days (in combination with ifosfamide, mesna, vinorelbine, and prednisolone) (Santoro, 2007)

Sarcomas (off-label use): IV:

Ewing’s sarcoma, refractory: 675 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Navid, 2008)

Osteosarcoma, refractory: 675 mg/m2 over 90 minutes days 1 and 8; repeat cycle every 21 days (in combination with docetaxel) (Navid, 2008) or 1000 mg/m2 weekly for 7 weeks followed by 1 week rest; then weekly for 3 weeks out of every 4 weeks (Merimsky, 2000)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution in patients with pre-existing renal dysfunction. Discontinue if severe renal toxicity or hemolytic uremic syndrome (HUS) occur during gemcitabine treatment.

Mild-to-severe renal impairment: No dosage adjustment necessary (Janus, 2010; Li, 2007).

ESRD (on hemodialysis): Hemodialysis should begin 6-12 hours after gemcitabine infusion (Janus 2010; Li, 2007).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Discontinue if severe hepatotoxicity occurs during gemcitabine treatment. The following adjustments have been reported:

Transaminases elevated (with normal bilirubin): No dosage adjustment necessary (Venook, 2000).

Serum bilirubin >1.6 mg/dL: Use initial dose of 800 mg/m2; may escalate if tolerated (Ecklund, 2005; Floyd, 2006; Venook, 2000).

Dosing: Adjustment for Toxicity

Nonhematologic toxicity (all indications):

Hold or decrease gemcitabine dose by 50% for the following: Severe (grade 3 or 4) nonhematologic toxicity until resolved (excludes nausea, vomiting, or alopecia [no dose modifications recommended])

Permanently discontinue gemcitabine for any of the following: Unexplained dyspnea (or other evidence of severe pulmonary toxicity), severe hepatotoxicity, hemolytic uremic syndrome (HUS), capillary leak syndrome (CLS), posterior reversible encephalopathy syndrome (PRES)

Hematologic toxicity:

Breast cancer:

Day 1:

Absolute granulocyte count (AGC) ≥1500/mm3 and platelet count ≥100,000/mm3: Administer 100% of full dose

AGC <1500/mm3 or platelet count <100,000/mm3: Hold dose

Day 8:

AGC ≥1200/mm3 and platelet count >75,000/mm3: Administer 100% of full dose

AGC 1000-1199/mm3 or platelet count 50,000-75,000/mm3: Administer 75% of full dose

AGC 700-999/mm3 and platelet count ≥50,000/mm3: Administer 50% of full dose

AGC <700/mm3 or platelet count <50,000/mm3: Hold dose

Non-small cell lung cancer (cisplatin dosage may also require adjustment):

AGC ≥1000/mm3 and platelet count ≥100,000/mm3: Administer 100% of full dose

AGC 500-999/mm3 or platelet count 50,000-99,999/mm3: Administer 75% of full dose

AGC <500/mm3 or platelet count <50,000/mm3: Hold dose

Ovarian cancer:

Day 1:

AGC ≥1500/mm3 and platelet count ≥100,000/mm3: Administer 100% of full dose

AGC <1500/mm3 or platelet count <100,000/mm3: Delay treatment cycle

Day 8:

AGC ≥1500/mm3 and platelet count ≥100,000/mm3: Administer 100% of full dose

AGC 1000-1499/mm3 or platelet count 75,000-99,999/mm3: Administer 50% of full dose

AGC <1000/mm3 or platelet count <75,000/mm3: Hold dose

Hematologic toxicity in previous cycle (dosing adjustment for subsequent cycles):

Initial occurrence: AGC <500/mm3 for >5 days, AGC <100/mm3 for >3 days, febrile neutropenia, platelet count <25,000/mm3, or cycle delay >1 week due to toxicity: Permanently reduce gemcitabine to 800 mg/m2 on days 1 and 8.

Subsequent occurrence: AGC <500/mm3 for >5 days, AGC <100/mm3 for >3 days, neutropenic fever, platelet count <25,000/mm3, or cycle delay >1 week due to toxicity: Permanently reduce gemcitabine to 800 mg/m2 and administer on day 1 only.

Pancreatic cancer:

AGC ≥1000/mm3 and platelet count ≥100,000/mm3: Administer 100% of full dose

AGC 500-999/mm3 or platelet count 50,000-99,999/mm3: Administer 75% of full dose

AGC <500/mm3 or platelet count <50,000/mm3: Hold dose

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Reconstitute lyophilized powder with preservative free NS; add 5 mL to the 200 mg vial, add 25 mL to the 1000 mg vial, or add 50 mL to the 2000 mg vial, resulting in a reconstituted concentration of 38 mg/mL (solutions must be reconstituted to ≤40 mg/mL to completely dissolve). Gemcitabine is also supplied as a concentrated solution for injection in different concentrations (40 mg/mL [Canada only] and 38 mg/mL); verify product concentration prior to preparation for administration.

Further dilute reconstituted lyophilized powder or concentrated solution for injection in NS for infusion; to concentrations as low as 0.1 mg/mL.

Administration

Infuse over 30 minutes; for off-label uses, infusion times may vary (refer to specific references). Note: Prolongation of the infusion time >60 minutes has been shown to increase toxicity. Gemcitabine has been administered at a fixed-dose rate (FDR) infusion rate of 10 mg/m2/minute to optimize the pharmacokinetics (off-label); prolonged infusion times increase the intracellular accumulation of the active metabolite, gemcitabine triphosphate (Ko, 2006; Tempero, 2003). Patients who receive gemcitabine FDR experience more grade 3/4 hematologic toxicity (Ko, 2006; Poplin, 2009).

For intravesicular (bladder) instillation (off-label route), gemcitabine was diluted in 50 to 100 mL normal saline; patients were instructed to retain in the bladder for 1 hour (Addeo, 2010; Dalbaghi, 2006)

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5W, NS.

Y-site administration: Incompatible with acyclovir, amphotericin B, cefotaxime, furosemide, ganciclovir, imipenem/cilastatin, irinotecan, methotrexate, methylprednisolone sodium succinate, mitomycin, pemetrexed, piperacillin, piperacillin/tazobactam, prochlorperazine edisylate.

Storage

Lyophilized powder: Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted vials are stable for 24 hours at room temperature. Do not refrigerate (may form crystals).

Solution for injection: Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze.

Solutions diluted for infusion in NS are stable for 24 hours at room temperature. Do not refrigerate.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bleomycin: Gemcitabine may enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Consider therapy modification

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluorouracil (Systemic): Gemcitabine may increase the serum concentration of Fluorouracil (Systemic). Monitor therapy

Fluorouracil (Topical): Gemcitabine may increase the serum concentration of Fluorouracil (Topical). Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Warfarin: Gemcitabine may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

Frequency of adverse reactions reported for single-agent use of gemcitabine only; bone marrow depression is the dose-limiting toxicity.

>10%:

Cardiovascular: Peripheral edema (20%), edema (13%)

Central nervous system: Drowsiness (11%)

Dermatologic: Skin rash (30%), alopecia (15%)

Gastrointestinal: Nausea and vomiting (69%), diarrhea (19%), stomatitis (11%)

Genitourinary: Proteinuria (45%), hematuria (35%)

Hematologic & oncologic: Anemia (68%; grade 3: 7%; grade 4: 1%), neutropenia (63%; grade 3: 19%; grade 4: 6%), thrombocytopenia (24%; grade 3: 4%; grade 4: 1%), hemorrhage (17%; grade 3: <1%; grade 4: <1%)

Hepatic: Increased serum ALT (68%; grade 3: 8%, grade 4: 2%), increased serum AST (67%; grade 3: 6%; grade 4: 2%), increased serum alkaline phosphatase (55%; grade 3: 7%; grade 4: 2%), increased serum bilirubin (13%; grade 3: 2%, grade 4: <1%)

Infection: Infection (16%)

Renal: Increased blood urea nitrogen (16%)

Respiratory: Dyspnea (23%; grade 3: 3%; grade 4: <1%), flu-like symptoms (19%)

Miscellaneous: Fever (41%)

1% to 10%:

Central nervous system: Paresthesia (10%; grade 3: <1%)

Local: Injection site reaction (4%)

Renal: Increased serum creatinine (8%)

Respiratory: Bronchospasm (<2%)

<1% (Limited to important or life-threatening; reported with single-agent use or with combination therapy): Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arthralgia, bullous skin disease, capillary leak syndrome, cardiac arrhythmia, cardiac failure, cellulitis, cerebrovascular accident (Kuenen 2002), constipation, desquamation, digital vasculitis, gangrene of skin or other tissue, hemolytic-uremic syndrome, hepatic failure, hepatic veno-occlusive disease, hepatotoxicity (rare), hyperglycemia, hypertension, hypocalcemia, hypotension, increased gamma-glutamyl transferase, interstitial pneumonitis, myocardial infarction, neuropathy, petechiae (Nishijima 2013; Zupancic 2007), pruritus (Curtis 2014), pulmonary edema, pulmonary fibrosis, radiation recall phenomenon, renal failure, respiratory failure, reversible posterior leukoencephalopathy syndrome, sepsis, supraventricular cardiac arrhythmia, thrombotic thrombocytopenic purpura (Nishijima 2013; Zupancic 2007)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause bone marrow suppression (neutropenia, thrombocytopenia, and anemia); myelosuppression is generally the dose-limiting toxicity and is increased when used in combination with other chemotherapy. Monitor blood counts; dosage adjustments are frequently required.

• Capillary leak syndrome: Capillary leak syndrome (CLS) with serious consequences has been reported, both with single-agent gemcitabine and with combination chemotherapy; discontinue if CLS develops.

• Hemolytic uremic syndrome: Hemolytic uremic syndrome (HUS) has been reported; may lead to renal failure and dialysis (including fatalities); monitor for evidence of anemia with microangiopathic hemolysis (elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or renal failure) and monitor renal function at baseline and periodically during treatment. Permanently discontinue if HUS or severe renal impairment occurs; renal failure may not be reversible despite discontinuation.

• Hepatotoxicity: Serious hepatotoxicity (including liver failure and death) has been reported (when used alone or in combination with other hepatotoxic medications); use in patients with hepatic impairment (history of cirrhosis, hepatitis, or alcoholism) or in patients with hepatic metastases may lead to exacerbation of hepatic impairment. Monitor hepatic function at baseline and periodically during treatment; consider dose adjustments with elevated bilirubin; discontinue if severe liver injury develops.

• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported, both with single-agent therapy and with combination chemotherapy. PRES may manifest with blindness, confusion, headache, hypertension, lethargy, seizure, and other visual and neurologic disturbances. If PRES diagnosis is confirmed (by MRI), discontinue therapy.

• Pulmonary toxicity: Pulmonary toxicity, including adult respiratory distress syndrome, interstitial pneumonitis, pulmonary edema, and pulmonary fibrosis, has been observed; may lead to respiratory failure (some fatal) despite discontinuation. Onset for symptoms of pulmonary toxicity may be delayed up to 2 weeks beyond the last dose. Discontinue for unexplained dyspnea (with or without bronchospasm) or other evidence of pulmonary toxicity.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Radiation therapy recipients: Not indicated for use with concurrent radiation therapy; radiation toxicity, including tissue injury, severe mucositis, esophagitis, or pneumonitis, has been reported with concurrent and nonconcurrent administration; has radiosensitizing activity when gemcitabine and radiation therapy are given together or ≤7 days apart; radiation recall may occur when gemcitabine and radiation therapy are given >7 days apart.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Infusion duration/frequency: Prolongation of the infusion duration >60 minutes or more frequent than weekly dosing have been shown to alter the half-life and increase toxicity (hypotension, flu-like symptoms, myelosuppression, weakness). A fixed-dose rate (FDR) infusion rate of 10 mg/m2/minute has been studied in adults in order to optimize the pharmacokinetics (off-label); prolonged infusion times increase the intracellular accumulation of the active metabolite, gemcitabine triphosphate (Ko, 2006; Tempero, 2003). Patients who receive gemcitabine FDR experience more grade 3/4 hematologic toxicity (Ko, 2006; Poplin, 2009).

Monitoring Parameters

CBC with differential and platelet count (prior to each dose); hepatic and renal function (prior to initiation of therapy and periodically, thereafter); monitor electrolytes, including potassium, magnesium, and calcium (when in combination therapy with cisplatin); monitor pulmonary function; signs/symptoms of capillary leak syndrome and posterior reversible encephalopathy syndrome

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy; adverse effects in reproduction are anticipated based on the mechanism of action.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, nausea, vomiting, diarrhea, lack of appetite, constipation, mouth sores, hair loss, loss of strength and energy, headache, or fatigue. Have patient report immediately to prescriber signs of infection, signs of capillary leak syndrome (abnormal heartbeat; angina; shortness of breath; weight gain; vomiting blood or vomit that looks like coffee grounds; black, tarry, or bloody stools; urinary retention or change in amount of urine passed; hematuria), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of high blood sugar (confusion, feeling sleepy, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of Hemolytic-uremic syndrome (urinary retention; loss of strength and energy; signs of bleeding or bruising; fever; or swelling of the face, hands, feet, or body), severe dizziness, passing out, shortness of breath, burning or numbness feeling, or severe injection site burning, redness, edema, pain, or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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