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Gemcitabine

Medically reviewed on August 12, 2018

Pronunciation

(jem SITE a been)

Index Terms

  • dFdC
  • dFdCyd
  • Difluorodeoxycytidine Hydrochlorothiazide
  • Gemcitabine HCl
  • Gemcitabine Hydrochloride
  • Gemzar, Inj
  • 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); 200 mg/2 mL (2 mL); 1 g/10 mL (10 mL); 1 g/26.3 mL (26.3 mL); 1.5 g/15 mL (15 mL); 2 g/20 mL (20 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); 2 g (1 ea)

Brand Names: U.S.

  • Gemzar

Pharmacologic Category

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

Pharmacology

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

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

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

Off Label Uses

Bladder cancer (advanced or metastatic)

Data from a large phase III randomized study supports the use of gemcitabine (in combination with cisplatin) for the treatment of advanced or metastatic bladder cancer [von der Maase 2000]. Data from a phase II/III study in patients with advanced bladder cancer who were ineligible to receive cisplatin supports the use of gemcitabine (in combination with carboplatin) in this population [De Santis 2012].

Bladder cancer (transitional cell, refractory)

Data from a small phase II study supports the use of intravesicular gemcitabine for the treatment of transitional cell carcinoma of the bladder in patients who are intolerant of or with disease refractory to intravesicular BCG instillation [Dalbagni 2006].

Cervical cancer (recurrent or persistent)

Data from a randomized phase III study comparing gemcitabine (in combination with cisplatin) to 3 other cisplatin-containing doublet regimens supports the use of gemcitabine for the treatment of advanced, recurrent or persistent cervical carcinoma [Monk 2009]. Data from 2 small phase II studies also support the use of gemcitabine (in combination with cisplatin) for the treatment of advanced, persistent, or recurrent cervical cancer [Brewer 2006], [Burnett 2000]. Data from a small phase II study in patients with recurrent or persistent non-squamous cell cervical cancer supports the use of gemcitabine as a single agent [Schilder 2005].

Ewing sarcoma (refractory)

Data from a small retrospective study (in patients ages 8 to 23 years) suggest that gemcitabine (in combination with docetaxel) may be beneficial for the treatment of refractory Ewing sarcoma [Navid 2008]. Additional data may be necessary to further define the role of gemcitabine in this condition.

Germ cell tumors (refractory) (pediatrics)

Data from a small phase II study (which included pediatric patients) supports the use of gemcitabine in the management of refractory germ cell tumors in adolescents 16 years of age and older [Einhorn 1999].

Head and neck cancer: nasopharyngeal (advanced or metastatic)

Data from a small phase II study supports the use of gemcitabine (as a single agent) in the management of advanced nasopharyngeal carcinoma after failure of platinum-based therapy [Zhang 2008]. Data from another phase II study supports the use of gemcitabine (in combination with vinorelbine) as salvage therapy in patients who had previously received platinum-based therapy for the treatment of metastatic nasopharyngeal carcinoma [Chen 2012].

Hepatobiliary cancer (advanced)

Data from a large randomized phase III study supports the use of gemcitabine (in combination with cisplatin) in the treatment of unresectable, recurrent or metastatic biliary tract cancers, including cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma [Valle 2010]. Data from 2 phase II studies support the use of gemcitabine (in combination with either oxaliplatin or capecitabine) for the treatment of advanced biliary tract cancers [André 2004], [Knox 2005].

Hodgkin lymphoma (relapsed)

Survival data from a phase I/II study in adults supports the use of gemcitabine (in combination with vinorelbine and doxorubicin liposomal) as a salvage regimen for relapsed or refractory Hodgkin lymphoma [Bartlett 2007]. Data from a study (in patients 17 years of age and older) supports the use of gemcitabine (in combination with ifosfamide, mesna, vinorelbine, and prednisolone) as salvage induction therapy for relapsed or refractory Hodgkin lymphoma [Santoro 2007]. Data from a phase II study in pediatric patients supports the use of gemcitabine (in combination with vinorelbine) for the treatment of recurrent or refractory Hodgkin lymphoma [Cole 2009].

Malignant pleural mesothelioma

Data from 2 multicenter phase II studies support the use of gemcitabine (in combination with cisplatin) in the management of malignant pleural mesothelioma [Nowak 2002], [van Haarst 2002].

Non-Hodgkin lymphoma (relapsed/refractory)

Data from a phase II study supports the use of gemcitabine (in combination with cisplatin and dexamethasone) for the treatment of relapsed or refractory diffuse large B cell non-Hodgkin lymphoma [Crump 2004]. Data from a phase II study supports the use of gemcitabine (in combination with oxaliplatin and rituximab) as salvage therapy for relapsed or refractory diffuse large B cell non-Hodgkin lymphoma [Lopez 2008].

Osteosarcoma (refractory)

Data from a small retrospective study (in patients ages 8 to 23 years) suggest that gemcitabine (in combination with docetaxel) may be beneficial for the treatment of refractory osteosarcoma [Navid 2008]. Data from a small phase II study in soft tissue and bone sarcomas (which included some osteosarcomas) supports the use of gemcitabine (as a single agent) in the treatment of refractory osteosarcoma [Merimsky 2000]. Additional data may be necessary to further define the role of gemcitabine in this condition.

Pancreatic cancer (adjuvant therapy)

Data from a randomized, multicenter phase III study supports the use of gemcitabine (in combination with capecitabine) in the adjuvant treatment of completely resected pancreatic adenocarcinoma [Neoptolemos 2017].

According to the American Society of Clinical Oncology Guidelines for Potentially Curable Pancreatic Cancer, patients with resected pancreatic cancer who did not receive pre-operative therapy should be offered 6 months of adjuvant therapy beginning within 8 weeks of resection (if recovery is complete); gemcitabine (in combination with capecitabine) is the preferred therapy in the absence of contraindications.

Renal carcinoma (metastatic)

Data from a multicenter phase II study support the use of gemcitabine (in combination with either cisplatin or carboplatin) for the treatment of metastatic collecting duct renal carcinoma [Oudard 2007]. Additional data may be necessary to further define the role of gemcitabine in this condition.

Small cell lung cancer (refractory or relapsed)

A small phase II study demonstrated modest activity but limited toxicity and supports the use of gemcitabine (as a single agent) in the treatment of relapsed or refractory small cell lung cancer [Masters 2003].

Soft tissue sarcoma (advanced)

Data from a phase II study supports the use of gemcitabine (in combination with docetaxel) in the treatment of metastatic soft tissue sarcoma [Maki 2007]. Data from a phase II study supports the use of gemcitabine (in combination with vinorelbine) in the treatment of advanced soft tissue sarcomas [Dileo 2007]. A retrospective review in patients with bone and soft tissue sarcoma suggest the utility of using gemcitabine (in combination with docetaxel) for the treatment of soft-tissue sarcoma [Leu 2004].

Testicular cancer (refractory germ cell)

Data from 3 phase II studies support the use of gemcitabine (in combination with oxaliplatin) in the treatment of cisplatin-refractory germ cell tumors [DeGiorgi 2006], [Kohllmannsberger 2004], [Pectasides 2004]. Data from a small phase II study supports the use of gemcitabine (in combination with paclitaxel) in the treatment of refractory germ cell tumors [Hinton 2002]. Additionally, a phase II study supports the use of gemcitabine (in combination with oxaliplatin and paclitaxel) for the treatment of refractory or relapsed (multiply relapsed) germ cell tumors [Bokemeyer 2008].

Thymic malignancies (refractory)

Preliminary data from a small phase II study suggest that gemcitabine (in combination with capecitabine) has activity in the treatment of refractory thymic malignancies [Palmieri 2010]. Additional data may be necessary to further define the role of gemcitabine in this condition.

Unknown-primary carcinoma

Data from a phase II study supports the use of gemcitabine (in combination with docetaxel) in the management of unknown primary carcinoma [Pouessel 2004]. Data from 2 small studies demonstrated activity with the use of gemcitabine (in combination with cisplatin) for management of unknown primary carcinoma [Culine 2003], [Gross-Goupil 2012]. Additional data may be necessary to further define the role of gemcitabine in the treatment of this condition.

Uterine cancer

Data from a phase II study supports the use of fixed-dose rate gemcitabine (in combination with docetaxel) for the treatment of metastatic uterine leiomyosarcoma [Hensley 2008]. Data from a phase II study supports the use of gemcitabine as a single agent for management of recurrent or persistent uterine leiomyosarcoma in patients who had received prior chemotherapy [Look 2004].

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: 1,250 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 (inoperable, locally advanced, or metastatic): IV: 1,000 mg/m2 over 30 minutes days 1, 8, and 15; repeat cycle every 28 days (in combination with cisplatin) or 1,250 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) or (off-label dosing/combination) 1,000 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) 1,000 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) 1,000 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) 1,000 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: 1,000 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) 1,000 mg/m2 over 30 to 60 minutes days 1 and 8; repeat cycle every 21 days (Mutch 2007)

Pancreatic cancer (locally advanced or metastatic): IV: Initial: 1,000 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) 1,000 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 1,000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (in combination with capecitabine) (Cunningham 2009) or 1,000 mg/m2 over 30 minutes days 1 and 15 every 28 days (in combination with cisplatin) (Heinemann 2006) or 1,000 mg/m2 infused at 10 mg/m2/minute every 14 days (in combination with oxaliplatin) (Louvet 2005) or 1,000 mg/m2 days 1, 8, and 15 every 28 days (in combination with paclitaxel [protein bound]) (Von Hoff 2013)

Pancreatic cancer (adjuvant therapy) (off-label use): IV: 1,000 mg/m2 on days 1, 8 and 15 every 28 days (in combination with capecitabine) for 6 cycles beginning within 12 weeks of resection (Neoptolemos 2017). American Society of Clinical Oncology guidelines recommend initiating within 8 weeks of resection (ASCO [Khorana 2017]).

Bladder cancer (off-label use):

Advanced or metastatic: IV: 1,000 mg/m2 over 30 to 60 minutes days 1, 8, and 15; repeat cycle every 28 days (in combination with cisplatin) (von der Maase 2000) or 1,000 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 (refractory): Intravesicular instillation: 2,000 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: 1,000 mg/m2 days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) (Monk 2009) or 1,250 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, advanced or metastatic (off-label use): IV: 1,000 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days (Zhang 2008) or 1,000 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: 1,000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin) (Valle 2010) or 1,000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with capecitabine) (Knox 2005) or 1,000 mg/m2 infused at 10 mg/m2/minute every 2 weeks (in combination with oxaliplatin) (Andre 2004)

Hodgkin lymphoma, relapsed (off-label use): IV: 1,000 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: 1,000 mg/m2 over 30 minutes days 1, 8 and 15 every 28 days for up to 6 cycles (Nowak 2002) or 1,250 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: 1,000 mg/m2 over 30 minutes days 1 and 8; repeat cycle every 21 days (in combination with cisplatin and dexamethasone) (Crump 2004) or 1,000 mg/m2 every 15 to 21 days (in combination with oxaliplatin and rituximab) (Lopez 2008)

Sarcomas (off-label uses): IV:

Ewing 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 1,000 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: 1,000 to 1,250 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: 1,000 to 1,250 mg/m2 over 30 minutes days 1 and 8 every 21 days (in combination with oxaliplatin) (DeGiorgi 2006; Kohllmannsberger 2004; Pectasides 2004) or 1,000 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: 1,250 mg/m2 days 1 and 8 every 21 days (in combination with cisplatin) (Culine 2003; Gross-Goupil 2012) or 1,000 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 1,000 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): Adolescents ≥16 years: IV: 1,200 mg/m2 over 30 minutes days 1, 8, and 15 every 28 days for a maximum of 6 cycles (Einhorn 1999)

Hodgkin lymphoma, relapsed (off-label use): IV: 1,000 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 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 1,000 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 to 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 to 1199/mm3 or platelet count 50,000 to 75,000/mm3: Administer 75% of full dose

AGC 700 to 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 to 999/mm3 or platelet count 50,000 to 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 to 1499/mm3 or platelet count 75,000 to 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, neutropenic fever, 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 (locally advanced or metastatic):

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

AGC 500 to 999/mm3 or platelet count 50,000 to 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

Lyophilized powder: Reconstitute lyophilized powder with preservative free NS; add 5 mL to the 200 mg vial, add 25 mL to the 1,000 mg vial, or add 50 mL to the 2,000 mg vial, resulting in a reconstituted concentration of 38 mg/mL (solutions must be reconstituted to ≤40 mg/mL to completely dissolve).

Solution for injection: Gemcitabine solution for injection may be available in various concentrations; verify product carefully prior to admixture to assure appropriate dose preparation.

Must be further diluted prior to 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

IV: Infuse over 30 minutes (for labeled indications); 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)

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: Varies by manufacturer; refer to product labeling.

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

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

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. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. 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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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. Consider therapy modification

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.

>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 alanine aminotransferase (68%), increased serum aspartate aminotransferase (67%), increased serum alkaline phosphatase (55%), increased serum bilirubin (13%)

Infection: Infection (16%)

Renal: Increased blood urea nitrogen (16%)

Respiratory: Dyspnea (23%), flu-like symptoms (19%)

Miscellaneous: Fever (41%)

1% to 10%:

Central nervous system: Paresthesia (10%)

Local: Injection site reaction (4%)

Renal: Increased serum creatinine (8%)

Respiratory: Bronchospasm (<2%)

<1%, postmarketing, and/or case reports (reported with single-agent use or with combination therapy): Adult respiratory distress syndrome, anaphylactoid reaction, bullous skin disease, capillary leak syndrome, cardiac arrhythmia, cardiac failure, cellulitis (including pseudocellulitis), cerebrovascular accident (Kuenen 2002), desquamation, gangrene of skin and/or subcutaneous tissues, hemolytic-uremic syndrome, hepatic failure, hepatic sinusoidal obstruction syndrome, hepatotoxicity, interstitial pneumonitis, myocardial infarction, petechia (Nishijima 2013; Zupancic 2007), pruritus (Curtis 2016), pulmonary edema, pulmonary fibrosis, radiation recall phenomenon, renal failure syndrome, respiratory failure, reversible posterior leukoencephalopathy syndrome, sepsis, supraventricular cardiac arrhythmia, thrombotic thrombocytopenic purpura (Nishijima 2013; Zupancic 2007), vasculitis (peripheral)

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.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.

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).

• Multiple concentrations: Gemcitabine is available in multiple formulations and concentrations; verify product and concentration prior to admixture to assure appropriate dose preparation.

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

Based on the mechanism of action and on findings from animal reproduction studies, gemcitabine may cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during treatment and for 6 months after the final gemcitabine dose. Men with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the final dose.

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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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