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Medication Safety Issues
Sound-alike/look-alike issues:
Gemcitabine may be confused with gemtuzumab
Gemzar® may be confused with Zinecard®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(jem SITE a been)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of metastatic breast cancer; locally-advanced or metastatic nonsmall cell lung cancer (NSCLC) or pancreatic cancer; advanced, relapsed ovarian cancer
Use: Unlabeled/Investigational
Treatment of bladder cancer, cervical cancer, Hodgkin's disease, non-Hodgkin's lymphomas, small cell lung cancer, hepatobiliary cancers
Pregnancy Risk Factor
D
Pregnancy Considerations
Embryotoxicity and fetal malformations (cleft palate, incomplete ossification, fused pulmonary artery, absence of gallbladder) have been reported in animal studies. There are no adequate and well-controlled studies in pregnant women. If patient becomes pregnant, she should be informed of risks.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to gemcitabine or any component of the formulation; pregnancy
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: May cause bone marrow suppression (leukopenia, thrombocytopenia, and anemia); myelosuppression is usually the dose-limiting toxicity.
• Fever: May cause fever in the absence of clinical infection.
• Hemolytic uremic syndrome: With use, hemolytic uremic syndrome has been reported; monitor for evidence of microangiopathic hemolysis (elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or renal failure).
• Hepatotoxicity: Serious hepatotoxicity has been reported; use caution with hepatic impairment (history of cirrhosis, hepatitis, or alcoholism) or in patients with hepatic metastases; may lead to exacerbation of hepatic impairment.
• Pulmonary toxicity: With use, pulmonary toxicity has occurred; discontinue if severe.
Disease-related concerns:
• Renal impairment: Use with caution in patients with pre-existing renal impairment.
Special populations:
• Elderly: Use with caution in the elderly; clearance is affected by age.
• Pediatrics: Efficacy has not been established in children.
• Radiation therapy recipients: Use with caution with concurrent radiation therapy; radiation toxicity has been reported with concurrent and nonconcurrent administration; may have radiosensitizing activity when gemcitabine and radiation therapy are given ?7 days apart; optimum regimen for combination therapy has not been determined for all tumor types.
Other warnings/precautions:
• Administration: Prolongation of the infusion time >60 minutes and more frequent than weekly dosing have been shown to increase toxicity.
Adverse Reactions
>10%:
Cardiovascular: Peripheral edema (20%), edema (13%)
Central nervous system: Pain (10% to 48%), fever (30% to 41%), somnolence (5% to 11%)
Dermatologic: Rash (24% to 30%), alopecia (15% to 18%), pruritus (13%)
Gastrointestinal: Nausea/vomiting (64% to 71%; grades 3/4: 1% to 13%), constipation (10% to 31%), diarrhea (19% to 30%), stomatitis (10% to 14%)
Hematologic: Anemia (65% to 73%; grade 4: 1% to 3%), leukopenia (62% to 71%; grade 4: ?1%), neutropenia (61% to 63%; grade 4: 6% to 7%), thrombocytopenia (24% to 47%; grade 4: ?1%), hemorrhage (4% to 17%; grades 3/4: <1% to 2%); myelosuppression is the dose-limiting toxicity
Hepatic: Transaminases increased (67% to 78%; grades 3/4: 1% to 12%), alkaline phosphatase increased (55% to 77%; grades 3/4: 2% to 16%), bilirubin increased (13% to 26%; grades 3/4: <1% to 6%)
Renal: Proteinuria (10% to 45%; grades 3/4: <1%), hematuria (13% to 35%; grades 3/4: <1%), BUN increased (8% to 16%; grades 3/4: 0%)
Respiratory: Dyspnea (6% to 23%)
Miscellaneous: Flu-like syndrome (19%), infection (8% to 16%; grades 3/4: <1% to 2%)
1% to 10%:
Local: Injection site reactions (4%)
Neuromuscular & skeletal: Paresthesia (2% to 10%)
Renal: Creatinine increased (2% to 8%)
Respiratory: Bronchospasm (<2%)
<1%, postmarketing, and/or case reports (reported with single-agent use or with combination therapy, all reported rarely): Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arrhythmias, bullous skin eruptions, cellulitis, cerebrovascular accident, CHF, chills, cough, desquamation, diaphoresis, gangrene, GGT increased, headache, hemolytic uremic syndrome (HUS), hepatotoxic reaction (rare), hypertension, insomnia, interstitial pneumonitis, liver failure, malaise, MI, peripheral vasculitis, petechiae, pulmonary edema, pulmonary fibrosis, radiation recall, renal failure, respiratory failure, rhinitis, sepsis, supraventricular arrhythmia, weakness
Drug Interactions
Bleomycin: Gemcitabine may enhance the adverse/toxic effect of Bleomycin. The risk of pulmonary toxicity may be increased. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Fluorouracil: Gemcitabine may increase the serum concentration of Fluorouracil. Risk C: 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. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F). Reconstituted vials are stable for up to 35 days and infusion solutions diluted in 0.9% sodium chloride are stable up to 7 days at 23°C when protected from light; however, the manufacturer recommends use within 24 hours for both reconstituted vials and infusion solutions. Do not refrigerate.
Reconstitution
Reconstitute the 200 mg vial with preservative free 0.9% NaCl 5 mL or the 1000 mg vial with preservative free 0.9% NaCl 25 mL. Resulting solution is 38 mg/mL. Dilute with 50-500 mL 0.9% sodium chloride injection or D5W to concentrations as low as 0.1 mg/mL.
Compatibility
Stable in D5W, NS.
Y-site administration: Compatible: Amifostine, amikacin, aminophylline, ampicillin, ampicillin/sulbactam, aztreonam, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, carmustine, cefazolin, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chlorpromazine, cimetidine, ciprofloxacin, cisplatin, clindamycin, co-trimoxazole, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, dexamethasone sodium phosphate, dexrazoxane, diphenhydramine, dobutamine, docetaxel, dopamine, doxorubicin, doxycycline, droperidol, enalaprilat, etoposide, etoposide phosphate, famotidine, floxuridine, fluconazole, fludarabine, fluorouracil, gatifloxacin, gentamicin, granisetron, haloperidol, heparin, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, idarubicin, ifosfamide, leucovorin, linezolid, lorazepam, mannitol, meperidine, mesna, metoclopramide, metronidazole, minocycline, mitoxantrone, morphine, nalbuphine, netilmicin, ofloxacin, ondansetron, paclitaxel, plicamycin, potassium chloride, promethazine, ranitidine, sodium bicarbonate, streptozocin, teniposide, thiotepa, ticarcillin, ticarcillin/clavulanate, tobramycin, topotecan, vancomycin, vinblastine, vincristine, vinorelbine, zidovudine. Incompatible: Acyclovir, amphotericin B, cefoperazone, cefotaxime, furosemide, ganciclovir, imipenem/cilastatin, irinotecan, methotrexate, methylprednisolone sodium succinate, mitomycin, piperacillin, piperacillin/tazobactam, prochlorperazine edisylate.
Mechanism of Action
A pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, specific for the S-phase of the cycle. 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.
Pharmacodynamics/Kinetics
Distribution: Infusions <70 minutes: 50 L/m2; Long infusion times: 370 L/m2
Protein binding: Low
Metabolism: Metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites
Half-life elimination:
Gemcitabine: Infusion time ?1 hour: 42-94 minutes; infusion time 3-4 hours: 4-10.5 hours
Metabolite (gemcitabine triphosphate), terminal phase: 1.7-19.4 hours
Time to peak, plasma: 30 minutes after completion of infusion
Excretion: Urine (92% to 98%; primarily as inactive uracil metabolite); feces (<1%)
Dosage
Refer to individual protocols. Note: Prolongation of the infusion time >60 minutes and administration more frequently than once weekly have been shown to increase toxicity. I.V.:
Pancreatic cancer: Initial: 1000 mg/m2 weekly for up to 7 weeks followed by 1 week rest; then weekly for 3 weeks out of every 4 weeks.
Dose adjustment: Patients who complete an entire cycle of therapy may have the dose in subsequent cycles increased by 25% as long as the absolute granulocyte count (AGC) nadir is >1500 x 106/L, platelet nadir is >100,000 x 106/L, and nonhematologic toxicity is less than WHO Grade 1. If the increased dose is tolerated (with the same parameters) the dose in subsequent cycles may again be increased by 20%.
Nonsmall cell lung cancer:
1000 mg/m2 days 1, 8, and 15; repeat cycle every 28 days
or
1250 mg/m2 days 1 and 8; repeat cycle every 21 days
Breast cancer: 1250 mg/m2 days 1 and 8; repeat cycle every 21 days
Ovarian cancer: 1000 mg/m2 days 1 and 8; repeat cycle every 21 days
Bladder cancer (unlabeled use):
I.V.: 1000 mg/m2 once weekly for 3 weeks; repeat cycle every 4 weeks
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)
Dosing adjustment for toxicity:
Pancreatic cancer: Hematologic toxicity:
AGC ?1000 x 106/L and platelet count ?100,000 x 106/L: Administer 100% of full dose
AGC 500-999 x 106/L or platelet count 50,000-90,000 x 106/L: Administer 75% of full dose
AGC <500 x 106/L or platelet count <50,000 x 106/L: Hold dose
Nonsmall cell lung cancer:
Hematologic toxicity: Refer to guidelines for pancreatic cancer. Cisplatin dosage may also need adjusted.
Severe (grades 3 or 4) nonhematologic toxicity (except alopecia, nausea and vomiting): Hold or decrease dose by 50%.
Breast cancer:
Hematologic toxicity: Adjustments based on granulocyte and platelet counts on day 8:
AGC ?1200 x 106/L and platelet count >75,000 x 106/L: Administer 100% of full dose
AGC 1000-1199 x 106/L or platelet count 50,000-75,000 x 106/L: Administer 75% of full dose
AGC 700-999 x 106/L and platelet count ?50,000 x 106/L: Administer 50% of full dose
AGC <700 x 106/L or platelet count <50,000 x 106/L: Hold dose
Severe (grades 3 or 4) nonhematologic toxicity (except alopecia, nausea, and vomiting): Hold or decrease dose by 50%. Paclitaxel dose may also need adjusted.
Ovarian cancer:
Hematologic toxicity: Adjustments based on granulocyte and platelet counts on day 8:
AGC ?1500 x 106/L and platelet count ?100,000 x 106/L: Administer 100% of full dose
AGC 1000-1499 x 106/L and/or platelet count 75,000-99,999 x 106/L: Administer 50% of full dose
AGC <1000 x 106/L and/or platelet count <75,000 x 106/L: Hold dose
Severe (grades 3 or 4) nonhematologic toxicity (except nausea and vomiting): Hold or decrease dose by 50%. Carboplatin dose may also need adjusted.
Dose adjustment for subsequent cycles:
AGC < 500 x 106/L for >5 days, AGC <100 x 106/L for >3 days, febrile neutropenia, platelet count <25,000 x 106/L, cycle delay >1 week due to toxicity: Reduce gemcitabine to 800 mg/m2 on days 1 and 8.
For recurrence of any of the above toxicities after initial dose reduction: Administer gemcitabine 800 mg/m2 on day 1 only for the subsequent cycle
Dosing adjustment in renal impairment: The FDA-approved labeling does not contain dosing adjustment guidelines; use caution. Gemcitabine has not been studied in patients with significant renal dysfunction.
Dosing adjustment in hepatic impairment: The FDA-approved labeling does not contain dosing adjustment guidelines; use caution. Gemcitabine has not been studied in patients with significant hepatic dysfunction. The following guidelines have been used by some clinicians (Floyd, 2006): Serum bilirubin >1.6 mg/dL: Use starting dose of 800 mg/m2
Dosage: Combination Regimens
Biliary adenocarcinoma:
Gemcitabine-Capecitabine
Gemcitabine-Cisplatin (Biliary Cancer)
GEMOX (Biliary Cancer)
Bladder cancer:
Gemcitabine-Carboplatin (Bladder Cancer)
Gemcitabine-Cisplatin (Bladder Cancer)
Gemcitabine-Docetaxel (Bladder Cancer)
Paclitaxel-Carboplatin-Gemcitabine
Paclitaxel-Gemcitabine
Cervical cancer: Gemcitabine-Cisplatin (Cervical Cancer)
Leukemia, acute lymphocytic: TVTG
Leukemia, acute myeloid: TVTG
Lung cancer (nonsmall cell):
Bevacizumab-Cisplatin-Gemcitabine
Gemcitabine-Carboplatin (NSCLC)
Gemcitabine-Cisplatin (NSCLC)
Gemcitabine-Vinorelbine
Vinorelbine-Gemcitabine
Lymphoma, Hodgkin's: Gemcitabine-Vinorelbine-Doxorubicin (Liposomal)
Lymphoma, non-Hodgkins: Gemcitabine-Oxaliplatin-Rituximab (NHL)
Osteosarcoma: Gemcitabine-Docetaxel (Sarcoma)
Ovarian cancer: Gemcitabine-Carboplatin (Ovarian Cancer)
Pancreatic cancer:
Gemcitabine-Capecitabine
Gemcitabine-Erlotinib
Gemcitabine-Irinotecan
Gemcitabine-Oxaliplatin (Pancreatic Cancer)
Soft tissue sarcoma: Gemcitabine-Docetaxel (Sarcoma)
Testicular cancer: GEMOX (Testicular Cancer)
Administration: I.V.
Infuse over 30 minutes. Note: Prolongation of the infusion time >60 minutes has been shown to increase toxicity. Gemcitabine is being investigated in clinical trials for fixed dose rate (FDR) infusion administration at doses from 1000 mg/m2 to 2200 mg/m2 at a rate of 10 mg/m2/minute. Prolonged infusion times increase the accumulation of the active metabolite, gemcitabine triphosphate. Patients who receive gemcitabine FDR experience more grade 3/4 hematologic toxicity.
Administration: I.V. Detail
pH: 2.7-3.3
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)
Patient Education
Do not take any new medication during therapy unless approved by prescriber. This drug can only be administered by infusion; report any redness, pain, or swelling at infusion site. During therapy, do not use alcohol. Maintain adequate hydration unless instructed to restrict fluid intake, and nutrition (small, frequent meals may help). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). You may experience fatigue, lethargy, somnolence (use caution when driving or engaging in potentially hazardous tasks until response to drug is known); nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); loss of hair (reversible); mouth sores (frequent mouth care and use of a soft toothbrush or cotton swabs may help); or diarrhea. This drug may cause sterility. Report extreme fatigue; severe GI upset or diarrhea; bleeding or bruising; fever, chills, sore throat; vaginal discharge; signs of fluid retention (swelling extremities, respiratory difficulty, unusual weight gain); yellowing of skin or eyes; change in color of urine or stool; muscle or skeletal pain or weakness; or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this medication. Consult prescriber for appropriate barrier contraceptive measures. This drug may cause severe fetal birth defects. Do not breast-feed.
Geriatric Considerations
Clearance is affected by age. There is no evidence; however, that unusual dose adjustment is necessary in patients older than 65 years of age. In general, adverse reaction rates were similar to patients older and younger than 65 years. Grade 3/4 thrombocytopenia was more common in the elderly. Older women were more likely to experience grade 3/4 neutropenia and thrombocytopenia.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
Leukopenia is common; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
See specific Administration directions (adverse reactions increase when infused over >60 minutes). Assess results of laboratory tests (eg, CBC with differential and platelet count), prior to each dose. Monitor patient response (symptom relief) and adverse reactions (eg, CNS changes, rash, gastrointestinal upset, anemia, myelosuppression, dyspnea) prior to each treatment and on a regular basis throughout therapy. Teach patient possible side effects/appropriate interventions and adverse symptoms to report.
Oncology: Emetic Potential
Low (10% to 30%)
Oncology: Vesicant
May be an irritant
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Gemzar®: 200 mg, 1 g
Pricing: U.S. (www.drugstore.com)
Solution (reconstituted) (Gemzar)
1 g (1): $809.28
200 mg (1): $162.41
References
Aapro MS, Martin C, and Hatty S, “Gemcitabine - A Safety Review,” Anticancer Drugs, 1998, 9(3):191-201.
Bredenfeld H, Franklin J, Nogova L, et al, “Severe Pulmonary Toxicity in Patients With Advanced-Stage Hodgkin's Disease Treated With a Modified Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, and Gemcitabine (BEACOPP) Regimen is Probably Related to the Combination of Gemcitabine and Bleomycin: A Report of the German Hodgkin's Lymphoma Study Group,” J Clin Oncol, 2004, 22(12):2424-9.
Correale P, Cerretani D, Marsili S, et al, “Gemcitabine Increases Systemic 5-Fluorouracil Exposure in Advanced Cancer Patients,” Eur J Cancer, 2003, 39(11):1547-51.
Dalbagni G, Russo P, Bochner B, et al, “Phase II Trial of Intravesical Gemcitabine in Bacille Calmette-Guerin-Refractory Transitional Cell Carcinoma of the Bladder,” J Clin Oncol, 2006, 24(18):2729-34.
Floyd J, Mirza I, Sachs B, et al, "Hepatotoxicity of Chemotherapy," Semin Oncol, 2006, 33(1):50-67.
Guchelaar HJ, Richel DJ, and van Knapen A, “Clinical, Toxicological and Pharmacological Aspects of Gemcitabine,” Cancer Treat Rev, 1996, 22(1):15-31.
Noble S and Goa KL, “Gemcitabine. A Review of its Pharmacology and Clinical Potential in Nonsmall Cell Lung Cancer and Pancreatic Cancer," Drugs, 1997, 54(3):447-72.
Pfisterer J, Vergote I, Du Bois A, et al, “Combination Therapy with Gemcitabine and Carboplatin in Recurrent Ovarian Cancer,” Int J Gynecol Cancer, 2005, 15 (Suppl 1):36-41.
Plunkett W, Huang P, Xu YZ, et al, “Gemcitabine: Metabolism, Mechanisms of Action, and Self-Potentiation,” Semin Oncol, 1995, 22(4 Suppl 11):3-10.
Storniolo AM, Allerheiligen SR, and Pearce HL, “Preclinical, Pharmacologic, and Phase I Studies of Gemcitabine,” Semin Oncol 1997, 24(2 Suppl 7):7-12.
Tempero M, Plunkett W, Ruiz Van Haperen V, “Randomized Phase II Comparison of Dose-Intense Gemcitabine: Thirty-Minute Infusion and Fixed Dose Rate Infusion in Patients With Pancreatic Adenocarcinoma,” J Clin Oncol, 2003, 21(18):3402-8.
Xu Q, Zhang Y, and Trissel LA, “Physical and Chemical Stability of Gemcitabine Hydrochloride Solutions,” J Am Pharm Assoc, 1999, 39(4):509-13.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
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