Professional Information

Gemcitabine (Systemic)

VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Gemzar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Antineoplastic —

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, pancreatic (treatment)—Gemcitabine is indicated as first-line therapy for locally advanced (nonresectable Stage II or III) or metastatic (Stage IV) adenocarcinoma of the pancreas. ^{01} It is also indicated as second-line therapy for patients who have previously been treated with fluorouracil. ^{01} Treatment with gemcitabine is primarily palliative. ^{13}

Carcinoma, lung, non–small cell—Gemcitabine is indicated in combination with cisplatin ^{01} as first-line therapy for inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non–small cell lung carcinoma. ^{02} ^{03} ^{04} ^{05} ^{06} ^{13}

[Carcinoma, biliary tract (treatment) ]¹or
[Carcinoma, gallbladder (treatment) ]¹—Gemcitabine is indicated for the treatment of locally advanced, unresectable, or metastatic biliary tract (i.e., cholangiocarcinoma, biliary tree carcinoma, bile duct carcinoma) and gallbladder carcinomas.^{77}^{78}^{79}^{80}^{81}^{82}^{83}^{84}^{85}^{86}^{87}^{88}^{89}^{90}^{91}^{92}^{93}^{94}^{95}^{96}^{97}^{98}^{99}^{100}^{101}^{102}^{103}^{104}^{105}^{106}

[Carcinoma, bladder]¹—Gemcitabine is indicated for treatment of metastatic bladder (urothelial) carcinoma, based on response rates (both complete and partial responses) achieved in clinical trials. ^{18} ^{19} ^{20} ^{21} ^{22}

[Carcinoma, breast (treatment)]¹—Gemcitabine is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with advanced or metastatic breast carcinoma (Evidence rating: IIID).^{23}

[Carcinoma, ovarian, epithelial (treatment) ]¹—Gemcitabine is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with advanced or relapsed epithelial ovarian carcinoma (Evidence rating: IIID).^{23}

[Lymphomas, Hodgkin's (treatment) ]¹ or
[Lymphomas, non-Hodgkin's (treatment) ]¹—Gemcitabine is indicated, alone or in combination with other agents, for the treatment of relapsed Hodgkin's and non-Hodgkin's lymphomas (T-cell and B-cell ).^{68}^{69}^{70}^{71}^{72}^{73}^{74}^{75}^{76}

[Tumors, germ cell (treatment)]¹
[Tumors, germ cell, ovarian (treatment) ]¹
[Tumors, germ cell, testicular (treatment) ]¹—Gemcitabine is indicated for the treatment of relapsed/refractory, progressive, metastatic, or nonseminomatous gonadal (i.e., testicular, ovarian) and extragonadal germ cell tumors.^{107}^{108}^{109}^{110}^{111}^{112}^{113}^{114}^{115}^{116}^{117}^{118}^{119}^{120}

Acceptance not established
Use of gemcitabine for the treatment of primary breast carcinoma has not been established, due to insufficient efficacy data.^{46}^{47}^{48}^{49}^{50}^{51}^{52}^{53}^{54}

Use of gemcitabine for the treatment of mesotheliomas has not been established. Although case reports state objective and subjective benefit in few patients, most phase II trials of an adequate sample size do not demonstrate an established benefit of gemcitabine therapy.^{55}^{56}^{57}^{58}^{59}^{60}^{61}^{62}^{63}^{64}^{65}^{66}^{67}

Use of gemcitabine for the treatment of advanced, metastatic, unresectable, refractory/relapsed sarcomas has not been established, due to insufficient data regarding efficacy and few well-conducted studies.^{121}^{122}^{123}^{124}^{125}^{126}^{127}^{128}^{129}^{130}^{131}^{132}^{133}^{134}^{135}^{136}^{137}

Use of gemcitabine for the treatment of advanced, metastatic, unresectable, relapsed/refractory, renal cell carcinoma has not been established, due to insufficient date regarding response/efficacy as a single agent and lack of peer-reviewed evidence.^{138}^{139}^{140}^{141}^{142}^{143}^{144}^{145}^{146}^{147}^{148}^{149}^{150}^{151}^{152}^{153}^{154}^{155}^{156}^{157}

Use of gemcitabine for the treatment of carcinoma of unknown primary site (CUPS) has not been established, due to insufficient data supporting efficacy. The role of gemcitabine in combination regimens has not been defined. Single-agent use needs more support.^{158}^{159}^{160}^{161}^{162}^{163}^{164}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Gemcitabine is a nucleoside ^{01} (deoxycytidine ^{02}) analog.
Molecular weight—
    Gemcitabine hydrochloride: 299.66 ^{07}

pH
    2.7 to 3.3 (after reconstitution). ^{14}

pKa—
    3.6 ^{02}

Solubility
    Practically insoluble in ethanol and polar organic solvents; soluble in water. ^{01}

Mechanism of action/Effect:

Gemcitabine is an antimetabolite of the pyrimidine analog type. ^{01} ^{02} Gemcitabine is cell cycle–specific for the S phase and for the G ₁/S phase boundary of cell division. ^{01} ^{02} Activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate. ^{01} ^{02} Gemcitabine diphosphate inhibits the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis, and gemcitabine triphosphate competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. ^{01} ^{02} The gemcitabine diphosphate–induced reduction in intracellular concentrations of deoxynucleoside triphosphates results in increased incorporation of gemcitabine triphosphate into DNA and, consequently, in inhibition of DNA synthesis. ^{01} ^{02} DNA polymerase epsilon is unable to remove the incorporated gemcitabine triphosphate and repair the DNA strands. ^{01}

Other actions/effects:

Gemcitabine is a potent ^{08} ^{09} radiation sensitizer ^{02} ^{08} ^{09}. In in vitro studies, it produced significant radiosensitization even in lower-than-cytotoxic concentrations. ^{09}

Distribution:

The volume of distribution is significantly affected by the duration of the gemcitabine infusion and the gender of the patient. ^{01} ^{02}

Short infusion (< 70 minutes)—50 liters per square meter of body surface area (L/m ²), indicating that gemcitabine is not distributed extensively into tissues. ^{01} ^{02}

Long infusion (70 to 285 minutes)—370 L/m ², indicating slow equilibration within the tissue compartment. ^{01} ^{02}

Protein binding:

Very low (< 10%). ^{01}

Biotransformation:

Gemcitabine undergoes intracellular metabolism, via nucleoside kinases, to produce two active metabolites (gemcitabine diphosphate and gemcitabine triphosphate) ^{01} and also undergoes deamination to ^{14} an inactive uracil metabolite. ^{01}

Half-life:

Gemcitabine—Elimination:

Short infusions (< 70 minutes)—

Females:

29 years of age—49 minutes. ^{01} ^{02}

45 years of age—57 minutes. ^{01} ^{02}

65 years of age—73 minutes. ^{01} ^{02}

79 years of age—94 minutes. ^{01} ^{02}

Males:

29 years of age—42 minutes. ^{01} ^{02}

45 years of age—48 minutes. ^{01} ^{02}

65 years of age—61 minutes. ^{01} ^{02}

79 years of age—79 minutes. ^{01} ^{02}

Long infusions (70 to 285 minutes)—245 to 638 minutes, depending on age and gender. ^{01} ^{02}

Gemcitabine triphosphate metabolite—Terminal (from peripheral blood mononuclear cells): 1.7 to 19.4 hours. ^{01}

Elimination:
    Renal—92 to 98% of a single dose of radiolabeled gemcitabine (1000 mg per square meter of body surface area, given over 30 minutes to five patients) was recovered within 1 week, primarily as the inactive uracil metabolite (approximately 89% of the excreted dose) and secondarily as unchanged gemcitabine (less than 10% of the excreted dose). ^{01} ^{02}
    Clearance is affected by age and gender as follows:
        Females—
        29 years of age: 69.4 liters per hour per square meter of body surface area (L/hr/m ²). ^{01} ^{02}

        45 years of age: 57 L/hr/m ². ^{01} ^{02}

        65 years of age: 41.5 L/hr/m ². ^{01} ^{02}

        79 years of age: 30.7 L/hr/m ². ^{01} ^{02}

        Males—
        29 years of age: 92.2 L/hr/m ². ^{01} ^{02}

        45 years of age: 75.7 L/hr/m ². ^{01} ^{02}

        65 years of age: 55.1 L/hr/m ². ^{01} ^{02}

        79 years of age: 40.7 L/hr/m ². ^{01} ^{02}

Precautions to Consider

Carcinogenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. ^{10} The risk of secondary malignancies developing after gemcitabine therapy is not known. ^{15}

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been done. ^{01} ^{02}

Mutagenicity

Gemcitabine was mutagenic in in vitro (mouse lymphoma assay) and in vivo (mouse micronucleus assay) mammalian test systems. However, it was not mutagenic in the Ames test, in vivo sister chromatid exchange, or in in vitro (chromosomal aberration assays and unscheduled DNA synthesis) test systems. ^{01}

Pregnancy/Reproduction
Fertility—
Intraperitoneal administration to male mice of 0.5 mg per kg of body weight (mg/kg) per day (0.14% of the recommended human dose on a mg per square meter of body surface area [mg/m ²] basis) resulted in moderate to severe ^{01} hypospermatogenesis ^{01} ^{02}, decreased fertility ^{01}, and decreased implantations ^{01}. The hypospermatogenesis was reversible. ^{02} Gemcitabine did not impair fertility ^{01} ^{02}, but caused maternal toxicity in female mice given doses of 1.5 mg/kg per day (0.5% of the recommended human dose on a mg/m ² basis) ^{01}.

Pregnancy—
Studies in humans have not been done. ^{01}

It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered. ^{10}

Other potential hazards to the fetus include adverse reactions seen in adults. ^{10}

In general, use of a contraceptive is recommended during therapy with cytotoxic medications. ^{10}

Gemcitabine caused fetal malformations (fusion of the pulmonary artery and absence of the gallbladder) in rabbits given 0.1 mg/kg per day (0.17% of the recommended human dose on a mg/m ² basis). The medication was embryotoxic (causing decreased fetal viability, reduced live litter sizes, and delayed development), and teratogenic (causing cleft palate and incomplete ossification) in mice given 1.5 mg/kg per day (0.5% of the recommended human dose on a mg/m ² basis). In mice, embryolethality or fetotoxicity occurred with intravenous doses as low as 0.25 mg/kg per day (0.08% of the recommended human dose on a mg/m ² basis). ^{01}

FDA Pregnancy Category D. ^{01}

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while gemcitabine is being administered, because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity). ^{10} It is not known whether gemcitabine or its metabolites are distributed into breast milk. ^{01} ^{02}

Pediatrics

Appropriate studies on the relationship of age to the effects of gemcitabine have not been performed in the pediatric population. Safety and efficacy have not been established. ^{01}

Geriatrics

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of gemcitabine in the elderly. ^{04} Although some pharmacokinetic parameters are altered in geriatric patients (increased elimination half-life and decreased clearance), no adjustment of the initial dose is recommended for patients older than 65 years of age. ^{01} ^{02} However, the risk of hematologic toxicity requiring reduction, delay, or omission of subsequent doses is higher in elderly patients than in younger adults. ^{01} Specifically, Grade 3 or 4 thrombocytopenia is more likely to occur in elderly men and women and Grade 3 or 4 neutropenia is more likely to occur in elderly women. ^{01} Nonhematologic toxicities did not occur more frequently in patients older than 65 years of age than in younger adults. ^{04}

Dental

The bone marrow depressant effects of gemcitabine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks. ^{10}

Gemcitabine causes stomatitis ^{01} ^{02}, usually mild ^{02}, in a minority of patients (incidence 11% ^{01} or lower ^{02} in various clinical trials).

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of gemcitabine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of gemcitabine, if necessary, should be based on blood counts ^{10})

» Bone marrow depressants, other (see Appendix II ) or
» Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively ^{10})

    (gemcitabine is a potent ^{08} ^{09} radiosensitizer ^{02} ^{08} ^{09}; depending on the site being irradiated, concurrent use of gemcitabine may cause severe, life-threatening esophagitis or pneumonitis ^{01} ^{02}; in one study, gemcitabine with radiation therapy caused severe stomatitis or pharyngeal damage requiring patients to be fed via feeding tube for as long as 10 to 12 months, even when gemcitabine was given in doses as low as 300 mg per square meter of body surface area [25% or less of the usual adult dose] ^{11})

» Immunosuppressants, other, such as:
Azathioprine
Chlorambucil
Corticosteroids, glucocorticoid
Cyclophosphamide
Cyclosporine
Mercaptopurine
Muromonab CD-3
Tacrolimus    (concurrent use with gemcitabine may increase the risk of infection ^{10})

Vaccines, killed virus    (because normal defense mechanisms may be suppressed by gemcitabine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)

^{10}
» Vaccines, live virus    (because normal defense mechanisms may be suppressed by gemcitabine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution, after careful review of the patient's hematologic status, and only with the knowledge and consent of the physician managing the gemcitabine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)

^{10}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin concentrations, serum    (values may be increased ^{01} ^{02}; in clinical trials, Grade 3 or 4 increases in ALT, alkaline phosphatase, AST, and bilirubin occurred in 10%, 9%, 8%, and 3% of all patients and in 11%, 20%, 17%, and 8% of pancreatic cancer patients, respectively ^{01}. However, continuation of gemcitabine therapy despite these elevations produced no evidence of increasing hepatotoxicity ^{01} ^{02})

Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be increased ^{01})

» Hemoglobin/hematocrit and
» Leukocyte count and
» Platelet count    (may be decreased ^{01} ^{02})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression    (will be exacerbated; reduction, delay, or omission of a gemcitabine dose may be necessary ^{01} ^{02})

» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease ^{10})

Hepatic function impairment, severe ^{16} or
Renal function impairment    (caution is recommended; gemcitabine has not been studied in patients with these medical problems ^{01} ^{02})

    (caution and careful monitoring of patients with renal function impairment are also recommended because hemolytic-uremic syndrome has been reported in a few patients during or immediately following gemcitabine therapy ^{02})

» Hypersensitivity to gemcitabine ^{01}
» Infection    (gemcitabine may decrease the patient's ability to fight an infection ^{10})

» Caution should be used also in patients who have had previous cytotoxic chemotherapy or radiation therapy ^{10}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin, serum and
Blood urea nitrogen (BUN) and
Creatinine concentrations, serum    (determinations recommended prior to initiation of gemcitabine therapy and at appropriate intervals during therapy ^{01} ^{02})

» Hemoglobin concentration and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to each course of gemcitabine therapy; reduction, delay, or omission of a dose may be required, depending on cell counts ^{01} ^{02})

Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration. ^{10}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Anemia ^{01} ^{02} (unusual tiredness or weakness)

dyspnea ^{01} ^{02} (shortness of breath)—may be due to underlying disease

edema ^{01} ^{02} (swelling of fingers, feet, or lower legs)

fever ^{01} ^{02} —may occur in the absence of infection, usually in conjunction with other flu-like symptoms ^{01} ^{02}

hematuria ^{01} ^{02} ( blood in urine)

leukopenia or neutropenia ^{01} ^{02} —usually asymptomatic

proteinuria ^{01} ^{02} (cloudy urine)

skin rash, with or without itching ^{01} ^{02}

thrombocytopenia ^{01} ^{02} (unusual bleeding or bruising ; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)— usually asymptomatic; symptoms occur less frequently

Note: Bone marrow suppression ( anemia, leukopenia, and thrombocytopenia ) is the dose-limiting adverse effect. ^{01}
Edema is usually peripheral, but rarely may become generalized. ^{01} ^{02}
Typically, gemcitabine-induced skin rashes are mild to moderate in severity and consist of macular or finely granular maculopapular eruptions on the trunk and extremities. ^{01} ^{02}

Incidence less frequent

Bronchospasm ^{01} ^{02} (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)

cardiovascular effects, including arrhythmia ^{01} ^{02} (fast or irregular heartbeat ), cerebrovascular accident ^{01} (headache, sudden and severe; slurred speech or inability to speak; weakness in arm and/or leg on one side of the body, sudden and severe), hypertension ^{01} ^{02} (high blood pressure), or myocardial infarction ^{01} ^{02} ( pain in chest, arm, or back; pressure or squeezing in chest)

febrile neutropenia or other infection (fever or chills; cough or hoarseness; lower back or side pain ; painful or difficult urination)

hemorrhage ^{01} ^{02}

Note: In clinical trials, cardiovascular effects occurred mostly in patients with a prior history of cardiovascular disease ^{01} ^{02}, and hemorrhage occurred mostly in patients with pancreatic carcinoma. ^{01}
Severe infections associated with leukopenia or neutropenia occurred in approximately 1% of patients in clinical studies. ^{01} ^{02}

Incidence rare

Anaphylactoid reaction ^{01} ^{02} (change in facial skin color; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and/or itching; swelling or puffiness of the face, especially the eyelids or area around the eyes)

heart failure ^{02} (coughing; noisy, rattling, or troubled breathing)

hemolytic-uremic syndrome ^{01} ^{02} (black, tarry stools; blood in urine or stools; fever; increased or decreased urination; pinpoint red spots on skin; swelling of face, fingers, feet, or lower legs; unusual bleeding or bruising; unusual tiredness or weakness; yellow eyes or skin ^{14})

lung toxicity, parenchymal, or pneumonitis ^{01} ^{02} ( coughing; shortness of breath)

pulmonary edema ^{02} (coughing; noisy, rattling, or troubled breathing)

Note: In clinical trials, hemolytic-uremic syndrome occurred in 6 of 2429 patients. ^{01} ^{02} Four cases occurred during gemcitabine treatment and two shortly after treatment had ended. ^{01} This complication may result in irreversible renal failure requiring dialysis. ^{01} ^{02}
Heart failure and pulmonary edema have been reported in patients being treated for lung carcinoma. ^{02}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Constipation ^{01} ^{02}

diarrhea ^{01} ^{02}

flu-like syndrome ^{01} ^{02} (chills; cough; fever; general feeling of illness; headache ; loss of appetite; muscle pain; runny nose; sweating; trouble in sleeping; weakness)

nausea and vomiting ^{01} ^{02}

Note: Weakness, while often occurring as part of a flu-like syndrome, may also occur as an isolated symptom. ^{01}
Nausea and vomiting are usually mild to moderate in severity, but may be severe in up to 15% of patients. ^{01}

Incidence less frequent

Irritation, pain, or redness at injection site ^{01} ^{02} —if extravasation occurs

paresthesia ^{01} ^{02} (numbness or tingling of hands or feet)

somnolence ^{01} ^{02} (drowsiness, severe)

stomatitis ^{01} ^{02} (sores, ulcers, or white spots on lips and in mouth)

Note: Gemcitabine is not a vesicant. Extravasation has not caused injection site necrosis. ^{01} ^{02}
Paresthesia is usually mild; however, severe paresthesia may occur rarely. ^{01}

Those not indicating need for medical attention
Incidence more frequent

Alopecia ^{01} ^{02} (loss of hair )—usually minimal

Note: Complete hair loss, which was reversible after discontinuation of treatment, occurred in less than 0.5% of patients in clinical trials. ^{02}

Overdose
For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic

Bone marrow suppression ^{01} ^{02} , including anemia ^{01} ^{02} (unusual tiredness or weakness), leukopenia or neutropenia, possibly with infection ^{01} ^{02} (chills; cough or hoarseness; lower back or side pain; painful or difficult urination), and thrombocytopenia ^{01} ^{02} (unusual bleeding or bruising ; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)

paresthesia ^{01} ^{02} ( numbness or tingling of hands or feet)

skin rash, severe ^{01} ^{02}

Treatment of overdose
There is no specific antidote to gemcitabine. ^{14}

The patient's blood count should be monitored and supportive therapy given, as needed. ^{01} Severe bone marrow depression may require transfusion of needed blood components. ^{01} ^{02} Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. ^{10}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Gemcitabine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to gemcitabine

Pregnancy—Use not recommended because of mutagenic, teratogenic, embryotoxic, and fetotoxic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected

Breast-feeding—Not recommended because of risk of serious adverse effects

Use in the elderly—Seriously low blood counts are more likely to occur in older patients
Other medications, especially other bone marrow depressants, other immunosuppressants, or other cytotoxic medication or radiation therapy
Other medical problems, especially chickenpox or recent exposure, herpes zoster, infection, or previous cytotoxic medication or radiation therapy

Proper use of this medication
Frequency of flu-like syndrome or nausea and vomiting; importance of continuing medication despite stomach upset or otherwise feeling ill

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician; periodic blood tests required to monitor blood counts

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

» Checking with physician immediately if dyspnea develops or worsens during treatment

Caution if bone marrow depression occurs
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands are washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur

Side/adverse effects
May cause adverse effects such as blood problems; importance of discussing possible effects with physician

Signs of potential side effects, especially anemia; dyspnea; edema; fever; hematuria; proteinuria; skin rash; thrombocytopenia; bronchospasm; cardiovascular effects; febrile neutropenia or other infection; hemorrhage; anaphylactoid reaction; hemolytic-uremic syndrome; and lung toxicity or pneumonitis

Physician or nurse can help in dealing with side effects

Possibility that some adverse effects may occur after treatment has ended; notifying physician if symptoms of serious adverse effects noted

Possibility of hair loss; normal hair growth should return after treatment has ended

General Dosing Information
Patients receiving gemcitabine should be under the supervision of a physician experienced in cancer chemotherapy. ^{01} ^{02}

Gemcitabine is to be administered only by intravenous infusion. ^{01} ^{02}

Adverse effects associated with gemcitabine therapy may occur more frequently and be more severe if gemcitabine is administered more frequently than once weekly or infused over a time period longer than 60 minutes. ^{01} ^{02}

If gemcitabine-induced pneumonitis is confirmed or suspected, treatment should be discontinued permanently. ^{02}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of gemcitabine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required. ^{10}

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. ^{10}

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: ^{10}    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.

Direct contact of skin or mucosa with gemcitabine requires immediate washing with soap and water or thoroughly flushing with water, respectively. ^{01} ^{02}

Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

GEMCITABINE FOR INJECTION

Usual adult dose
Carcinoma, pancreatic
Intravenous infusion (over thirty minutes), 1000 mg per square meter of body surface area, once a week for up to seven weeks (depending on toxicity experienced by the patient), followed by a one-week rest. Each subsequent cycle of therapy consists of administering the medication once a week for three weeks followed by a one-week rest ^{01}.

Carcinoma, lung, non–small cell
Intravenous infusion (over thirty minutes), 1000 mg per square meter of body surface area per day on days one, eight, and fifteen of a regimen that is repeated every twenty-eight days ^{01} ^{02} or

Intravenous infusion (over thirty minutes), 1250 mg per square meter of body surface area per day on days one and eight of a regimen that is repeated every twenty-one days ^{01}.
Note: Gemcitabine is given in combination with cisplatin 100 mg per square meter of body surface area, administered intravenously on day one of either the twenty-one- or twenty-eight-day regimen, after infusion of gemcitabine ^{01}.

[ Carcinoma, bladder]¹
Intravenous infusion (over thirty minutes), 1000 ^{21} to 1200 ^{18} ^{19} mg per square meter of body surface area, once a week for three weeks, followed by a one-week rest. ^{22}

Note: In the treatment of [breast carcinoma ]¹doses of 600 (with cisplatin)^{27}^{44} or 800 to 1250 mg per square meter of body surface area, by intravenous infusion, once a week for two or three weeks, followed by a one-week rest have been used^{24}^{25}^{28}^{31}^{32}^{33}^{34}^{44}^{45}. In the treatment of [ epithelial ovarian carcinoma]¹ doses of 800 to 1250 mg per square meter of body surface area, once a week, for two or three weeks, followed by a one-^{35}^{36}^{38}^{39}^{40}^{41}^{42}^{43} to two-week rest^{37} have been used.^{44}^{45}

Note: The development of neutropenia and thrombocytopenia may require an adjustment of gemcitabine dosage. If the absolute granulocyte and platelet counts measured prior to each dose are—

• 500 to 999 × 10 ⁶ cells per liter and 50,000 to 99,000 × 10 ⁶ cells per liter, respectively: The dosage of gemcitabine should be decreased to 75% of the full dose. ^{01} However, some oncologists recommend that, because treatment for pancreatic carcinoma and lung carcinoma is primarily palliative, gemcitabine should be withheld until cell counts recover, then resumed at the lower dose level. ^{17}Less than 500 × 10 ⁶ cells per liter and 50,000 × 10 ⁶ cells per liter, respectively: Gemcitabine should be withheld until cell counts recover. ^{01}

If one complete cycle of therapy (seven weeks or three weeks) at the recommended initial dose is well tolerated (i.e., the granulocyte count nadir remains higher than 1500 × 10 ⁶ cells per liter, the platelet count nadir exceeds 100,000 × 10 ⁶ cells per liter, and nonhematologic toxicities are no more severe than Grade 1), the dose of gemcitabine for the next cycle may be increased by 25% (e.g., from 1000 to 1250 mg per square meter of body surface area). If the medication remains well tolerated during a complete cycle at this higher dose (i.e., toxicities remain within the specified parameters), the dose may be increased a second time (e.g., from 1250 to 1500 mg per square meter of body surface area). ^{01}

[Carcinoma, biliary tract]¹ or
[ Carcinoma, gallbladder]¹ or
[Tumors, germ cell]¹ or
[Tumors, germ cell, ovarian]¹ or
[Tumors, germ cell, testicular ]¹
Because several doses and regimens using gemcitabine are showing activity, no individual dose/regimen is listed here. Consult medical literature and/or experts in the field of oncology for information on dosage.^{77}^{107}

[Lymphomas, Hodgkin's]¹ or
[ Lymphomas, non-Hodgkin's]¹
Patients have benefited from intravenous doses of 1000 to 1250 mg/m² (up to 1500 mg/m ² in some patients), by 30-minute infusion, on days 1, 8, and 15 of a 28-day treatment cycle, for up to 9 treatment cycles.^{68}

Usual pediatric dose
Safety and efficacy have not been established. ^{01}

Usual geriatric dose
See Usual adult dose . ^{01}

Size(s) usually available:
U.S.—

200 mg (single-dose vial) (Rx) [Gemzar ( mannitol 200 mg) (sodium acetate 12.5 mg)]^{01}

1 gram (single-dose vial) (Rx) [Gemzar ( mannitol 1 gram) (sodium acetate 62.5 mg)]^{01}

Canada—

200 mg (single-dose vial) (Rx) [Gemzar ( mannitol 200 mg) (sodium acetate 12.5 mg)]^{02}

1 gram (single-dose vial) (Rx) [Gemzar ( mannitol 1 gram) (sodium acetate 62.5 mg)]^{02}

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F) ^{01}, unless otherwise specified by manufacturer.

Preparation of dosage form:
Gemcitabine for injection is reconstituted for intravenous use by adding 5 or 25 mL of 0.9% sodium chloride injection (without preservative) to the 200-mg or 1-gram vial, respectively, producing a clear, colorless to light straw-colored solution containing 38 mg of gemcitabine per mL. ^{12} Incomplete dissolution may occur if gemcitabine is reconstituted to a concentration greater than 40 mg per mL. ^{01} The resulting solution may be further diluted with 0.9% sodium chloride injection, if necessary, to a concentration as low as 0.1 mg per mL. ^{01}

Stability:
After reconstitution, gemcitabine injections are stable for 24 hours at controlled room temperature (20 to 25 °C [68 to 77 °F]). ^{01}

Unused portions of gemcitabine injection should be discarded. ^{01}

Reconstituted gemcitabine should not be refrigerated because of the possibility of crystal formation. ^{01}

Auxiliary labeling:
   • Do not refrigerate. ^{01}

Developed: 08/21/1997
Revised: 03/06/2003

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Reviewers' consensus on the use of gemcitabine for the treatment of sarcomas ballot, 5/1/02.

Mani S, Vogelzang NJ, Bertucci D, et al. Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors. Cancer 2001; 92(6): 1567-76.

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Szelenyi H, Thiel E, Nieerle N, et al. A phase I trial of gemcitabine and treosulfan (GeT) to overcome multidrug resistance in patients with advanced solid tumors. Proc Am Soc Clin Oncol 1999; 18: 228a [Abst 880].

Stadler WM, Dumas M, Flickinger S, et al. Gemcitabine (GEM) and 5-fluorouracil (5FU) in metastatic renal carcinoma (RC): a University of Chicago phase II consortium study. Proc Am Soc Clin Oncol 1999; 18: 332a [Abst 1277].

Ryan CW, Vogelzang NJ, Dumas MC, et al. A phase II trial of gemcitabine (GEM) and 5-FU with IL-2 and interferon-alfa (IFNA) in patients (pts) with metastatic renal cell cancer (RCC). Proc Am Soc Clin Oncol 1999; 18: 329a [Abst 1264].

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Rohde D, De Mulder PH, Weissbach L, et al. Experimental and clinical efficacy of 2', 2'-difluorodeoxycytidine (gemcitabine) against renal cell carcinoma. Oncology 1996; 53(6): 476-81.

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Poplin EA, Corbett T, Flaherty L, et al. Difluorodeoxycytidine (dFdC)- gemcitabine: a phase I study. Invest New Drugs 1992; 10(3): 165-70.

Reviewers' consensus on the use of gemcitabine for the treatment of renal cell carcinoma ballot, 5/1/02.

Greco FA, Burris HA III, Litchy S, et al. Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol 2002 Mar 15; 20(6): 1651-6.

Hainsworth JD, Burris HA III, Calvert SW, et al. Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl Cancer Research Network. . Cancer Invest 2001; 19(4): 335-9.

Greco FA, Hainsworth JD, Yardley DA, et al. Sequential paclitaxel/ carboplatin/etoposide (PCE) followed by irinotecan/gemcitabine for patients (pts) with carcinoma of unknown primary site (CUP): a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol 2002; 21: [Abst 642].

Lortholary A, Culine S, Bouzy J, et al. Cisplatin in combination with either gemcitabine (GC) or irinotecan (IC) in carcinomas of unknown primary (CUP): results of a randomized phase II study. Proc Am Soc Clin Oncol 2002; 21: [Abst 609].

Mousseau M, Rebischung C, Garnier C, et al. Phase I/II Study in Advanced Pancreatic Adenocarcinoma (APA) and Carcinoma of Unknown Primary (CUP): A Combination of Leucovorin (LV), 5 FU Bolus and Infusion, Gemcitabine (GEM) and Oxaliplatine (L.OHP) (FOLFU GEMOX Regimen). Proc Am Soc Clin Oncol 2000; 19: 233a [Abst 913].

Kath R, Sauer-Heilborn A, Schneider _P, et al. Severe nonhematologic toxicity after treatment with gemcitabine. Proc ASCO 1999; 18: 598a [Abst 2313].

Reviewers' consensus on the use of gemcitabine for the treatment of carcinoma of unknown primary site (CUPS) evidence table, 2/22/03.

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