Gemcitabine

DRUG NAME: Gemcitabine

SYNONYM(S): gemcitabine hydrochloride, difluorodeoxycytidine, 2’,2’-difluorodeoxycytidine, dFdC, LY 188011

COMMON TRADE NAME(S): GEMZAR

CLASSIFICATION: antimetabolite

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Gemcitabine, a pyrimidine analog, is structurally similar to cytarabine, but has a wider spectrum of antitumour activity
1
due to its different cellular pharmacology and mechanism of action. Gemcitabine is metabolized intracellularly to
two active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The cytotoxic
effects of gemcitabine are exerted through incorporation of dFdCTP into DNA with the assistance of dFdCDP,
2,3 3
resulting in inhibition of DNA synthesis and induction of apoptosis. Gemcitabine is a radiation-sensitizing agent. It
3
is cell-cycle phase specific (S and G 1 /S-phases).

PHARMACOKINETICS:
4
Interpatient variability 3- to 4-fold interpatient and intrapatient variability
Oral absorption no information found
5
Distribution widely distributed into tissues; also present in ascitic fluid.
cross blood brain barrier? no information found
2
volume of distribution IV infusion < 70 min: 50 L/m ;
2
IV infusion 70-285 min: 370 L/m
3
plasma protein binding < 10%
Metabolism Metabolized intracellularly by nucleoside kinases to active metabolites dFdCDP and
dFdCTP; also metabolized intracellularly and extracellularly by cytidine deaminase to
3,4
inactive metabolite difluorodeoxyuridine (dFdU).
active metabolite(s) dFdCDP, dFdCTP
inactive metabolite(s) dFdU
Excretion mainly renal excretion
urine 92-98% over one week (89% as dFdU, < 10% as
2
gemcitabine) after a single dose of 1000 mg/m given
3
over 30 minutes.
terminal half life IV infusion <70 min: 0.7-1.6 h;
IV infusion 70-285 min: 4.1-10.6 h
2
clearance IV infusion < 70 min: 41-92 L/h/m (male)
2
31-69 L/h/m (female)
Gender decreased volume of distribution and clearance in women
Elderly decreased clearance and increased half-life with increasing age
Adapted from reference2 unless specified otherwise.

BC Cancer Drug Manual© Page 1 of 8 Gemcitabine

Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

USES:
Primary uses: Other uses:
6-8
*Lung cancer, non-small cell Breast cancer
9
*Pancreatic cancer Cervical Cancer
10-12 13,14
Bladder cancer Head and neck cancer
15,16
Lung cancer, small cell
17
Lymphoma, cutaneous T-cell
18
Lymphoma, Hodgkin’s disease
19
Mesothelioma
20
Ovarian cancer
*Health Canada Therapeutic Products Programme approved indication

No pediatric indications.

SPECIAL PRECAUTIONS:

Carcinogenicity: No information found.

Mutagenicity: Not mutagenic in Ames test but mutagenic in mammalian in vitro mutation test. Gemcitabine is
3
clastogenic in mammalian in vitro and in vivo chromosome tests.
3
Fertility: Decreased spermatogenesis and fertility in male mice.
3
Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use
in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for
a serious disease for which safer drugs cannot be used or are ineffective).
3
Breastfeeding is not recommended due to the potential secretion into breast milk.

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they
were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be
clinically important.

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics
21
allergy/immunology allergic reaction (4%, severe 0.2%)
blood/bone marrow anemia (68%, severe 8%)
febrile neutropenia leukopenia (62%, severe 9%)
22
neutropenia (63%, severe 25%); nadir 7-10 days, recovery within 7 days
22
thrombocytopenia (24%, severe 5%); nadir 7-10 days, recovery within 7 days
21
cardiovascular (arrhythmia) cardiac arrhythmia (2%, severe 0.2%)
23
cardiovascular (general) edema/peripheral edema (28%, severe 3%)
coagulation hemolytic uremic syndrome (0.3%); see paragraph following Side Effects table
21
constitutional symptoms asthenia (42%, severe 2%)

BC Cancer Drug Manual© Page 2 of 8 Gemcitabine

Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

fever (37%, severe <1%); see paragraph following Side Effects table
24-29
dermatology/skin extravasation hazard: irritant
alopecia (14%)
30
injection site reactions (4%) ; see paragraph following Side Effects table
skin rash (25%, severe <1%); see paragraph following Side Effects table
31
gastrointestinal emetogenic potential: low moderate
constipation (8%, severe <1%)
diarrhea (12%, severe <1%)
nausea and vomiting (64%, severe 18%)
stomatitis (8%, severe <1%)
hemorrhage hematuria (31%, severe <1%)
hepatic elevated alkaline phosphatase (55%, severe 9%); see paragraph following Side
Effects table
elevated AST (67%, severe 9%); see paragraph following Side Effects table
elevated ALT (68%, severe 10%); see paragraph following Side Effects table
elevated bilirubin (13%, severe 2%); see paragraph following Side Effects table
infection infection (9%, severe 1%)
neurology decreased level of consciousness (9%, severe <1%)
32
peripheral neuropathy (3%)
pain pain (16%, severe 1%)
pulmonary dyspnea (8%, severe 1%); see paragraph following Side Effects table
renal/genitourinary elevated BUN (16%, severe 0%)
elevated creatinine (7%, severe <1%)
proteinuria (36%, severe <1%)
21
syndromes flu-like symptoms (19%, severe 1%) ; see paragraph following Side Effects table
vascular digital ischemia; see paragraph following Side Effects table
33,34
peripheral vasculitis (<1%) ; see paragraph following Side Effects table
2
Adapted from reference unless specified otherwise.

Dosing schedule and toxicity: Infusion time prolonged beyond 60 minutes has been shown to increase volume of
33
distribution and has been associated with an increase in toxicity. However, given in the context of a fixed dose
rate (FDR) regimen, prolonged infusions have also been reported to produce a higher response rate than standard
35-38
regimens in association with a higher intracellular accumulation of its active metabolite (dFdCTP). Refer to
protocol by which patient is being treated for direction regarding duration of infusion.
2
Hemolytic uremic syndrome has been infrequently reported and is characterized by microangiopathic hemolytic
anemia, thrombocytopenia and renal failure. The syndrome can present either acutely with severe hemolysis,
thrombocytopenia and rapidly progressive renal failure, or more insidiously with mild or no thrombocytopenia and
39
slowly progressive renal failure. The etiology of hemolytic uremic syndrome is unknown. The onset of the
syndrome has been reported to occur during and shortly after gemcitabine therapy. If not treated promptly, the
3
syndrome may result in irreversible renal failure requiring dialysis. Therefore, patients with impaired renal function
2,21
should be monitored closely while being treated with gemcitabine.

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Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

Elevated liver enzymes: Gemcitabine causes transient and reversible elevations of liver function enzymes in about
two-thirds of patients. However, these increases are rarely of clinical significance and there is no evidence of
2,21
increasing hepatic toxicity with either longer duration of gemcitabine treatment or cumulative dose.

Fever/Flu-like symptoms: Fever of any severity was reported in 37% of patients. It is frequently associated with
2
other flu-like symptoms such as headache, chills, cough, rhinitis, myalgia, fatigue, sweating and insomnia. These
symptoms are usually mild and transient, and rarely dose-limiting. The use of acetaminophen may provide
21
symptomatic relief.

Injection site reactions are reported in 4% of patients. Extravasation of gemcitabine does not cause tissue
30
necrosis . Anecdotally BC Cancer nurses have reported frequent injection site reactions to gemcitabine infusion.
Although no further specific published reports have been identified, more recent practice guidelines have either
25-28 29
reclassified gemcitabine as an irritant or noted its ability to cause a chemical phlebitis. Therefore, it has been
proposed to reclassify gemcitabine as an irritant. See BC Cancer Policy Number III-20 Prevention and
Management of Extravasation of Chemotherapy.

Severe pulmonary toxicity: Acute dyspnea may sometimes occur with gemcitabine therapy, but is usually self-
limiting. However, severe pulmonary toxicities such as pulmonary edema, interstitial pneumonitis and adult
2
respiratory distress syndrome have rarely been reported. The symptoms are manifested as progressive dyspnea,
tachypnea, hypoxemia and pulmonary infiltrates on chest radiograph that are sometimes accompanied by fever and
40-42
cough. Pulmonary toxicities usually occur after several cycles of gemcitabine, but have also been seen as early
as the first cycle. Risk factors for pulmonary toxicities include prior radiation to the mediastinum. Because of its
structural similarities to cytarabine, gemcitabine is thought to cause lung injury by the same mechanism by inducing
40,41
pulmonary capillary leakage. Management of pulmonary toxicities consists of discontinuation of gemcitabine and
2,40-42
early supportive care with bronchodilators, corticosteroids, diuretics, and/or oxygen. Although pulmonary
toxicities may be reversible with treatment, fatal recurrence of severe pulmonary symptoms was reported in one
40
patient upon rechallenge with gemcitabine.

Skin rash: Typically mild to moderate in severity, with macular or finely granular maculopapular pruritic eruption on
2,32
the trunk and extremities. It is not dose-limiting and usually responds to topical corticosteroids. If needed,
32
antihistamines such as diphenhydramine can be used.

Vascular toxicity, including cases of thrombotic microangiopathy, veno-occlusive disease, and digital ischemic
changes and necrosis, have been reported. The exact mechanism is unknown, although it is suggested to be more
2 33,43-45
common and more severe after cumulative doses of 10,000 mg/m or in the setting of combination therapy.

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT

46
warfarin increased anticoagulant possibly decreased monitor INR carefully
effect of warfarin metabolism of warfarin during and for 1-2 months
and decreased hepatic after gemcitabine therapy;
synthesis of clotting adjust warfarin dose as
factors needed

SUPPLY AND STORAGE:

Injection:
Pfizer Canada /Hospira Healthcare Corporation supplies gemcitabine as 200 mg, 1000 mg, and 2000 mg vials of
47,48
ready-to-use preservative-free aqueous solution in a concentration of 38 mg/mL. Refrigerate.

Accord Healthcare Inc. supplies gemcitabine hydrochloride as 200 mg, 1000 mg, and 2000 mg vials of sterile
49
lyophilized powder. Store at room temperature.

BC Cancer Drug Manual© Page 4 of 8 Gemcitabine

Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability
Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability
Chart in Appendix.

Additional information: Solutions of reconstituted gemcitabine should not be refrigerated as crystallization may
33
occur.

Compatibility: consult detailed reference

PARENTERAL ADMINISTRATION:

BC Cancer administration guideline noted in bold, italics

Subcutaneous no information found
Intramuscular no information found
Direct intravenous no information found
• over 30 min ; can also be given over 60 min
33 6,10,12
Intermittent infusion
• over greater than 60 minutes using a fixed dose rate (FDR) of 10 mg/m /min
2 50,51

2
Continuous infusion investigational, has been used in clinical trials at lower dosages (100 mg/m ) over
52,53
24 h
Intraperitoneal no information found
Intrapleural no information found
Intrathecal no information found
Intra-arterial no information found
54-59
Intravesical induction doses of 2000 mg (in solution volumes of 50-100 mL) have been used
once to twice weekly for 3 to 6 weeks, followed by monthly maintenance doses for
10 months; gemcitabine (as 38 mg/mL concentration) may be used undiluted (~53
mL) or diluted with NS up to100 mL; solutions are retained for 1-2 h after instillation

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to
cytotoxic/radiation therapy or in patients with other toxicities.

Adults:
BC Cancer usual dose noted in bold, italics
Cycle length:
6,60 2 2
Intravenous: 2 weeks : 2500 mg/m (range 1250-2500 mg/m ) IV for one dose on
day 1

BC Cancer Drug Manual© Page 5 of 8 Gemcitabine

Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

2 2
3 weeks: 1250 mg/m (range 800-1250 mg/m ) IV for one dose on
days 1 and 8
2
(total dose per cycle 2500 mg/m [range 1600-2500
2 2,20
mg/m ])

2 2
4 weeks: 1000 mg/m (range 500-1250 mg/m ) IV for one dose on
days 1, 8 and 15
2
(total dose per cycle 3000 mg/m [range 1500-3750
2 2,32,61
mg/m ])

2 2
8 weeks: 1000 mg/m (range 500-1000 mg/m ) IV for one dose on
days 1, 8, 15, 22, 29, 36 and 42 for the first cycle, then
continue with the 4-week dose schedule (see above)
2
(total dose per 8-week cycle 7000 mg/m [range 3500-7000
2 2,32
mg/m ]).

2 2
3 weeks: 900 mg/m (range 750-1200 mg/m ) IV for one dose on
50,51
days 1 and 8.

2 62,63
Concurrent with radiation: investigational, 100-400 mg/m IV once daily every week

Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix "Dosage Modification for Myelosuppression"

Dosage in renal failure: No dosing recommendation available. However, caution should be used in
64
patients with renal dysfunction.

Dosage in hepatic failure: When used as a single agent in 4-week cycle treatment, no dose adjustment is
required with elevated AST; may consider using a lower starting dose of 800
mg/m with total bilirubin > 27 μmol/L. Dosage adjustment for increased
2 64

bilirubin does not appear to be necessary in regimens using fixed dose rate
65
infusion of gemcitabine.

Dosage in dialysis: no information found

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Developed: September 1994
Limited revision: 1 November 2018
 Gemcitabine

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Limited revision: 1 November 2018
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BC Cancer Drug Manual© Page 8 of 8 Gemcitabine

Developed: September 1994
Limited revision: 1 November 2018