Gemcitabine Hcl
Gemcitabine hydrochloride 1.14 mg is approximately equiv-
alent to I mg of gemcitabine.
Adverse Effects, Treatment, and Precautions
As for Cytarabine, although gemcitabine
maybe somewhat better tolerated, with myelo-
toxicity reported to be modest even at high doses.
Oedema (including pulmonary oedema), hypoten-
sion, and alopecia have also been reported. Gemcit-
abine may produce somnolence: patients so affected
should not drive or operate machinery. Severe
toxicity, in the form of potentially life-threatening
oesophagitis and pneumonitis has been seen in pa-
tients given radical radiotherapy to the thorax in as-
sociation with gemcitabine. It should be used with
caution in patients with impaired renal or hepatic
function. Haemolytic-uraemic syndrome has been
reported and has led to irreversible renal failure;
gemcitabine should be discontinued at the first signs
of microangiopathic haemolytic anaemia.
Effects on the nervous system. A report of autonomic
neuropathy associated with gemcitabine therapy. Symptoms
resolved 4 weeks after stopping therapy.
Pharmacokinetics
Following intravenous administration gemcitabine
is rapidly cleared from the blood and metabolised by
cytidine deaminase in the liver, kidney, blood, and
other tissues. Clearance is approximately 30% lower
in women than in men. Almost all of the dose is ex-
creted in urine as 2'-deoxy-2',2'-difluorouridine
(dFdU), only about 1% being found in the faeces.
Intracellular metabolism produces mono-, di-, and
triphosphate metabolites, the latter two active. The
mean terminal half-life of gemcitabine is 17 min-
utes: the intracellular half-life of the triphosphate is
stated to range from 0.7 to 12 hours.
Uses and Administration
Gemcitabine is an analogue of cytarabine
which is metabolised intracellularly to active di-
phosphate and triphosphate nucleosides, which in-
hibit DNA synthesis and induce apoptosis. It is
primarily active against cells in S-phase. It is given
in the management of solid tumours including those
of the lung and pancreas . It is also being tried in cancers of
the bladder, breast, and ovary.
Gemcitabine is given intravenously as the hydro-
chloride; doses are calculated in terms of the base.
Doses are reconstituted in sodium chloride 0.9% in-
jection. The concentration of the infusion solution
should not exceed the equivalent of 40 mg of gem-
citabine per mL. The recommended initial dose is
the equivalent of I g of gemcitabine per sq.m body-
surface, by infusion over 30 minutes. The dose may
be repeated at weekly intervals adjusted according
to response and toxicity. In the treatment of non-
small cell lung cancer, doses are given once weekly
for 3 weeks, followed by a one-week rest period. In
the treatment of pancreatic cancer, an initial course
of up to 7 doses at weekly intervals may be given,
followed after a one-week recovery period by a reg-
imen of infusions once weekly for 3 consecutive
weeks out of 4.
1
(GEMCITABINE HCl)
FOR INJECTION
DESCRIPTION Gemzar
?
(gemcitabine HCl) is a nucleoside analogue that exhibits antitumor activity.
Gemcitabine HCl is -deoxy-difluorocytidine monohydrochloride-isomer).
The structural formula is as follows:
The empirical formula for gemcitabine HCl is C9H11F2N3O4 ?HCl. It has a molecular weight
of 299.66.
Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in
methanol, and practically insoluble in ethanol and polar organic solvents.
The clinical formulation is supplied in a sterile form for intravenous use only. Vials of Gemzar
contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with
mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as
a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added
for pH adjustment.
CLINICAL PHARMACOLOGY Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis
(S-phase) and also blocking the progression of cells through the G1/S-phase boundary.
Gemcitabine is metabolized intracellularly by nucleoside kinases to the active
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of
gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate
nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits
ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the
deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate
nucleoside causes a reduction in the concentrations of deoxynucleotides, including dCTP.
Second, gemcitabine triphosphate competes with dCTP for incorporation into DNA. The
reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances
the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the
gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the
growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA
polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA
strands (masked chain termination). In CEM T lymphoblastoid cells, gemcitabine induces
internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
Gemcitabine demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect
of cisplatin on gemcitabine triphosphate accumulation or DNA double-strand breaks was
observed. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1
and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or
NCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine
xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest
interaction.
Human Pharmacokinetics - Gemcitabine disposition was studied in 5 patients who received a
single 1000 mg/m 2 /30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of
the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil
metabolite, ?????-deoxy-?????,?????-difluorouridine (dFdU), accounted for 99% of the excreted dose. The
metabolite dFdU is also found in plasma. Gemcitabine plasma protein binding is negligible.
The pharmacokinetics of gemcitabine were examined in 353 patients, about 2/3 men, with
various solid tumors. Pharmacokinetic parameters were derived using data from patients treated
for varying durations of therapy given weekly with periodic rest weeks and using both short
infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose varied
from 500 to 3600 mg/m 2 .
Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model.
Population pharmacokinetic analyses of combined single and multiple dose studies showed that
the volume of distribution of gemcitabine was significantly influenced by duration of infusion
and gender. Clearance was affected by age and gender. Differences in either clearance or volume
of distribution based on patient characteristics or the duration of infusion result in changes in
half-life and plasma concentrations. Table 1 shows plasma clearance and half-life of gemcitabine
following short infusions for typical patients by age and gender.
Table 1: Gemcitabine Clearance and Half-Life for the “Typical” Patient
Age Clearance Clearance Half-Life a Half-Life a
Men Women Men Women
(L/hr/m 2 ) (L/hr/m 2 ) (min) (min)
29 92.2 69.4 42 49
45 75.7 57.0 48 57
65 55.1 41.5 61 73
79 40.7 30.7 79 94
a Half-life for patients receiving a short infusion (<70 min).
Gemcitabine half-life for short infusions ranged from 32 to 94 minutes, and the value for long
infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly
increased volume of distribution with longer infusions. The lower clearance in women and the
elderly results in higher concentrations of gemcitabine for any given dose.
The volume of distribution was increased with infusion length. Volume of distribution of
gemcitabine was 50 L/m 2 following infusions lasting <70 minutes, indicating that gemcitabine,
after short infusions, is not extensively distributed into tissues. For long infusions, the volume of
distribution rose to 370 L/m 2 , reflecting slow equilibration of gemcitabine within the tissue
compartment.
The maximum plasma concentrations of dFdU (inactive metabolite) were achieved up to
30 minutes after discontinuation of the infusions and the metabolite is excreted in urine without
undergoing further biotransformation. The metabolite did not accumulate with weekly dosing,
but its elimination is dependent on renal excretion, and could accumulate with decreased renal
function.
The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have
not been assessed.
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood
mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from
mononuclear cells ranges from 1.7 to 19.4 hours.
Drug Interactions - When gemcitabine (1250 mg/m 2 on Days 1 and 8) and cisplatin
(75 mg/m 2 on Day 1) was administered in NSCLC patients, the clearance of gemcitabine on
Day 1 was 128 L/hr/m 2 and on Day 8 was 107 L/hr/m 2 . The clearance of cisplatin in the same
study was reported to be 3.94 mL/min/m 2 with a corresponding half-life of 134 hours (see Drug
Interactions under PRECAUTIONS).
CLINICAL STUDIES Non-Small Cell Lung Cancer (NSCLC) - Data from 2 randomized clinical studies
(657 patients) support the use of Gemzar in combination with cisplatin for the first-line treatment
of patients with locally advanced or metastatic NSCLC.
Gemzar plus cisplatin versus cisplatin: This study was conducted in Europe, the US, and
Canada in 522 patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received
prior chemotherapy. Gemzar 1000 mg/m 2 was administered on Days 1, 8, and 15 of a 28-day
cycle with cisplatin 100 mg/m 2 administered on Day 1 of each cycle. Single-agent cisplatin
100 mg/m 2 was administered on Day 1 of each 28-day cycle. The primary endpoint was survival.
Patient demographics are shown in Table 2. An imbalance with regard to histology was observed
with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar plus cisplatin arm
having adenocarcinoma.
The Kaplan-Meier survival curve is shown in Figure 1. Median survival time on the Gemzar
plus cisplatin arm was 9.0 months compared to 7.6 months on the single-agent cisplatin arm
(Logrank p=0.008, two-sided). Median time to disease progression was 5.2 months on the
Gemzar plus cisplatin arm compared to 3.7 months on the cisplatin arm (Logrank p=0.009,
two-sided). The objective response rate on the Gemzar plus cisplatin arm was 26% compared to
10% with cisplatin (Fisher's Exact p<0.0001, two-sided). No difference between treatment arms
with regard to duration of response was observed.
Gemzar plus cisplatin versus etoposide plus cisplatin: A second, multi-center, study in
Stage IIIB or IV NSCLC randomized 135 patients to Gemzar 1250 mg/m 2 on Days 1 and 8, and
cisplatin 100 mg/m 2 on Day 1 of a 21-day cycle or to etoposide 100 mg/m 2 I.V. on Days 1, 2,
and 3 and cisplatin 100 mg/m 2 on Day 1 on a 21-day cycle (Table 2).
There was no significant difference in survival between the two treatment arms (Logrank
p=0.18, two-sided). The median survival was 8.7 months for the Gemzar plus cisplatin arm
versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for
the Gemzar plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus
cisplatin arm (Logrank p=0.015, two-sided). The objective response rate for the Gemzar plus
cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher's Exact
p=0.01, two-sided).
Quality of Life (QOL): QOL was a secondary endpoint in both randomized studies. In the
Gemzar plus cisplatin versus cisplatin study, QOL was measured using the FACT-L, which
assessed physical, social, emotional and functional well-being, and lung cancer symptoms. In the
study of Gemzar plus cisplatin versus etoposide plus cisplatin, QOL was measured using the
EORTC QLQ-C30 and LC13, which assessed physical and psychological functioning and
symptoms related to both lung cancer and its treatment. In both studies no significant differences
were observed in QOL between the Gemzar plus cisplatin arm and the comparator arm.
Survival p=0.008 p=0.18
Median, months 9.0 7.6 8.7 7.0
(95%, C.I.) months 8.2, 11.0 6.6, 8.8 7.8, 10.1 6.0, 9.7
Time to Disease Progression p=0.009 p=0.015
Median, months 5.2 3.7 5.0 4.1
(95%, C.I.) months 4.2, 5.7 3.0, 4.3 4.2, 6.4 2.4, 4.5
Tumor Response 26% 10% p<0.0001 d 33% 14% p=0.01 d
a 28-day schedule - Gemzar plus cisplatin: Gemzar 1000 mg/m 2 on Days 1, 8, and 15 and cisplatin 100 mg/m 2 on
Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m 2 on Day 1 every 28 days. b 21-day schedule - Gemzar plus cisplatin: Gemzar 1250 mg/m 2 on Days 1 and 8 and cisplatin 100 mg/m 2 on Day 1
every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m 2 on Day 1 and I.V. etoposide
100 mg/m 2 on Days 1, 2, and 3 every 21 days. c Karnofsky Performance Status. d p-value for tumor response was calculated using the two-sided Fisher's exact test for difference in binomial
proportions. All other p-values were calculated using the Logrank test for difference in overall time to an event.
N/A Not applicable.
Pancreatic Cancer - Data from 2 clinical trials evaluated the use of Gemzar in patients with
locally advanced or metastatic pancreatic cancer. The first trial compared Gemzar to
5-Fluorouracil (5-FU) in patients who had received no prior chemotherapy. A second trial studied
the use of Gemzar in pancreatic cancer patients previously treated with 5-FU or a
5-FU-containing regimen. In both studies, the first cycle of Gemzar was administered
intravenously at a dose of 1000 mg/m 2 over 30 minutes once weekly for up to 7 weeks (or until
toxicity necessitated holding a dose) followed by a week of rest from treatment with Gemzar.
Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every
4 weeks.
The primary efficacy parameter in these studies was “clinical benefit response,” which is a
measure of clinical improvement based on analgesic consumption, pain intensity, performance
status, and weight change. Definitions for improvement in these variables were formulated
prospectively during the design of the 2 trials. A patient was considered a clinical benefit
responder if either:
i) the patient showed a ?50% reduction in pain intensity (Memorial Pain Assessment Card)
or analgesic consumption, or a 20-point or greater improvement in performance status
(Karnofsky Performance Scale) for a period of at least 4 consecutive weeks, without
showing any sustained worsening in any of the other parameters. Sustained worsening was
defined as 4 consecutive weeks with either any increase in pain intensity or analgesic
consumption or a 20-point decrease in performance status occurring during the first
12 weeks of therapy.
OR:
ii) the patient was stable on all of the aforementioned parameters, and showed a marked,
sustained weight gain ?7% increase maintained for ?4 weeks) not due to fluid
accumulation.
The first study was a multi-center (17 sites in US and Canada), prospective, single-blinded,
two-arm, randomized, comparison of Gemzar and 5-FU in patients with locally advanced or
metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 5-FU was
administered intravenously at a weekly dose of 600 mg/m 2 for 30 minutes. The results from this
randomized trial are shown in Table 3. Patients treated with Gemzar had statistically significant
increases in clinical benefit response, survival, and time to disease progression compared to
5-FU. The Kaplan-Meier curve for survival is shown in Figure 2. No confirmed objective tumor
responses were observed with either treatment.
Table 3: Gemzar Versus 5-FU in Pancreatic Cancer
Gemzar 5-FU
Number of patients 63 63
Male 34 34
Female 29 29
Median age 62 years 61 years
Range 37 to 79 36 to 77
Stage IV disease 71.4% 76.2%
Baseline KPS a =70 69.8% 68.3%
Clinical benefit response 22.2% 4.8% p=0.004
(N c =14) (N=3)
Survival p=0.0009
Median 5.7 months 4.2 months
6-month probability b (N=30) 46% (N=19) 29%
9-month probability b (N=14) 24% (N=4) 5%
1-year probability b (N=9) 18% (N=2) 2%
Range 0.2 to18.6 months 0.4 to 15.1+ months
95% C.I. of the median 4.7 to 6.9 months 3.1 to 5.1 months
Time to Disease Progression p=0.0013
Median 2.1 months 0.9 months
Range 0.1+ to 9.4 months 0.1 to 12.0+ months
95% C.I. of the median 1.9 to 3.4 months 0.9 to 1.1 months
a Karnofsky Performance Status. b Kaplan-Meier estimates. c N=number of patients.
+ No progression at last visit; remains alive.
The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial
proportions. All other p-values were calculated using the Logrank test for difference in overall time to an event.
Clinical benefit response was achieved by 14 patients treated with Gemzar and 3 patients
treated with 5-FU. One patient on the Gemzar arm showed improvement in all 3 primary
parameters (pain intensity, analgesic consumption, and performance status). Eleven patients on
the Gemzar arm and 2 patients on the 5-FU arm showed improvement in analgesic consumption
and/or pain intensity with stable performance status. Two patients on the Gemzar arm showed
improvement in analgesic consumption or pain intensity with improvement in performance
status. One patient on the 5-FU arm was stable with regard to pain intensity and analgesic
consumption with improvement in performance status. No patient on either arm achieved a
clinical benefit response based on weight gain.
The second trial was a multi-center (17 US and Canadian centers), open-label study of Gemzar
in 63 patients with advanced pancreatic cancer previously treated with 5-FU or a
5-FU-containing regimen. The study showed a clinical benefit response rate of 27% and median
survival of 3.9 months.
Other Clinical Studies - When Gemzar was administered more frequently than once weekly
or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1
study of Gemzar to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed
that patients developed significant hypotension and severe flu-like symptoms that were
intolerable at doses above 10 mg/m 2 . The incidence and severity of these events were
dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only
65 mg/m 2 (30-minute infusion) and 150 mg/m 2 (5-minute bolus). The dose-limiting toxicities
were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess
the maximum tolerated infusion time, clinically significant toxicity, defined as
myelosuppression, was seen with weekly doses of 300 mg/m 2 at or above a 270-minute infusion
time. The half-life of gemcitabine is influenced by the length of the infusion (see CLINICAL
PHARMACOLOGY) and the toxicity appears to be increased if Gemzar is administered more
frequently than once weekly or with infusions longer than 60 minutes (see WARNINGS).
INDICATIONS AND USAGE
Therapeutic Indications Non-Small Cell Lung Cancer - Gemzar is indicated in combination with cisplatin for the
first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or
metastatic (Stage IV) non-small cell lung cancer.
Pancreatic Cancer - Gemzar is indicated as first-line treatment for patients with locally
advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the
pancreas. Gemzar is indicated for patients previously treated with 5-FU.
CONTRAINDICATION Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see
Allergic under ADVERSE REACTIONS).
WARNINGS Caution - Prolongation of the infusion time beyond 60 minutes and more frequent than
weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES).
Hematology - Gemzar can suppress bone marrow function as manifested by leukopenia,
thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is
usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during
therapy. See DOSAGE AND ADMINISTRATION for recommended dose adjustments.
Pulmonary - Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe
lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive
care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing
experience in ADVERSE REACTIONS section).
Renal - Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported
following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis,
despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal
failure leading to death were due to HUS (see Renal under Single-Agent Use and under
Post-marketing experience in ADVERSE REACTIONS section).
Hepatic - Serious hepatotoxicity, including liver failure and death, has been reported very
rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic
drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in
ADVERSE REACTIONS section).
Pregnancy - Pregnancy Category D. Gemzar can cause fetal harm when administered to a
pregnant woman. Gemcitabine is embryotoxic causing fetal malformations (cleft palate,
incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended
human dose on a mg/m 2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused
pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the
recommended human dose on a mg/m 2 basis). Embryotoxicity was characterized by decreased
fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar
in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant
while taking Gemzar, the patient should be apprised of the potential hazard to the fetus.
PRECAUTIONS General - Patients receiving therapy with Gemzar should be monitored closely by a physician
experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and
do not need to result in discontinuation, although doses may need to be withheld or reduced.
There was a greater tendency in women, especially older women, not to proceed to the next
cycle.
Laboratory Tests - Patients receiving Gemzar should be monitored prior to each dose with a
complete blood count (CBC), including differential and platelet count. Suspension or
modification of therapy should be considered when marrow suppression is detected (see
DOSAGE AND ADMINISTRATION).
Laboratory evaluation of renal and hepatic function should be performed prior to initiation of
therapy and periodically thereafter (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies to evaluate
the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward
mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo
mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister
chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled
DNA synthesis in vitro. Gemcitabine I.P. doses of 0.5 mg/kg/day (about 1/700 the human dose
on a mg/m 2 basis) in male mice had an effect on fertility with moderate to severe
hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility
was not affected but maternal toxicities were observed at 1.5 mg/kg/day I.V. (about 1/200 the
human dose on a mg/m 2 basis) and fetotoxicity or embryolethality was observed at
0.25 mg/kg/day I.V. (about 1/1300 the human dose on a mg/m 2 basis).
Pregnancy - Category D. See WARNINGS.
Nursing Mothers - It is not known whether Gemzar or its metabolites are excreted in human
milk. Because many drugs are excreted in human milk and because of the potential for serious
adverse reactions from Gemzar in nursing infants, the mother should be warned and a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother and the potential risk to the infant.
Elderly Patients - Gemzar clearance is affected by age (see CLINICAL
PHARMACOLOGY). There is no evidence, however, that unusual dose adjustments,
(i.e., other than those already recommended in the DOSAGE AND ADMINISTRATION
section) are necessary in patients over 65, and in general, adverse reaction rates in the
single-agent safety database of 979 patients were similar in patients above and below 65.
Grade 3/4 thrombocytopenia was more common in the elderly.
Gender - Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY). In
the single-agent safety database (N=979 patients), however, there is no evidence that unusual
dose adjustments (i.e., other than those already recommended in the DOSAGE AND
ADMINISTRATION section) are necessary in women. In general, in single-agent studies of
gemcitabine, adverse reaction rates were similar in men and women, but women, especially older
women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4
neutropenia and thrombocytopenia.
Pediatric Patients - Gemzar has not been studied in pediatric patients. Safety and
effectiveness in pediatric patients have not been established.
Patients with Renal or Hepatic Impairment - Gemzar should be used with caution in patients
with preexisting renal impairment or hepatic insufficiency. Gemzar has not been studied in
patients with significant renal or hepatic impairment.
Drug Interactions - No specific drug interaction studies have been conducted. For
information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug
Interactions under CLINICAL PHARMACOLOGY section.
Radiation Therapy - Safe and effective regimens for the administration of Gemzar with
therapeutic doses of radiation have not yet been determined.
ADVERSE REACTIONS Gemzar has been used in a wide variety of malignancies, both as a single-agent and in
combination with other cytotoxic drugs. The following discussion focuses on single-agent use
where the effects of Gemzar can be most readily determined and on the specific combination use
that is the basis for its use in NSCLC.
Single-Agent Use: Myelosuppression is the principal dose-limiting toxicity with Gemzar
therapy. Dosage adjustments for hematologic toxicity are frequently needed and are described in
the DOSAGE AND ADMINISTRATION section.
The data in Table 4 are based on 979 patients receiving Gemzar as a single-agent administered
weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemzar
starting doses ranged from 800 to 1250 mg/m 2 . Data are also shown for the subset of patients
with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO
Grade 3 or 4) adverse events were generally similar in the single-agent safety database of
979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the
single-agent safety database resulted in discontinuation of Gemzar therapy in about 10% of
patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse
reactions was 14.3% for the gemcitabine arm and 4.8% for the 5-FU arm.
All WHO-graded laboratory events are listed in Table 4, regardless of causality.
Non-laboratory adverse events listed in Table 4 or discussed below were those reported,
regardless of causality, for at least 10% of all patients, except the categories of Extravasation,
Allergic, and Cardiovascular and certain specific events under the Renal, Pulmonary, and
Infection categories. Table 5 presents the data from the comparative trial of Gemzar and 5-FU in
pancreatic cancer for the same adverse events as those in Table 4, regardless of incidence.
Table 4: Selected WHO-Graded Adverse Events in Patients Receiving Single-Agent Gemzar
WHO Grades (% incidence)
All Patients a Pancreatic Cancer Patients b Discontinuations (%)c
All Grade Grade3 Grades 4 All Grade Grade 3 Grade 4 All Patients
Laboratory d
Hematologic
Anemia 68 7 1 73 8 2 <1
Leukopenia 62 9 <1 64 8 1 <1
Neutropenia 63 19 6 61 17 7 -
Thrombocytopenia 24 4 1 36 7 <1 <1
Hepatic <1
ALT 68 8 2 72 10 1
AST 67 6 2 78 12 5
Alkaline Phosphatase 55 7 2 77 16 4
Bilirubin 13 2 <1 26 6 2
Renal <1
Proteinuria 45 <1 0 32 <1 0
Hematuria 35 <1 0 23 0 0
BUN 16 0 0 15 0 0
Creatinine 8 <1 0 6 0 0
Non-laboratory e
Nausea and Vomiting 69 13 1 71 10 2 <1
Pain 48 9 <1 42 6 <1 <1
Fever 41 2 0 38 2 0 <1
Rash 30 <1 0 28 <1 0 <1
Dyspnea 23 3 <1 10 0 <1 <1
Constipation 23 1 <1 31 3 <1 0
Diarrhea 19 1 0 30 3 0 0
Hemorrhage 17 <1 <1 4 2 <1 <1
Infection 16 1 <1 10 2 <1 <1
Alopecia 15 <1 0 16 0 0 0
Stomatitis 11 <1 0 10 <1 0 <1
Somnolence 11 <1 <1 11 2 <1 <1
Paresthesias 10 <1 0 10 <1 0 0
Grade based on criteria from the World Health Organization (WHO). a N=699-974; all patients with laboratory or non-laboratory data. b N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data. c N=979. d Regardless of causality. e Table includes non-laboratory data with incidence for all patients ?10%. For approximately 60% of the patients,
non-laboratory events were graded only if assessed to be possibly drug-related.
Table 5: Selected WHO-Graded Adverse Events from Comparative Trial of Gemzar and 5-FU in Pancreatic Cancer
WHO Grades (% incidence)
Gemzar a 5-FU b
All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4
Laboratory c
Hematologic
Anemia 65 7 3 45 0 0
Leukopenia 71 10 0 15 2 0
Neutropenia 62 19 7 18 2 3
Thrombocytopenia 47 10 0 15 2 0
Hepatic
ALT 72 8 2 38 0 0
AST 72 10 2 52 2 0
Alkaline Phosphatase 71 16 0 64 10 3
Bilirubin 16 2 2 25 6 3
Renal
Proteinuria 10 0 0 2 0 0
Hematuria 13 0 0 0 0 0
BUN 8 0 0 10 0 0
Creatinine 2 0 0 0 0 0
Non-laboratory d
Nausea and Vomiting 64 10 3 58 5 0
Pain 10 2 0 7 0 0
Fever 30 0 0 16 0 0
Rash 24 0 0 13 0 0
Dyspnea 6 0 0 3 0 0
Constipation 10 3 0 11 2 0
Diarrhea 24 2 0 31 5 0
Hemorrhage 0 0 0 2 0 0
Infection 8 0 0 3 2 0
Alopecia 18 0 0 16 0 0
Stomatitis 14 0 0 15 0 0
Somnolence 5 2 0 7 2 0
Paresthesias 2 0 0 2 0 0
Grade based on criteria from the World Health Organization (WHO). a N=58-63; all Gemzar patients with laboratory or non-laboratory data. b N=61-63; all 5-FU patients with laboratory or non-laboratory data. c Regardless of causality. d Non-laboratory events were graded only if assessed to be possibly drug-related.
Hematologic - In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity
with Gemzar, but <1% of patients discontinued therapy for either anemia, leukopenia, or
thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence
of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was
reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients
should be monitored for myelosuppression during Gemzar therapy and dosage modified or
suspended according to the degree of hematologic toxicity (see DOSAGE AND
ADMINISTRATION).
Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were usually of
mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of
patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.
Hepatic - In clinical trials, Gemzar was associated with transient elevations of one or both
serum transaminases in approximately 70% of patients, but there was no evidence of increasing
hepatic toxicity with either longer duration of exposure to Gemzar or with greater total
cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very
rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic
drugs (see Hepatic under Post-marketing experience).
Renal - In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical
findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of
2429 patients (0.25%) receiving Gemzar in clinical trials. Four patients developed HUS on
Gemzar therapy, 2 immediately post-therapy. The diagnosis of HUS should be considered if the
patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or
LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of
serum creatinine or BUN). Gemzar therapy should be discontinued immediately. Renal failure
may not be reversible even with discontinuation of therapy and dialysis may be required (see
Renal under Post-marketing experience).
Fever - The overall incidence of fever was 41%. This is in contrast to the incidence of
infection (16%) and indicates that Gemzar may cause fever in the absence of clinical infection.
Fever was frequently associated with other flu-like symptoms and was usually mild and clinically
manageable.
Rash - Rash was reported in 30% of patients. The rash was typically a macular or finely
granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and
extremities. Pruritus was reported for 13% of patients.
Pulmonary ??In clinical trials, dyspnea, unrelated to underlying disease, has been reported in
association with Gemzar therapy. Dyspnea was occasionally accompanied by bronchospasm.
Pulmonary toxicity has been reported with the use of Gemzar (see Pulmonary under
Post-marketing experience). The etiology of these effects is unknown. If such effects develop,
Gemzar should be discontinued. Early use of supportive care measures may help ameliorate these
conditions.
Edema - Edema (13%), peripheral edema (20%), and generalized edema (<1%) were
reported. Less than 1% of patients discontinued due to edema.
Flu-like Symptoms - “Flu syndrome” was reported for 19% of patients. Individual symptoms
of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported.
Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis,
sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to
flu-like symptoms.
Infection - Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).
Alopecia - Hair loss, usually minimal, was reported by 15% of patients.
Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of severe
paresthesias.
Extravasation - Injection-site related events were reported for 4% of patients. There were no
reports of injection site necrosis. Gemzar is not a vesicant.
Allergic - Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction
has been reported rarely. Gemzar should not be administered to patients with a known
hypersensitivity to this drug (see CONTRAINDICATION).
Cardiovascular - During clinical trials, 2% of patients discontinued therapy with Gemzar due
to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and
hypertension. Many of these patients had a prior history of cardiovascular disease (see
Cardiovascular under Post-marketing experience).
Combination Use in Non-Small Cell Lung Cancer: In the Gemzar plus cisplatin vs. cisplatin
study, dose adjustments occurred with 35% of Gemzar injections and 17% of cisplatin injections
on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in
greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations
for possibly drug-related adverse events occurred in 15% of patients on the combination arm and
8% of patients on the cisplatin arm. With a median of 4 cycles of Gemzar plus cisplatin
treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly
treatment-related adverse events. With a median of 2 cycles of cisplatin treatment, 61 of
260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse
events.
In the Gemzar plus cisplatin vs. etoposide plus cisplatin study, dose adjustments occurred with
20% of Gemzar injections and 16% of cisplatin injections in the Gemzar plus cisplatin arm
compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus
cisplatin arm. With a median of 5 cycles of Gemzar plus cisplatin treatment, 15 of 69
patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse events.
With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%)
experienced 22 hospitalizations due to possibly treatment-related adverse events. In patients who
completed more than one cycle, dose adjustments were reported in 81% of the Gemzar plus
cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study
discontinuations for possibly drug-related adverse events occurred in 14% of patients on the
gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The
incidence of myelosuppression was increased in frequency with Gemzar plus cisplatin
treatment ?90%) compared to that with the Gemzar monotherapy ?60%). With combination
therapy Gemzar dosage adjustments for hematologic toxicity were required more often while
cisplatin dose adjustments were less frequently required.
Table 6 presents the safety data from the Gemzar plus cisplatin vs. cisplatin study in non-small
cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug
combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths,
including 3 resulting from myelosuppression with infection and 1 case of renal failure associated
with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm.
Nine cases of febrile neutropenia were reported on the combination therapy arm compared to
2 on the cisplatin arm. More patients required RBC and platelet transfusions on the Gemzar plus
cisplatin arm.
Myelosuppression occurred more frequently on the combination arm, and in 4 possibly
treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients
on the Gemzar plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were
required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm.
Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin
arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in
39% of the patients on the Gemzar plus cisplatin arm, versus 13% on the cisplatin arm. The data
suggest cumulative anemia with continued Gemzar plus cisplatin use.
Nausea and vomiting despite the use of antiemetics occurred slightly more often with Gemzar
plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent
Gemzar, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function
abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity
occurred more often with Gemzar plus cisplatin than with cisplatin monotherapy. Neurohearing
toxicity was similar on both arms.
Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with
Gemzar plus cisplatin compared to one (<1%) Grade 3 dysrrhythmia reported with cisplatin
therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the
Gemzar plus cisplatin combination arm.
Table 7 presents data from the randomized study of Gemzar plus cisplatin versus etoposide
plus cisplatin in 135 patients with NSCLC for the same WHO-graded adverse events as those in
Table 5. One death (1.5%) was reported on the Gemzar plus cisplatin arm due to febrile
neutropenia associated with renal failure which was possibly treatment-related. No deaths related
to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4
neutropenia on the Gemzar plus cisplatin arm was less than on the etoposide plus cisplatin
arm (28% vs. 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3
anemia and Grade 3/4 thrombocytopenia were more common on the Gemzar plus cisplatin arm.
RBC transfusions were given to 29% of the patients who received Gemzar plus cisplatin vs. 21%
of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the
patients who received Gemzar plus cisplatin vs. 8% of patients who received etoposide plus
cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemzar plus cisplatin
arm. On the Gemzar plus cisplatin arm, 7% of participants were hospitalized due to febrile
neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many
patients had dose reductions or omissions of a scheduled dose of Gemzar as compared to
etoposide, which may explain the differences in the incidence of neutropenia and febrile
neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the
Gemzar plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on
the Gemzar plus cisplatin arm reported edema compared to 1 patient (2%) on the etoposide plus
cisplatin arm.
Table 6: Selected CTC-Graded Adverse Events from Comparative Trial of Gemzar plus Cisplatin versus Single-Agent Cisplatin in NSCLC
CTC Grades (% incidence)
Gemzar plus Cisplatin a Cisplatin b
All Grades Grade 3 Grade 4 All Grades Grade3 Grade 4
Laboratory c
Hematologic
Anemia 89 22 3 67 6 1
RBC Transfusion d 39 13
Leukopenia 82 35 11 25 2 1
Neutropenia 79 22 35 20 3 1
Thrombocytopenia 85 25 25 13 3 1
Platelet Transfusions d 21 <1
Lymphocytes 75 25 18 51 12 5
Hepatic
Transaminase 22 2 1 10 1 0
Alkaline Phosphatase 19 1 0 13 0 0
Renal
Proteinuria 23 0 0 18 0 0
Hematuria 15 0 0 13 0 0
Creatinine 38 4 <1 31 2 <1
Other Laboratory
Hyperglycemia 30 4 0 23 3 0
Hypomagnesemia 30 4 3 17 2 0
Hypocalcemia 18 2 0 7 0 <1
Non-laboratory e
Nausea 93 25 2 87 20 <1
Vomiting 78 11 12 71 10 9
Alopecia 53 1 0 33 0 0
Neuro Motor 35 12 0 15 3 0
Constipation 28 3 0 21 0 0
Neuro Hearing 25 6 0 21 6 0
Diarrhea 24 2 2 13 0 0
Neuro Sensory 23 1 0 18 1 0
Infection 18 3 2 12 1 0
Fever 16 0 0 5 0 0
Neuro Cortical 16 3 1 9 1 0
Neuro Mood 16 1 0 10 1 0
Local 15 0 0 6 0 0
Neuro Headache 14 0 0 7 0 0
Stomatitis 14 1 0 5 0 0
Hemorrhage 14 1 0 4 0 0
Dyspnea 12 4 3 11 3 2
Hypotension 12 1 0 7 1 0
Rash 11 0 0 3 0 0
Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse events with incidence ?10% in
either arm. a N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gemzar at 1000 mg/m 2 on
Days 1, 8, and 15 and cisplatin at 100 mg/m 2 on Day 1 every 28 days. b N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m 2 on Day 1 every
28 days. c Regardless of causality. d Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. e Non-laboratory events were graded only if assessed to be possibly drug-related.