1
`B1.0 NL 4063 AMP
`
`GEMZAR®
`(GEMCITABINE HCl)
`FOR INJECTION
`DESCRIPTION
`Gemzar® (gemcitabine HCl) is a nucleoside analogue that exhibits antitumor activity.
`Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).
`The structural formula is as follows:
`
`NH 2•HCl
`
`N
`
`HO
`
`O
`
`N
`
`O
`
`F F
`
`H
`OH
`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.
`
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`
`AVENTIS EXHIBIT 2208
`Mylan v. Aventis IPR2016-00712
`
`

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`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/m2/30 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, 2´-deoxy-2´,2´-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/m2.
`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
`Half-Lifea
`Half-Lifea
`Age
`Clearance
`Clearance
`Men
`Women
`Men
`Women
`(L/hr/m2)
`(L/hr/m2)
`(min)
`(min)
`92.2
`69.4
`42
`49
`29
`75.7
`57.0
`48
`57
`45
`55.1
`41.5
`61
`73
`65
`40.7
`30.7
`79
`94
`79
`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/m2 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/m2, 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,
`
`

`
`3
`
`
`
`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 Gemzar (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on
`Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was
`128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was
`reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours (see Drug
`Interactions under PRECAUTIONS).
`CLINICAL STUDIES
`Breast Cancer — Data from a multi-national, randomized Phase 3 study (529 patients) support
`the use of Gemzar in combination with paclitaxel for treatment of breast cancer patients who
`have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically
`contraindicated. Gemzar 1250 mg/m2 was administered on Days 1 and 8 of a 21-day cycle with
`paclitaxel 175 mg/m2 administered prior to Gemzar on Day 1 of each cycle. Single-agent
`paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle as the control arm.
`The addition of Gemzar to paclitaxel resulted in statistically significant improvement in time to
`documented disease progression and overall response rate compared to monotherapy with
`paclitaxel as shown in Table 2 and Figure 1. Further, there was a strong trend toward improved
`survival for the group given Gemzar based on an interim survival analysis.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`p<0.0001
`
`
`p<0.0001
`p<0.0001
`
`
`2.9 (2.6, 3.7)
`5.2 (4.2, 5.6)
`0.650 (0.524, 0.805)
`
`Table 2: Gemzar Plus Paclitaxel Versus Paclitaxel in Breast Cancer
`
`Gemzar/Paclitaxel
`Paclitaxel
`Number of patients
`267
`262
`Median age, years
`53
`52
` Range
`26 to 83
`26 to 75
`Metastatic disease
`97.0%
`96.9%
`Baseline KPSa ≥90
`70.4%
`74.4%
`Number of tumor sites
`
`
` 1-2
`56.6%
`58.8%
` ≥3
`43.4%
`41.2%
`Visceral disease
`73.4%
`72.9%
`Prior anthracycline
`96.6%
`95.8%
`
`
`
`Time to Documented Disease
`
`
`Progressionb
` Median (95%, C.I.), months
` Hazard Ratio (95% C.I.)
`Overall Response Rateb
` (95%, C.I.)
`a Karnofsky Performance Status.
`b These represent reconciliation of investigator and Independent Review Committee assessments according to a
`predefined algorithm.
`
`
`40.8% (34.9, 46.7)
`
`
`22.1% (17.1, 27.2)
`
`76
`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
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`

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`4
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`
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`103
`104
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`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`128
`129
`130
`131
`132
`
`
`Figure 1: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemzar
`plus Paclitaxel versus Paclitaxel Breast Cancer Study (N=529).
`
`
`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
`2 was administered on Days 1, 8, and 15 of a 28-day
`prior chemotherapy. Gemzar 1000 mg/m
`cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle. Single-agent cisplatin
`100 mg/m2 was administered on Day 1 of each 28-day cycle. The primary endpoint was survival.
`Patient demographics are shown in Table 3. 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 2. 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
`2 on Days 1 and 8, and
`Stage IIIB or IV NSCLC randomized 135 patients to Gemzar 1250 mg/m
`cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to etoposide 100 mg/m2 I.V. on Days 1, 2,
`and 3 and cisplatin 100 mg/m2 on Day 1 on a 21-day cycle (Table 3).
`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
`
`

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`5
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`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`145
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`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.
`
`
`Median Survival
`Gem / Cis 9.0 months
`Cis
`7.6 months
`
`1-Year Survival
`39%
`28 %
`
`Test Statistic p-value
`Logrank 0.008
`Wilcoxon 0.018
`
`Gemcitabine/Cisplatin
`(N=260)
`
`Survival
`probability
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Cisplatin
`(N=262)
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Survival time (months)
`
`146
`
`
`
`Figure 2: Kaplan-Meier Survival Curve in Gemzar plus Cisplatin versus
`Cisplatin NSCLC Study (N=522).
`
`

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`Table 3: Randomized Trials of Combination Therapy with Gemzar plus Cisplatin in NSCLC
`21-day Scheduleb
`28-day Schedulea
`Trial
`Treatment Arm
`Gemzar/
`Cisplatin
`Gemzar/
`Cisplatin/
`Cisplatin
`Cisplatin
`Etoposide
`260
`69
`66
`182
`64
`61
`78
`5
`5
`62
`58
`60
`36 to 88
`33 to 76
`35 to 75
`7%
`N/A
`N/A
`26%
`48%
`52%
`67%
`52%
`49%
`41%
`45%
`52%
`57%
`55%
`49%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`9.0
`8.2, 11.0
`
`
`
`7.6
`6.6, 8.8
`
`
`P=0.008
`
`
`P=0.009
`
`
`8.7
`7.8, 10.1
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`
`
`7.0
`6.0, 9.7
`
`
`p=0.18
`
`
`p=0.015
`
`262
`186
`76
`63
`35 to 79
`7%
`23%
`70%
`44%
`55%
`
`
`
`
`
`
`
`
`
`
`
`Number of patients
` Male
` Female
`Median age, years
` Range
`Stage IIIA
`Stage IIIB
`Stage IV
`Baseline KPSc 70 to 80
`Baseline KPSc 90 to 100
`
`Survival
` Median, months
` (95%, C.I.) months
`Time to Disease
`Progression
`
`4.1
`5.0
`
`3.7
`5.2
` Median, months
`
`2.4, 4.5
`4.2, 6.4
`
`3.0, 4.3
`4.2, 5.7
` (95%, C.I.) months
`p=0.01d
`p<0.0001d
`14%
`33%
`10%
`26%
`Tumor Response
`a 28-day schedule — Gemzar plus cisplatin: Gemzar 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on
`Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days.
`
`
`b 21-day schedule — Gemzar plus cisplatin: Gemzar 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on
`Day 1
`every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and I.V. etoposide
`
`
`100 mg/m2 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/m2 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:
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`147
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`149
`150
`151
`152
`153
`154
`155
`156
`157
`158
`159
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`172
`173
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`

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`7
`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.
`
`i)
`
`
`
`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/m2 for 30 minutes. The results from this
`randomized trial are shown in Table 4. 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 3. No confirmed objective tumor
`responses were observed with either treatment.
`
`
`
`Number of patients
` Male
` Female
`Median age
` Range
`Stage IV disease
`Baseline KPSa ≤70
`
`
`Table 4: Gemzar Versus 5-FU in Pancreatic Cancer
`Gemzar
`5-FU
`63
`63
`34
`34
`29
`29
`62 years
`61 years
`37 to 79
`36 to 77
`71.4%
`76.2%
`69.8%
`68.3%
`
`
`
`
`
`
`
`
`
`
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`187
`188
`189
`190
`191
`192
`193
`
`194
`
`

`
`
`
`Clinical benefit response
`
`195
`196
`197
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`
`212
`
`Gemzar
`
`5-FU
`
`0
`
`4
`
`8
`12
`Survival Time (months)
`
`
`16
`
`20
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Fraction Surviving
`
`22.2%
`(Nc=14)
`
`5.7 months
`(N=30) 46%
`(N=14) 24%
`(N=9) 18%
`0.2 to 18.6 months
`4.7 to 6.9 months
`
`2.1 months
`0.1+ to 9.4 months
`1.9 to 3.4 months
`
`4.8%
`(N=3)
`
`4.2 months
`(N=19) 29%
`(N=4) 5%
`(N=2) 2%
`0.4 to 15.1+ months
`3.1 to 5.1 months
`
`0.9 months
`0.1 to 12.0+ months
`0.9 to 1.1 months
`
`8
`
`p=0.004
`
`p=0.0009
`
`
`
`
`
`
`p=0.0013
`
`
`
`
`Survival
` Median
` 6-month probabilityb
` 9-month probabilityb
` 1-year probabilityb
` Range
` 95% C.I. of the median
`Time to Disease Progression
` Median
` Range
` 95% C.I. of the median
`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.
`
`
`

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`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`254
`255
`256
`257
`258
`259
`
`Figure 3: Kaplan-Meier Survival Curve.
`
`
`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/m2. 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/m2 (30-minute infusion) and 150 mg/m2 (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/m2 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
`Breast Cancer — Gemzar in combination with paclitaxel is indicated for the first-line
`treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing
`adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.
`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
`
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`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/m2 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/m2 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/m2 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/m2 basis) and fetotoxicity or embryolethality was observed at
`0.25 mg/kg/day I.V. (about 1/1300 the human dose on a mg/m2 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.
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`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
`Gemzar, 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 — The effectiveness of Gemzar in pediatric patients has not been
`demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory
`leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes
`three times weekly followed by a one week rest period. Gemzar was also evaluated in a Phase 2
`trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous
`leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a
`one week rest period. Toxicities observed included bone marrow suppression, febrile
`neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were
`similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2
`trial.
`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.
`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 5 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/m2. 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 5, regardless of causality.
`Non-laboratory adverse events listed in Table 5 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 6 presents the data from the comparative trial of Gemzar and 5-FU in
`pancreatic cancer for the same adverse events as those in Table 5, regardless of incidence.
`
`
`

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`12
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`
`
`
`Discontinuations
`(%)c
`All
`Patients
`
`
`<1
`<1
`-
`<1
`<1
`
`
`
`
`<1
`
`
`
`
`
`<1
`<1
`<1
`<1
`<1
`0
`0
`<1
`<1
`0
`<1
`<1
`0
`
`Table 5: Selected WHO-Graded Adverse Events in Patients Receiving Single-Agent Gemzar
`WHO Grades (% incidence)
`All Patientsa
`Pancreatic Cancer
`Patientsb
`Grade
`3
`
`
`8
`8
`17
`7
`
`10
`12
`16
`6
`
`<1
`0
`0
`0
`
`10
`6
`2
`<1
`0
`3
`3
`2
`2
`0
`<1
`2
`<1
`
`All
`Grade
`Grade
`All
`Grades
`4
`3
`Grades
`Laboratoryd
`
`
`
`
`
`
`
`
` Hematologic
`73
`1
`7
`68
` Anemia
`64
`<1
`9
`62
` Leukopenia
`61
`6
`19
`63
` Neutropenia
`36
`1
`4
`24
` Thrombocytopenia
`
`
`
`
` Hepatic
`72
`2
`8
`68
` ALT
`78
`2
`6
`67
` AST
`77
`2
`7
`55
` Alkaline Phosphatase
`26
`<1
`2
`13
` Bilirubin
`
`
`
`
` Renal
`32
`0
`<