Gemcitabine for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Gemcitabine for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Breast Cancer, Breast Cancer, Metastatic, Non-Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer
Class: Antimetabolites
Form: Liquid solution, Intravenous (IV)
Ingredients: Gemcitabine Hydrochloride, Mannitol, Sodium Acetate, Sodium Hydroxide, Hydrochloric Acid

Description

Gemcitabine for Injection, USP is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-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.

Gemcitabine for injection is supplied in a sterile form for intravenous use only. Vials of gemcitabine contain either 200 mg, 1 g or 2 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg, 1 g or 2 g, respectively) and sodium acetate (12.5 mg, 62.5 mg, or 125 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

Clinical Pharmacology

Mechanism of Action

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. 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, which eventually results in the initiation of apoptotic cell death.

Pharmacokinetics

Absorption and Distribution

The pharmacokinetics of gemcitabine were examined in 353 patients, 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 gemcitabine for injection dose varied from 500 to 3,600 mg/m2.

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/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. Gemcitabine plasma protein binding is negligible.

Metabolism

Gemcitabine disposition was studied in 5 patients who received a single 1,000 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.

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.

Elimination

Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of gemcitabine for any given dose. 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 Men (L/hr/m2) Clearance Women (L/hr/m2) Half-Lifea Men (min) Half-Lifea Women (min)
29 92.2 69.4 42 49
45 75.7 57 48 57
65 55.1 41.5 61 73
79 40.7 30.7 79 94

a Half-life for patients receiving <70 minute infusion.

Gemcitabine half-life for short infusions ranged from 42 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.

Drug Interactions

When gemcitabine (1,250 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. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine for injection has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine for injection have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine IP 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 administered intravenously (about 1/200 the human dose on a mg/m2 basis)and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1,300 the human dose on a mg/m2 basis).

Clinical Studies

Ovarian Cancer

The safety and efficacy of gemcitabine for injection was studied in a randomized trial of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1,000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine for injection infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS).

Patient characteristics are shown in Table 2. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 2 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Table 2: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer-Baseline Demographics and Clinical Characteristics
  Gemcitabine/Carboplatin Carboplatin
Number of randomized patients 178 178
Median age, years
Range
59
36 to 78
58
21 to 81
Baseline ECOG performance status 0-1a 94% 95%
Disease Status
Evaluable
Bidimensionally measurable

8%
92%

3%
96%
Platinum-free intervalb
6 to 12 months
>12 months

40%
59%

40%
60%
First-line therapy
Platinum-taxane combination
Platinum-non-taxane combination
Platinum monotherapy

70%
29%
1%

71%
28%
1%

a 5 patients on Gemcitabine plus carboplatin arm and 4 patients on carboplatin arm with no baseline Eastern Cooperative Oncology Group (ECOG) performance status.

b 2 on Gemcitabine plus carboplatin arm and 1 on carboplatin arm had platinum-free interval <6 months. Table 3: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer — Efficacy Outcomes

Table 3: Randomized Trial of Gemcitabine plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy Outcomes
Gemcitabine/Carboplatin(N=178) Carboplatin(N=178)
Progression-free Survival Median (95% CIa) monthsHazard Ratio (95% CI) 8.6 (8, 9.7) 5.8 (5.2, 7.1)
0.72 (0.57, 0.90)
p-valueb p=0.0038
Overall SurvivalMedian (95% CI) monthsHazard Ratio (95% CI) 18 (16.2, 20.3) 17.3 (15.2, 19.3)
0.98 (0.78, 1.24)
p-valueb p=0.8977
Investigator ReviewedOverall Response Rate 47.2% 30.9%
p-valuec p=0.0016
CRd PR plus PRNMe 14.6%
32.6%
6.2%
24.7%
Independently Reviewed Overall Response Ratef    
p-valuec p=0.11
CRd PR plus PRNMe 9.1%
37.2%
4.0%
31.7%

a CI=confidence interval.

b Log rank, unadjusted.

c Chi square.

d CR=Complete response.

e PR plus PRNM=Partial response plus partial response, non-measurable disease.

fIndependently reviewed cohort — gemcitabine/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to measure disease detected by sonography or physical exam.


Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabine plus Carboplatin versus Carboplatin

Breast Cancer

The safety and efficacy of gemcitabine were evaluated in a multi-national, randomized, open-label trial conducted in women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive gemcitabine for injection 1,250 mg/m2 on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to gemcitabine for injection on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262).The primary efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled; 267 were randomized to gemcitabine and paclitaxel and 262 to paclitaxel alone. Demographic and baseline characteristics were similar between treatment arms (see Table 4). Efficacy results are presented in Table 13 and Figure 2. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.

Table 4: Randomized Trial of Gemcitabine plus Paclitaxel versus Paclitaxel in Breast Cancer
Gemcitabine/Paclitaxel Paclitaxel
Number of patients 267 262
Demographic/Entry Characteristics
Median age (years)
Range

53
26 to 83

52
26 to 75
Metastatic disease 97% 97%
Baseline KPSa ≥90 70% 74%
Number of tumor sites
1 to 2
≥3

57%
43%

59%
41%
Visceral disease 73% 73%
Prior anthracycline 97% 96%
Efficacy Outcomes    
Time to Documented Disease Progressionb    
Median in months
(95% CI)
5.2
(4.2, 5.6)
2.9
(2.6, 3.7)
Hazard Ratio (95% CI) 0.650 (0.524, 0.805)
p-value p<0.0001
Overall Survivalc    
Median Survival in months
(95% CI)
18.6
(16.5, 20.7)
15.8
(14.1, 17.3)
Hazard Ratio (95% CI) 0.86 (0.71, 1.04)
p-value Not Significant
Overall Response Rate(95% CI)


p-value
40.8%
(34.9, 46.7)
22.1%
(17.1, 27.2)
p<0.0001

a Karnofsky Performance Status.

b These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.

c Based on the ITT population.


Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabine Plus Paclitaxel Versus Paclitaxel Breast Cancer Study (N=529)

Non-Small Cell Lung Cancer (NSCLC)

The safety and efficacy of gemcitabine was evaluated in two randomized, multicenter trials.

28-Day Schedule

A multinational, randomized trial compared gemcitabine plus cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive gemcitabine for injection 1,000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine plus cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.

21-Day Schedule

A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine for injection 1,250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m2intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle.

There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two sided, see Table 5). The median survival was 8.7 months for the gemcitabine plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the gemcitabine plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided).


Figure 3: Kaplan-Meier Survival Curve in Gemcitabine plus Cisplatin versus Cisplatin in Patients with NSCLC Study (N=522).

Table 5: Randomized Trials of Gemcitabine plus Cisplatin in Patients with NSCLC
Trial 28-day Schedulea 21-day Scheduleb
Treatment Arm Gemcitabine plusCisplatin Cisplatin Gemcitabine plus Cisplatin Etoposide plusCisplatin
Number of patients
Demographic/EntryCharacteristics
Male
Median age, years
Range

260
70%
62
36 to 88

262
71%
63
35 to 79

69
93%
58
33 to 76

66
92%
60
35 to 75
Stage IIIA
Stage IIIB
Stage IV
7%
26%
67%
7%
23%
70%
N/Ac
48%
52%
N/Ac
52%
49%
Baseline KPSd 70 to 80 41% 44% 45% 52%
Baseline KPSd 90 to100 57% 55% 55% 49%
Efficacy Outcomes        
Survival
Median in months (95% CIe) months

p-valuef
9
8.2, 11
7.6
6.6, 8.8
8.7
7.8, 10.1
7
6.0, 9.7
p=0.008 p=0.18
Time to Disease Progression
Median in months (95% CIe ) months

p-valuef
5.2
4.2, 5.7
3.7
3, 4.3
5
4.2, 6.4
4.1
2.4, 4.5
p=0.009 p=0.015
Tumor Responsep-valuef 26% 10% 33% 14%
p<0.0001 p=0.01

a 28-day schedule — Gemcitabine plus cisplatin: Gemcitabine 1,000 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 — Gemcitabine plus cisplatin: Gemcitabine 1,250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2on Days 1, 2, and 3 every 21 days.

c N/A Not applicable.

d Karnofsky Performance Status.

e CI=confidence intervals.

f p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses.

Pancreatic Cancer

The safety and efficacy of gemcitabine for injection was evaluated in two trials, a randomized, single-blind, two-arm, active-controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive gemcitabine for injection 1,000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received gemcitabine for injection 1,000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles.

The primary efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to have had a clinical benefit response if either of the following occurred:

  • The patient achieved 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 Status) 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

  • 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 randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry characteristics were similar between the arms (Table 6). The efficacy outcome results are shown in Table 6 and for overall survival in Figure 4. Patients treated with gemcitabine for injection had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor responses were observed in either treatment arm.

Table 6: Randomized Trial of Gemcitabine versus 5-Fluorouracil in Pancreatic Cancer
Gemcitabine 5-FU
Number of patients 63 63
Demographic/Entry Characteristics Male 54% 54%
Median age 62 years 61 years
Range 37 to 79 36 to 77
Stage IV disease 71% 76%
Baseline KPSa ≤70 70% 68%
Efficacy Outcomes
Clinical benefit response 22.2% 4.8%
p-valueb p=0.004
Survival    
Median 5.7 months 4.2 months
(95% CI) (4.7, 6.9) (3.1, 5.1)
p-valueb p=0.0009
Time to Disease Progression    
Median 2.1 months 0.9 months
(95% CI) (1.9, 3.4) (0.9, 1.1)
p-valueb p=0.0013

a Karnofsky Performance Status.

b p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.


Figure 4: Kaplan-Meier Survival Curve