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Gemzar (Gemcitabine Hydrochloride) - Description and Clinical Pharmacology

 
 



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:

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/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

Age

Clearance
Men
(L/hr/m2)

Clearance
Women
(L/hr/m2)

Half–Life 1
Men
(min)

Half–Life
Women
(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

1 Half–life for patients receiving a short infusion (<70 min).

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. 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, 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). Analysis of data from metastatic breast cancer patients shows that, on average, Gemzar 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 Gemzar. Data from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics of Gemzar or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

CLINICAL STUDIES

Ovarian Cancer

Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first–line platinum–based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21–day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single–agent carboplatin AUC 5 administered on Day 1 of each 21–day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).

Patient characteristics are shown in Table 2. The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 3 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms.

Table 2: Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer – Baseline Demographics and Clinical Characteristics

Gemzar/Carboplatin

Carboplatin

 Number of randomized patients

178

178

 Median age, years

59

58

   Range

36 to 78

21 to 81

 Baseline ECOG performance status 0–1 1

94%

95%

 Disease Status

   Evaluable

7.9%

2.8%

   Bidimensionally measurable

91.6%

95.5%

 Platinum–free interval 2

   6–12 months

39.9%

39.9%

   >12 months

59.0%

59.6%

 First–line therapy

   Platinum–taxane combination

70.2%

71.3%

   Platinum–non–taxane combination

28.7%

27.5%

   Platinum monotherapy

1.1%

1.1%

1 Nine patients (5 on the Gemzar plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.
2 Three patients (2 on the Gemzar plus carboplatin arm and 1 on the carboplatin arm) had a platinum–free interval of less than 6 months.

Table 3: Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer – Results of Efficacy Analysis

Gemzar/Carboplatin

(N=178)

Carboplatin

(N=178)

 PFS

   Median (95%, C.I.) months

8.6 (8.0, 9.7)

5.8 (5.2, 7.1)

p=0.0038 1

   Hazard Ratio (95%, C.I.)

0.72 (0.57, 0.90)

 Overall Survival

   Median (95%, C.I.) months

18.0 (16.2, 20.3)

17.3 (15.2, 19.3)

p=0.8977

   Hazard Ratio (95%, C.I.)

0.98 (0.78, 1.24)

   Adjusted 2 Hazard Ratio (95%, C.I.)

0.86 (0.67, 1.10)

 Investigator Reviewed

 Overall Response Rate

47.2%

30.9%

p=0.0016 3

   CR

14.6%

6.2%

   PR+PRNM 4

32.6%

24.7%

 Independently Reviewed

 Overall Response Rate 5 , 6

46.3%

35.6%

p=0.11

   CR

9.1%

4.0%

   PR+PRNM

37.2%

31.7%

1 Log Rank, unadjusted
2 Treatment adjusted for performance status, tumor area, and platinum–free interval.
3 Chi Square
4 Partial response non–measurable disease
5 Independent reviewers could not evaluate disease demonstrated by sonography or physical exam.
6 Independently reviewed cohort – Gemzar/Carboplatin N=121, Carboplatin N=101

Figure 1: Kaplan–Meier Curve of Progression Free Survival in Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)

Figure 1: Kaplan–Meier Curve of Progression Free Survival in Gemzar Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)

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 4 and Figure 2. Further, there was a strong trend toward improved survival for the group given Gemzar based on an interim survival analysis.

Table 4: 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 KPS 1 ≥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   Progression 2

p<0.0001

     Median (95%, C.I.), months

5.2 (4.2, 5.6)

2.9 (2.6, 3.7)

     Hazard Ratio (95%, C.I.)

0.650 (0.524, 0.805)

p<0.0001

  Overall Response Rate

p<0.0001

     (95%, C.I.)

40.8% (34.9, 46.7)

22.1% (17.1, 27.2)

1 Karnofsky Performance Status.
2 These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.

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

Figure 2: 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 prior chemotherapy. Gemzar 1000 mg/m2 was administered on Days 1, 8, and 15 of a 28–day 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 5. 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 3. Median survival time on the Gemzar plus cisplatin arm was 9.0 months compared to 7.6 months on the single–agent cisplatin arm (Log rank 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 (Log rank 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, multicenter, study in Stage IIIB or IV NSCLC randomized 135 patients to Gemzar 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21–day cycle or to etoposide 100 mg/m2 IV on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21–day cycle (Table 5).

There was no significant difference in survival between the two treatment arms (Log rank 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 (Log rank 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.

Figure 3: Kaplan–Meier Survival Curve in Gemzar Plus Cisplatin Versus Cisplatin NSCLC Study (N=522)

Figure 3: Kaplan–Meier Survival Curve in Gemzar Plus Cisplatin Versus Cisplatin NSCLC Study (N=522)

Table 5: Randomized Trials of Combination Therapy With Gemzar Plus Cisplatin in NSCLC

  Trial

28–day Schedule 1

21–day Schedule 2

  Treatment Arm

Gemzar/
Cisplatin

Cisplatin

Gemzar/
Cisplatin

Cisplatin/
Etoposide

  Number of patients

260

262

69

66

     Male

182

186

64

61

     Female

78

76

5

5

  Median age, years

62

63

58

60

     Range

36 to 88

35 to 79

33 to 76

35 to 75

  Stage IIIA

7%

7%

N/A 3

N/A

  Stage IIIB

26%

23%

48%

52%

  Stage IV

67%

70%

52%

49%

  Baseline KPS 4 70 to 80

41%

44%

45%

52%

  Baseline KPS 90 to 100

57%

55%

55%

49%

 

  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 5

33%

14%

p=0.01

1 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.
2 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.
3 N/A Not applicable
4 Karnofsky Performance Status.
5 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 Log rank test for difference in overall time to an event.

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:

  1. 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 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:

  2. 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 multicenter (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 6. 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 4. No confirmed objective tumor responses were observed with either treatment.

Table 6: 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 1 ≤70

69.8%

68.3%

 

  Clinical benefit response

22.2%
(N 2 =14)

4.8%
(N=3)

p=0.004 3

  Survival

p=0.0009

     Median

5.7 months

4.2 months

     6–month probability 4

(N=30) 46%

(N=19) 29%

     9–month probability

(N=14) 24%

(N=4) 5%

     1–year probability

(N=9) 18%

(N=2) 2%

     Range

0.2 to 18.6 months

0.4 to 15.1+ 5 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

1 Karnofsky Performance Status.
2 N=number of patients.
3 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 Log rank test for difference in overall time to an event.
4 Kaplan-Meier estimates.
5 No progression at last visit; remains alive.

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.

Figure 4: Kaplan–Meier Survival Curve

Figure 4: Kaplan–Meier Survival Curve

The second trial was a multicenter (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).

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