Question about GEMZAR?
Ask Our Health Experts!

Type your question here

 letters left

GEMZAR Label and GEMZAR General Information

View Reported GEMZAR side effects

gemzar (Gemcitabine hydrochloride)  injection, powder, lyophilized, for solution 
[Eli Lilly and Company]

DESCRIPTION

Gemzar® (gemcitabine HCl) is a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl is 2′-deoxy-2′,2′-difluorocytidine monohydrochloride (ß–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

* Half–life for patients receiving a short infusion (<70 min).
Age	Clearance Men (L/hr/m2)	Clearance Women (L/hr/m2)	Half–Life* 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

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 post–study chemotherapy. Only 13 of 120 patients with documented post–study 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

* 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. † 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.
	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*	94%	95%
Disease Status
Evaluable	7.9%	2.8%
Bidimensionally measurable	91.6%	95.5%
Platinum–free interval†
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%

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

* Log Rank, unadjusted † Treatment adjusted for performance status, tumor area, and platinum–free interval. ‡ Chi Square § Partial response non–measurable disease ¶ Independent reviewers could not evaluate disease demonstrated by sonography or physical exam. # Independently reviewed cohort – Gemzar/Carboplatin N=121, Carboplatin N=101
	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*
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† Hazard Ratio (95%, C.I.)	0.86 (0.67, 1.10)
Investigator Reviewed
Overall Response Rate	47.2%	30.9%	p=0.0016‡
CR	14.6%	6.2%
PR+PRNM§	32.6%	24.7%
Independently Reviewed
Overall Response Rate¶#	46.3%	35.6%	p=0.11‡
CR	9.1%	4.0%
PR+PRNM	37.2%	31.7%

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

* Karnofsky Performance Status. † These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
	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*≥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†			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)

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, multi–center, 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 I.V. 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 monthson 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.

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

N/A Not applicable
* 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. † 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. ‡ Karnofsky Performance Status. § 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.
Trial	28–day Schedule*			21–day Schedule†
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	N/A
Stage IIIB	26%	23%		48%	52%
Stage IV	67%	70%		52%	49%
Baseline KPS‡ 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§	33%	14%	p=0.01§

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 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 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

* Karnofsky Performance Status. † N=number of patients. ‡ 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. § Kaplan-Meier estimates. ¶ No progression at last visit; remains alive.
	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*≤70	69.8%	68.3%
Clinical benefit response	22.2% (N†=14)	4.8% (N=3)	p=0.004‡
Survival			p=0.0009
Median	5.7 months	4.2 months
6–month probability§	(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+¶ 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

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/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

Ovarian Cancer

Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum–based therapy.

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 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. In the randomized clinical trial of Gemzar in combination with carboplatin for recurrent ovarian cancer (see CLINICAL STUDIES), 125 women treated with Gemzar plus carboplatin were <65 years and 50 were ≥65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no substantial differences in toxicity profile of Gemzar plus carboplatin based on age.

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 as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a pre–existing medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.

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

A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non–concurrent use of Gemzar.

Non–concurrent (given >7 days apart)— Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation.

Concurrent (given together or ≤7 days apart)— Pre–clinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non–small cell lung cancer, significant toxicity in the form of severe, and potentially life–threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types.

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 7 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 Gemzar arm and 4.8% for the 5–FU arm.

All WHO–graded laboratory events are listed in Table 7, regardless of causality. Non–laboratory adverse events listed in Table 7 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 8 presents the data from the comparative trial of Gemzar and 5–FU in pancreatic cancer for the same adverse events as those in Table 7, regardless of incidence.

Table 7: Selected WHO–Graded Adverse Events in Patients Receiving Single–Agent Gemzar WHO Grades (% incidence)*

* Grade based on criteria from the World Health Organization (WHO). † N=699–974; all patients with laboratory or non–laboratory data. ‡ N=161–241; all pancreatic cancer patients with laboratory or non–laboratory data. § N=979. ¶ Regardless of causality. # 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.
	All Patients†			Pancreatic Cancer Patients‡			Discontinuations (%)§
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4	All Patients
Laboratory¶
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#
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

Table 8: Selected WHO–Graded Adverse Events From Comparative Trial of Gemzar and 5–FU in Pancreatic Cancer WHO Grades (% incidence)*

* Grade based on criteria from the World Health Organization (WHO). † N=58–63; all Gemzar patients with laboratory or non–laboratory data. ‡ N=61–63; all 5–FU patients with laboratory or non–laboratory data. § Regardless of causality. ¶ Non–laboratory events were graded only if assessed to be possibly drug–related.
	Gemzar†			5–FU‡
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Laboratory