Sunday, June 12, 2011

GEMZAR(GEMCITABINE HCl)FORINJECTION

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

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
AgeClearance
Men
(L/hr/m2)
Clearance
Women
(L/hr/m2)
Half–LifeHalf–life for patients receiving a short infusion (<70 min).
Men
(min)
Half–Life
Women
(min)
2992.269.44249
4575.757.04857
6555.141.56173
7940.730.77994
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

Gemzar/CarboplatinCarboplatin
 Number of randomized patients178178
 Median age, years5958
   Range36 to 7821 to 81
 Baseline ECOG performance status 0–1Nine 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.94%95%
 Disease Status

   Evaluable7.9%2.8%
   Bidimensionally measurable91.6%95.5%
 Platinum–free intervalThree patients (2 on the Gemzar plus carboplatin arm and 1 on the carboplatin arm) had a platinum–free interval of less than 6 months.

   6–12 months39.9%39.9%
   >12 months59.0%59.6%
 First–line therapy

   Platinum–taxane combination70.2%71.3%
   Platinum–non–taxane combination28.7%27.5%
   Platinum monotherapy1.1%1.1%
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.) months8.6 (8.0, 9.7)5.8 (5.2, 7.1)p=0.0038Log Rank, unadjusted
   Hazard Ratio (95%, C.I.)0.72 (0.57, 0.90)
 Overall Survival


   Median (95%, C.I.) months18.0 (16.2, 20.3)17.3 (15.2, 19.3)p=0.8977
   Hazard Ratio (95%, C.I.)0.98 (0.78, 1.24)
   AdjustedTreatment adjusted for performance status, tumor area, and platinum–free interval. Hazard Ratio (95%, C.I.)0.86 (0.67, 1.10)
 Investigator Reviewed


 Overall Response Rate47.2%30.9%p=0.0016Chi Square
   CR14.6%6.2%
   PR+PRNMPartial response non–measurable disease 32.6%24.7%
 Independently Reviewed


 Overall Response RateIndependent reviewers could not evaluate disease demonstrated by sonography or physical exam.Independently reviewed cohort – Gemzar/Carboplatin N=121, Carboplatin N=10146.3%35.6%p=0.11
   CR9.1%4.0%
   PR+PRNM37.2%31.7%
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/PaclitaxelPaclitaxel
  Number of patients267262
  Median age, years5352
     Range26 to 8326 to 75
  Metastatic disease97.0%96.9%
  Baseline KPSKarnofsky Performance Status. ≥9070.4%74.4%
  Number of tumor sites


     1–256.6%58.8%
     ≥343.4%41.2%
  Visceral disease73.4%72.9%
  Prior anthracycline96.6%95.8%



  Time to Documented Disease   ProgressionThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.

p<0.0001
     Median (95%, C.I.), months5.2 (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)
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, 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.
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
N/A Not applicable
  Trial28–day Schedule28–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 Schedule21–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.
  Treatment ArmGemzar/
Cisplatin
Cisplatin
Gemzar/
Cisplatin
Cisplatin/
Etoposide

  Number of patients260262
6966
     Male182186
6461
     Female7876
55
  Median age, years6263
5860
     Range36 to 8835 to 79
33 to 7635 to 75
  Stage IIIA7%7%
N/AN/A
  Stage IIIB26%23%
48%52%
  Stage IV67%70%
52%49%
  Baseline KPSKarnofsky Performance Status. 70 to 8041%44%
45%52%
  Baseline KPS 90 to 10057%55%
55%49%






  Survival

p=0.008

p=0.18
     Median, months9.07.6
8.77.0
     (95%, C.I.) months8.2, 11.06.6, 8.8
7.8, 10.16.0, 9.7
  Time to Disease Progression

p=0.009

p=0.015
     Median, months5.23.7
5.04.1
     (95%, C.I.) months4.2, 5.73.0, 4.3
4.2, 6.42.4, 4.5
  Tumor Response26%10% p<0.0001p–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. 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:
  • 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:
  • 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

Gemzar5–FU
  Number of patients6363
     Male3434
     Female2929
  Median age62 years61 years
     Range37 to 7936 to 77
  Stage IV disease71.4%76.2%
  Baseline KPSKarnofsky Performance Status.≤7069.8%68.3%



  Clinical benefit response22.2%
(NN=number of patients.=14)
4.8%
(N=3)
p=0.004The 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.
  Survival

p=0.0009
     Median5.7 months4.2 months
     6–month probabilityKaplan-Meier estimates.(N=30) 46%(N=19) 29%
     9–month probability(N=14) 24%(N=4) 5%
     1–year probability(N=9) 18%(N=2) 2%
     Range0.2 to 18.6 months0.4 to 15.1+No progression at last visit; remains alive. months
     95% C.I. of the median4.7 to 6.9 months3.1 to 5.1 months
  Time to Disease Progression

p=0.0013
     Median2.1 months0.9 months
     Range0.1+ to 9.4 months0.1 to 12.0+ months
     95% C.I. of the median1.9 to 3.4 months0.9 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.
Figure 4: 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

CONTRAINDICATION

WARNINGS

PRECAUTIONS

General

Laboratory Tests

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

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

Radiation Therapy

ADVERSE REACTIONS

OVERDOSAGE

There is no known antidote for overdoses of Gemzar. Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by I.V. infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

DOSAGE AND ADMINISTRATION

Adults

Instructions for Use/Handling

The recommended diluent for reconstitution of Gemzar is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for Gemzar upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.
To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200–mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1–g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200–mg vial or 1.3 mL for the 1–g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial spans will provide 200 mg or 1 g of gemcitabine, respectively. The appropriate amount of drug may be administered as prepared or further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL.
Reconstituted Gemzar is a clear, colorless to light straw–colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer.
When prepared as directed, Gemzar solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [See USP]. Discard unused portion. Solutions of reconstituted Gemzar should not be refrigerated, as crystallization may occur.
The compatibility of Gemzar with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Unopened vials of Gemzar are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) [See USP].
Caution should be exercised in handling and preparing Gemzar solutions. The use of gloves is recommended. If Gemzar solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug–related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.
Procedures for proper handling and disposal of anti–cancer drugs should be considered. Several guidelines on this subject have been published.1–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

REFERENCES

  • Recommendations for the safe handling of parenteral antineoplastic drugs. NIH publication No. 83–2621. US Government Printing Office, Washington, DC 20402.
  • Council on Scientific Affairs: Guidelines for handling parenteral antineoplastics. JAMA 1985;253:1590.
  • National Study Commission on Cytotoxic Exposure — Recommendations for handling cytotoxic agents, 1987. Available from Louis P Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902.
  • Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust 1983;1:426.
  • Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. CA 1983;33(Sept/Oct):258.
  • American Society of Hospital Pharmacists: Technical assistance bulletin on handling cytotoxic drugs in hospitals. Am J Hosp Pharm 1990;47:1033.
  • Controlling Occupational Exposure to Hazardous Drugs, OSHA Work Practice Guidelines. Am J Health–Sys Pharm 1996;53:1669–1685.
  • ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32–41.
Literature revised July 14, 2006
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