Gemcitabine Injection is for intravenous use only. Gemcitabine Injection may be administered on an outpatient basis.
2.1 Ovarian Cancer
Gemcitabine Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after Gemcitabine Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.
Dose Modifications
Gemcitabine Injection dosage adjustments for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabine Injection dosage should be modified according to guidelines in Table 1.
Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine Injection in Combination with Carboplatin
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1500
And
≥100,000
100
1000-1499
And/or
75,000-99,999
50
<1000
And/or
<75,000
Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with Gemcitabine Injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer’s prescribing information.
Dose adjustment for Gemcitabine Injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemcitabine Injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:
Absolute granulocyte count <500 x 106/L for more than 5 days
Absolute granulocyte count <100 x 106/L for more than 3 days
Febrile neutropenia
Platelets <25,000 x 106/L
Cycle delay of more than one week due to toxicity
If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, Gemcitabine Injection should be given on Day 1 only at 800 mg/m2.
2.2 Breast Cancer
Gemcitabine Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before Gemcitabine Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.
Dose Modifications
Gemcitabine Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabine Injection dosage should be modified according to the guidelines in Table 2.
Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine Injection in Combination with Paclitaxel
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1200
And
>75,000
100
1000-1199
Or
50,000-75,000
75
700-999
And
≥50,000
50
<700
Or
<50,000
Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemcitabine Injection should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.
2.3 Non-Small Cell Lung Cancer
Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, Gemcitabine Injection should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine Injection. With the 3-week schedule, Gemcitabine Injection should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of Gemcitabine Injection on Day 1. See prescribing information for cisplatin administration and hydration guidelines.
Dose Modifications
Dosage adjustments for hematologic toxicity may be required for Gemcitabine Injection and for cisplatin. Gemcitabine Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemcitabine Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemcitabine Injection plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for Gemcitabine Injection plus cisplatin was 5% versus 2% for cisplatin alone).
2.4 Pancreatic Cancer
Gemcitabine Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.
Dose Modifications
Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Patients receiving Gemcitabine Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.
Table 3: Dosage Reduction Guidelines
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1000
And
≥100,000
100
500-999
Or
50,000-99,999
75
<500
Or
<50,000
Hold
Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.
Patients treated with Gemcitabine Injection who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemcitabine Injection at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.
2.5 Dose Modifications for Non-Hematologic Adverse Reactions
Permanently discontinue Gemcitabine for any of the following
Unexplained dyspnea or other evidence of severe pulmonary toxicity
Severe hepatic toxicity
Hemolytic-Uremic Syndrome
Capillary Leak Syndrome
Posterior reversible encephalopathy syndrome
Withhold Gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.
2.6 Preparation and Administration Precautions
Caution should be exercised in handling and preparing Gemcitabine Injection and diluted solution. The use of gloves is recommended. If Gemcitabine Injection and diluted 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 [see References (15)].
2.7 Preparation for Intravenous Infusion Administration
Each vial contains a gemcitabine concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of gemcitabine, respectively. The appropriate amount of drug should be further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL.
After dilution with 0.9% Sodium Chloride Injection the solution should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution or container permits. If particulate matter or discoloration is found, do not administer.
When prepared as directed, diluted gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion.
The compatibility of Gemcitabine Injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
2.1 Ovarian Cancer
Gemcitabine Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after Gemcitabine Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.
Dose Modifications
Gemcitabine Injection dosage adjustments for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabine Injection dosage should be modified according to guidelines in Table 1.
Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine Injection in Combination with Carboplatin
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1500
And
≥100,000
100
1000-1499
And/or
75,000-99,999
50
<1000
And/or
<75,000
Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with Gemcitabine Injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer’s prescribing information.
Dose adjustment for Gemcitabine Injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemcitabine Injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:
Absolute granulocyte count <500 x 106/L for more than 5 days
Absolute granulocyte count <100 x 106/L for more than 3 days
Febrile neutropenia
Platelets <25,000 x 106/L
Cycle delay of more than one week due to toxicity
If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, Gemcitabine Injection should be given on Day 1 only at 800 mg/m2.
2.2 Breast Cancer
Gemcitabine Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before Gemcitabine Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.
Dose Modifications
Gemcitabine Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabine Injection dosage should be modified according to the guidelines in Table 2.
Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine Injection in Combination with Paclitaxel
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1200
And
>75,000
100
1000-1199
Or
50,000-75,000
75
700-999
And
≥50,000
50
<700
Or
<50,000
Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemcitabine Injection should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.
2.3 Non-Small Cell Lung Cancer
Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, Gemcitabine Injection should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine Injection. With the 3-week schedule, Gemcitabine Injection should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of Gemcitabine Injection on Day 1. See prescribing information for cisplatin administration and hydration guidelines.
Dose Modifications
Dosage adjustments for hematologic toxicity may be required for Gemcitabine Injection and for cisplatin. Gemcitabine Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemcitabine Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemcitabine Injection plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for Gemcitabine Injection plus cisplatin was 5% versus 2% for cisplatin alone).
2.4 Pancreatic Cancer
Gemcitabine Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.
Dose Modifications
Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Patients receiving Gemcitabine Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.
Table 3: Dosage Reduction Guidelines
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1000
And
≥100,000
100
500-999
Or
50,000-99,999
75
<500
Or
<50,000
Hold
Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.
Patients treated with Gemcitabine Injection who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemcitabine Injection at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.
2.6 Preparation and Administration Precautions
Caution should be exercised in handling and preparing Gemcitabine Injection and diluted solution. The use of gloves is recommended. If Gemcitabine Injection and diluted 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 [see References (15)].
2.7 Preparation for Intravenous Infusion Administration
Each vial contains a gemcitabine concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of gemcitabine, respectively. The appropriate amount of drug should be further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL.
After dilution with 0.9% Sodium Chloride Injection the solution should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution or container permits. If particulate matter or discoloration is found, do not administer.
When prepared as directed, diluted gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion.
The compatibility of Gemcitabine Injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
