Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Gemcitabine
Ovarian Cancer
Gemcitabine 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
Gemcitabine 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
Gemcitabine 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
Gemcitabine 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. Gemcitabine is indicated for patients previously treated with 5-FU.
Gemcitabine Dosage and Administration
Gemcitabine for Injection, USP is for intravenous use only. Gemcitabine for Injection, USP may be administered on an outpatient basis.
Ovarian Cancer
Gemcitabine 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 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 dosage adjustment 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 dosage should be modified according to guidelines in Table 1.
| 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 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 in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemcitabine 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 should be given on Day 1 only at 800 mg/m2.
Breast Cancer
Gemcitabine 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 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 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 dosage should be modified according to the guidelines in Table 2.
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 should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.
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 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. With the 3-week schedule, Gemcitabine 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 on Day 1. See prescribing information for cisplatin administration and hydration guidelines.
Dose Modifications
Dosage adjustments for hematologic toxicity may be required for Gemcitabine and for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemcitabine 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 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 plus cisplatin was 5% versus 2% for cisplatin alone).
Pancreatic Cancer
Gemcitabine 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 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.
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 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 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 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.
Preparation and Administration Precautions
Caution should be exercised in handling and preparing Gemcitabine solutions. The use of gloves is recommended. If Gemcitabine 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)].
Preparation for Intravenous Infusion Administration
The recommended diluent for reconstitution of Gemcitabine for Injection, USP is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for Gemcitabine 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 contents will provide 200 mg or 1 g of Gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.
Reconstituted Gemcitabine for Injection, USP 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, 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. Solutions of reconstituted Gemcitabine should not be refrigerated, as crystallization may occur.
The compatibility of Gemcitabine with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Dosage Forms and Strengths
Gemcitabine for Injection, USP is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g Gemcitabine.
Contraindications
Gemcitabine is contraindicated in those patients with a known hypersensitivity to the drug.
Warnings and Precautions
Patients receiving therapy with Gemcitabine should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.
Infusion Time
Caution - Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)].
Hematology
Gemcitabine can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].
Pulmonary
Pulmonary toxicity has been reported with the use of Gemcitabine. In cases of severe lung toxicity, Gemcitabine therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)].
Renal
Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemcitabine. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)].
Gemcitabine should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use in Specific Populations (8.6)].
Hepatic
Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)].
Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)].
Pregnancy
Gemcitabine can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, Gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of Gemcitabine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Laboratory Tests
Patients receiving Gemcitabine 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 (2.1, 2.2, 2.3, and 2.4)].
Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage and Administration (2.4)].
Radiation Therapy
A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemcitabine.
Non-concurrent (given >7 days apart) - Analysis of the data does not indicate enhanced toxicity when Gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemcitabine 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) - Preclinical and clinical studies have shown that Gemcitabine has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemcitabine, frequency of Gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemcitabine 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 Gemcitabine administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemcitabine with therapeutic doses of radiation has not yet been determined in all tumor types.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.
Gemcitabine 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 Gemcitabine therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].
The data in Table 4 are based on 979 patients receiving Gemcitabine as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemcitabine 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 reactions 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 Gemcitabine therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the Gemcitabine arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 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 adverse reactions under the Renal, Pulmonary, and Infection categories.
| All Patientsb | Pancreatic Cancer Patientsc | Discontinuations (%)d | ||||
All Grades | Grade 3 | Grade 4 | All Grades | Grade 3 | Grade 4 | All Patients | |
| Laboratorye Hematologic Anemia Leukopenia Neutropenia Thrombocytopenia |
68 62 63 24 |
7 9 19 4 |
1 <1 6 1 |
73 64 61 36 |
8 8 17 7 |
2 1 7 <1 |
<1 <1 - <1 |
| Hepatic ALT AST Alkaline Phosphatase Bilirubin |
68 67
55 13 |
8 6
7 2 |
2 2
2 <1 |
72 78
77 26 |
10 12
16 6 |
1 5
4 2 | <1
|
Renal Proteinuria Hematuria BUN Creatinine |
45 35 16 8 |
<1 <1 0 <1 |
0 0 0 0 |
32 23 15 6 |
<1 0 0 0 |
0 0 0 0 | <1
|
| Non-laboratoryf Nausea and Vomiting Fever Rash Dyspnea Diarrhea Hemorrhage Infection Alopecia Stomatitis Somnolence Paresthesias |
69 41 30 23 19 17 16 15 11 11 10 |
13 2 <1 3 1 <1 1 <1 <1 <1 <1 |
1 0 0 <1 0 <1 <1 0 0 <1 0 |
71 38 28 10 30 4 10 16 10 11 10 |
10 2 <1 0 3 2 2 0 <1 2 <1 |
2 0 0 <1 0 <1 <1 0 0 <1 0 |
<1 <1 <1 <1 0 <1 <1 0 <1 <1 0 |
a Grade based on criteria from the World Health Organization (WHO). b N=699-974; all patients with laboratory or non-laboratory data. c N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data. d N=979. e Regardless of causality. f Table includes non-laboratory data with incidence for all patients ≥10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related. | |||||||
Hematologic - In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with Gemcitabine, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during Gemcitabine therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].
Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.
Hepatic - In clinical trials, Gemcitabine was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to Gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemcitabine alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)].
Renal - In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemcitabine in clinical trials. Four patients developed HUS on Gemcitabine therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemcitabine therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)].
Fever - The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that Gemcitabine may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable.
Rash - Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients.
Pulmonary - In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with Gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of Gemcitabine [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, Gemcitabine should be discontinued. Early use of supportive care measures may help ameliorate these conditions.
Edema - Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema.
Flu-like Symptoms - "Flu syndrome" was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.
Infection - Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).
Alopecia - Hair loss, usually minimal, was reported by 15% of patients.
Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.
Extravasation - Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemcitabine is not a vesicant.
Allergic - Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)].
Cardiovascular - During clinical trials, 2% of patients discontinued therapy with Gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)].
Combination Use in Non-Small Cell Lung Cancer:
In the Gemcitabine plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of Gemcitabine injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of Gemcitabine plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions.
In the Gemcitabine plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of Gemcitabine injections and 16% of cisplatin injections in the Gemcitabine plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of Gemcitabine plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the Gemcitabine plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the Gemcitabine plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with Gemcitabine plus cisplatin treatment (~90%) compared to that with the Gemcitabine monotherapy (~60%). With combination therapy Gemcitabine dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.
Table 5 presents the safety data from the Gemcitabine plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the Gemcitabine plus cisplatin arm.
Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the Gemcitabine plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the Gemcitabine plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued Gemcitabine plus cisplatin use.
Nausea and vomiting despite the use of antiemetics occurred more often with Gemcitabine plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent Gemcitabine, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with Gemcitabine plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms.
Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with Gemcitabine plus cisplatin compared to one (<1%) Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the Gemcitabine plus cisplatin combination arm.
Table 6 presents data from the randomized study of Gemcitabine plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the Gemcitabine plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the Gemcitabine plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the Gemcitabine plus cisplatin arm. RBC transfusions were given to 29% of the patients who received Gemcitabine plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received Gemcitabine plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemcitabine plus cisplatin arm. On the Gemcitabine plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of Gemcitabine as compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the Gemcitabine plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the Gemcitabine plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm.
| Gemcitabine plus Cisplatinb | Cisplatinc | ||||
All Grades | Grade 3 | Grade 4 | All Grades | Grade 3 | Grade 4 | |
| Laboratoryd Hematologic Anemia RBC Transfusione Leukopenia Neutropenia Thrombocytopenia Platelet Transfusionse Lymphocytes | 89 39 82 79 85
21 75 | 22
35 22 25
25 | 3
11 35 25
18 | 67 13 25 20 13
<1 51 | 6
2 3 3
12 | 1
1 1 1
5 |
Hepatic Transaminase Alkaline Phosphatase | 22 19 | 2 1 | 1 0 | 10 13 | 1 0 | 0 0 |
Renal Proteinuria Hematuria Creatinine |
23 15 38 |
0 0 4 |
0 0 <1 |
18 13 31 |
0 0 2 |
0 0 <1 |
Other Laboratory Hyperglycemia Hypomagnesemia Hypocalcemia |
30 30 18 |
4 4 2 |
0 3 0 |
23 17 7 |
3 2 0 |
0 0 <1 |
| Non-laboratoryf Nausea Vomiting Alopecia Neuro Motor Neuro Hearing Diarrhea Neuro Sensory Infection Fever Neuro Cortical Neuro Mood Local Neuro Headache Stomatitis Hemorrhage Dyspnea Hypotension Rash |
93 78 53 35 25 24 23 18 16 16 16 15 14 14 14 12 12 11 |
25 11 1 12 6 2 1 3 0 3 1 0 0 1 1 4 1 0 |
2 12 0 0 0 2 0 2 0 1 0 0 0 0 0 3 0 0 |
87 71 33 15 21 13 18 12 5 9 10 6 7 5 4 11 7 3 |
20 10 0 3 6 0 1 1 0 1 1 0 0 0 0 3 1 0 |
<1 9 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 |
a Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse reactions with incidence ≥10% in either arm. b N=217-253; all Gemcitabine plus cisplatin patients with laboratory or non-laboratory data. Gemcitabine at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days. c N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days. d Regardless of causality. e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events. f Non-laboratory events were graded only if assessed to be possibly drug-related. | ||||||
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