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These highlights do not include all the information needed to use INFUGEM safely and effectively. See full prescribing information for INFUGEM.   INFUGEM (gemcitabine in sodium chloride injection), for intravenous use Initial U.S. Approval: 1996   | INFUGEM [Sun Pharmaceutical Industries, Inc.] | BioPortfolio

13:06 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

INFUGEM 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.

INFUGEM 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.

INFUGEM 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.

INFUGEM 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. INFUGEM is indicated for patients previously treated with fluorouracil.

Recommended Dose and Schedule

The recommended dose of INFUGEM is 1000 mg/m as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after INFUGEM administration on Day 1 of each 21-day cycle. Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 5 [see Dosage and Administration (2.6)].

Refer to the carboplatin prescribing information for additional information.

Dosage Modifications

Recommended INFUGEM dosage modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to the dosage modifications recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

Table 1: Recommended Dosage Modifications for INFUGEM for Myelosuppression on Day of Treatment in Ovarian Cancer

Table 2: Recommended Dosage Modification for INFUGEM for Myelosuppression in Previous Cycle in Ovarian Cancer

Treatment Day
Absolute Neutrophil Count
(x 106/L)
 
Platelet Count
(x 106/L)
Dosage Modification
 
Day 1
Greater than or equal to 1500
and
 Greater than or equal to 100,000
None
Less than 1500
or
Less than 100,000
Delay treatment cycle
 
 
Day 8
 
 Greater than or equal to 1500
and
 Greater than or equal to 100,000
None
1000 to 1499
or
75,000 to 99,999
50% of full dose
Less than 1000
or
Less than 75,000
Hold
Occurrence
Myelosuppression During Treatment Cycle
Dosage Modification
Initial Occurrence
Absolute neutrophil count less than 500 x 106/L for more than 5 days or
Absolute neutrophil count less than 100 x 106/L for more than 3 days or
Febrile neutropenia or
Platelets less than 25,000x106/L or
Cycle delay of more than one week due to toxicity
Permanently reduce INFUGEM to 800 mg/m2 on Days 1 and 8
Subsequent Occurrence
If any of the above toxicities occur after the initial dose reduction
Permanently reduce INFUGEM dose to 800 mg/m2 on Day 1 only

Recommended Dose and Schedule

The recommended dose of INFUGEM is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m on Day 1 as a 3-hour intravenous infusion before INFUGEM administration. Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 6 [see Dosage and Administration (2.6)].

Refer to the paclitaxel prescribing information for additional information.

Dosage Modifications

Recommended INFUGEM dosage modifications for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to the dosage modification recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

Table 3: Recommended Dosage Modifications for INFUGEM for Myelosuppression on Day of Treatment in Breast Cancer

Treatment Day
Absolute Neutrophil Count
(x 106/L)
Platelet Count
(x 106/L)
Dosage Modification
 
Day 1
 Greater than or equal to 1500
and
 Greater than or equal to 100,000
 
None
Less than 1500
or
Less than 100,000
Hold
 
 
 
Day 8
 
 
 Greater than or equal to 1200
and
Greater than 75,000
None
1000 to 1199
or
50,000 to 75,000
75% of full dose
700 to 999
and
Greater than or equal to 50,000
50% of full dose
 
Less than 700
or
Less than 50,000
Hold

Recommended Dose and Schedule

Every 4-week schedule

The recommended dose of INFUGEM is 1000 mg/m intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m on Day 1 after the infusion of INFUGEM. Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 5 [see Dosage and Administration (2.6)].

Every 3-week schedule

The recommended dose of INFUGEM is 1250 mg/m intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m on Day 1 after the infusion of INFUGEM. Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 6 [see Dosage and Administration (2.6)].

Refer to the cisplatin prescribing information for additional information.

Dosage Modifications

Recommended INFUGEM dosage modifications for myelosuppression are described in Table 4 [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]. Refer to the dosage modifications recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

Recommended Dose and Schedule

The recommended dose of INFUGEM is 1000 mg/m over 30 minutes intravenously. The recommended treatment schedule is as follows:

Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 5 [see Dosage and Administration (2.6)].

Dosage Modifications

Recommended dosage modifications for INFUGEM for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to the dosage modifications recommendations for non-hematologic adverse reactions [see Dosage and Administration (2.5)].

Table 4: Recommended INFUGEM Dosage Modifications for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer

Absolute Neutrophil Count
(x 106/L)
Platelet Count
(x 106/L)
Dosage Modification
 Greater than or equal to 1000
 
and
 
 Greater than or equal to 100,000
None
 
500 to 999
or
50,000 to 99,999
75% of full dose
Less than 500
or
Less than 50,000
Hold

Permanently discontinue INFUGEM for any of the following:

Withhold INFUGEM or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved.

See the INFUGEM Instructions for Use for additional information concerning premixed infusion bag(s) selection and spiking the infusion bag instructions.

Infusion Bag Selection

INFUGEM is provided in premixed bags that are ready for infusion and do not require any further preparation prior to use. Do not dilute prior to use. Do not remove or add medication.

Select the INFUGEM premixed bag(s) for infusion based on the patient’s BSA range as outlined below in Table 5 for 1000 mg/m (ovarian cancer, non-small cell lung cancer, and pancreatic cancer) and Table 6 for 1250 mg/m (breast cancer, non-small cell lung cancer). The INFUGEM administered dose may vary from the BSA-calculated dose by no more than 5%.

Use another formulation of gemcitabine for patients who require a dose that is less than those listed in the Table 5 or Table 6 below (i.e., <1150 mg).

Table 5: INFUGEM Infusion Bag(s) Selection for Gemcitabine Doses of 1000 mg/m (Non-Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer)

Suggested combination. Other possible combinations can be used to reach the appropriate dose.

Table 6:  INFUGEM Infusion Bag(s) Selection for Gemcitabine Doses of 1250 mg/m (Breast Cancer Non-Small Cell Lung Cancer)

Combinations represented above are suggested combinations. Other possible combinations of bags can be used to reach the appropriate dose.

Administration

Infuse all doses of INFUGEM over 30 minutes.  If two premixed infusion bags are required to achieve the prescribed dose, infuse the total volume of both bags over 30 minutes. 

After removing the overwrap check for leaks by squeezing the inner bag firmly. If leaks are found, discard the bag.

INFUGEM injection is a clear, colorless solution. Visually inspect for any particulate matter or discoloration prior to use. Discard if particulate matter or discoloration is found.

INFUGEM is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Exercise caution and wear gloves when handling INFUGEM. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if INFUGEM contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.

BSA Range (m2)
 INFUGEM Infusion Bag(s)
1.16 to 1.25
1200 mg
1.26 to 1.35
1300 mg
1.36 to 1.45
1400 mg
1.46 to 1.55
1500 mg
1.56 to 1.65
1600 mg
1.66 to 1.75
1700 mg
1.76 to 1.85
1800 mg
1.86 to 1.95
1900 mg
1.96 to 2.10
2000 mg
2.11 to 2.30
2200 mg
2.31 to 2.45
2400 mg (1200 mg and 1200 mg)
2.46 to 2.55
2500 mg (1200 mg and 1300 mg)
2.56 to 2.64
2600 mg (1300 mg and 1300 mg)a
BSA (m2)
INFUGEM
Infusion Bag(s)
1.16 to 1.24
1500 mg
1.25 to 1.32
1600 mg
1.33 to 1.40
1700 mg
1.41 to 1.47
1800 mg
1.48 to 1.56
1900 mg
1.57 to 1.68
2000 mg
1.69 to 1.84
2200 mg
1.85 to 1.96
2400 mg (1200 mg and 1200 mg)
1.97 to 2.04
2500 mg (1300 mg and 1200 mg)
2.05 to 2.12
2600 mg (1300 mg and 1300 mg)a
2.13 to 2.20
2700 mg (1200 mg and 1500 mg)a
2.21 to 2.28
2800 mg (1400 mg and 1400 mg)a
2.29 to 2.36
2900 mg (1200 mg and 1700 mg)a
2.37 to 2.44
3000 mg (1500 mg and 1500 mg)a
2.45 to 2.52
3100 mg (1200 mg and 1900 mg)a
2.53 to 2.60
3200 mg (1600 mg and 1600 mg)a
2.61 to 2.64
3300 mg (1600 mg and 1700 mg)a

Injection: 10 mg/mL of gemcitabine, a clear, colorless, sterile solution in sodium chloride available in the following single-dose, premixed intravenous infusion bags: 

INFUGEM is contraindicated in patients with a known hypersensitivity to gemcitabine [see Adverse Reactions (6.1)].

In clinical trials evaluating the maximum tolerated dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of gemcitabine is influenced by the length of the infusion [see Clinical Pharmacology (12.3)]. Refer to the recommended INFUGEM dosing schedule [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with INFUGEM as a single agent, and the risks are increased when INFUGEM is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent gemcitabine. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving gemcitabine in combination with another drug [see Adverse Reactions (6.1)].

Monitor patients receiving INFUGEM prior to each dose with a complete blood count (CBC), including differential and platelet count, and modify the dosage as recommended [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of INFUGEM.

Permanently discontinue INFUGEM in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].

Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur in patients treated with INFUGEM. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 6.2)].

Assess renal function prior to initiation of INFUGEM and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN). Permanently discontinue INFUGEM in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.

Drug-induced liver injury, 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)]. Administration of INFUGEM in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency.

Assess hepatic function prior to initiation of INFUGEM and periodically during treatment. Permanently discontinue INFUGEM in patients that develop severe liver injury.

INFUGEM can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INFUGEM and for 6 months after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the final dose of INFUGEM [see Use in Specific Populations (8.1, 8.3)].

INFUGEM is not recommended for use in combination with radiation therapy.

Concurrent (given together or ≤7 days apart) — Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which gemcitabine was administered at a dose of 1000 mg/m to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.

Non-concurrent (given >7 days apart) — Excessive toxicity has not been observed when gemcitabine is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive gemcitabine after prior radiation.

Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. Permanently discontinue INFUGEM if CLS develops during therapy.

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving gemcitabine as a single agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic disturbances.

Confirm the diagnosis of PRES with magnetic resonance imaging (MRI) and permanently discontinue INFUGEM if PRES develops during therapy.

The following serious adverse reactions are discussed in greater detail in another section of the label

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 clinical practice.

Single-Agent Use:

The data described below reflect exposure to gemcitabine as a single agent administered at doses between 800 mg/m to 1250 mg/m over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent gemcitabine are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued gemcitabine due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Tables 7 and 8 present the incidence of adverse reactions and laboratory abnormalities, respectively, reported in 979 patients with various malignancies receiving single-agent gemcitabine across 5 clinical trials.

Table 7: Selected Adverse Reactions Occurring in >10% Patients Receiving Single-Agent Gemcitabine

Grade based on criteria from the World Health Organization (WHO)

N=699-974

Regardless of causality

For approximately 60% of patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.

Table 8: Selected Laboratory Abnormalities Occurring in Patients Receiving Single-Agent Gemcitabine

a Grade based on criteria from the World Health Organization (WHO)

b N=699-974

c Regardless of causality

Additional adverse reactions include the following:

Non-Small Cell Lung Cancer:

Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities respectively, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine  with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine  with cisplatin (n=262) administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)].

Patients randomized to gemcitabine  with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving gemcitabine  with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the gemcitabine  with cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possible treatment-related deaths, including 3 cases 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.

Table 9: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine  with Cisplatin and at a Higher Incidence than Patients Receiving Single-Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3

National Cancer Institute Common Toxicity Criteria (CTC) for severity grading

N=217-253; all gemcitabine  with cisplatin patients with laboratory or non-laboratory data gemcitabine at 1000 mg/m  on Days 1, 8, and 15 and cisplatin at 100 mg/m  on Day 1 every 28 days

N=213-248; all cisplatin patients with laboratory or non-laboratory data; cisplatin at 100 mg/m on Day 1 every 28 days

Adverse Reactions were graded only if assessed to be possibly drug-related.

Table 10: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine  with Cisplatin and at a Higher Incidence than Patients Receiving Single-Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 3

National Cancer Institute Common Toxicity Criteria (CTC) for severity grading

N=217-253; all gemcitabine  with cisplatin patients with laboratory data gemcitabine at 1000 mg/m on Days 1, 8, and 15 and cisplatin at 100 mg/m on Day 1 every 28 days

N=213-248; all cisplatin patients with laboratory data; cisplatin at 100 mg/m on Day 1 every 28 days

Regardless of causality

Percent of patients receiving transfusions

Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities, respectively, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine  with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine  with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)].

Patients in the gemcitabine cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm. The incidence of hospitalizations for treatment-related adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the GC arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm.

Table 11: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine  with Cisplatin in Study 4

Grade based on criteria from the World Health Organization (WHO)

N=67-69; all gemcitabine  with cisplatin patients with laboratory or non-laboratory data gemcitabine at 1250 mg/m  on Days 1 and 8 and cisplatin at 100 mg/m on Day 1 every 21 days

N=57-63; all cisplatin with etoposide patients with laboratory or non-laboratory data; cisplatin at 100 mg/m  on Day 1 and intravenous etoposide at 100 mg/m  on Days 1, 2, and 3 every 21 days

Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.

Flu-like syndrome and edema were not graded.

Table 12: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine  with Cisplatin in Study 4

Grade based on criteria from the World Health Organization (WHO)

N=67-69; all gemcitabine  with cisplatin patients with non-laboratory data; gemcitabine at 1250 mg/m  on Days 1 and 8 and cisplatin at 100 mg/m  on Day 1 every 21 days

N=57-63; all cisplatin with etoposide patients with non-laboratory data; cisplatin at 100 mg/mon Day 1 and intravenous etoposide at 100 mg/m  on Days 1, 2, and 3 every 21 days

Regardless of causality

WHO grading scale not applicable to proportion of patients with transfusions 

Breast Cancer

Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities respectively, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine  with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine  with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)].

The requirement for dose reduction of paclitaxel was higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

Table 13: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine  with Paclitaxel and at a Higher Incidence than Patients Receiving Single-Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2

Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0

Regardless of causality

Non-laboratory events were graded only if assessed to be possibly drug-related.

Table 14: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine  with Paclitaxel and at a Higher Incidence than Patients Receiving Single-Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2

Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0

Regardless of causality 

Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine  with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0).

Ovarian Cancer

Tables 15 and 16 present the incidence of selected adverse reactions and laboratory abnormalities respectively, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine  with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine  with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following Table 16.

The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar between arms. Dose adjustment for gemcitabine occurred in 10.4% of patients and gemcitabine dose was omitted in 13.7% of patients in the gemcitabine/carboplatin arm.

Table 15: Adverse Reactions Occurring in >10% of Patients Receiving in Gemcitabine  with Carboplatin and at a Higher Incidence than Patients Receiving Single-Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1

Grade based on Common Toxicity Criteria (CTC) Version 2.0

Regardless of causality

Table 16: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at a Higher Incidence than Patients Receiving Single-Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1

Grade based on National Cancer Institute Common Toxicity Criteria (NCI CTC) Version 2.0

Regardless of causality

Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: granulocyte growth factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).

The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine  with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

 
 
Adverse Reactionc,d
All Patientsb
All Grades (%)
Grade 3
(%)
Grade 4
(%)
Nausea and Vomiting
69
13
1
Fever
41
2
0
Rash
30
<1
0
Dyspnea
23
3
<1
Diarrhea
19
1
0
Hemorrhage
17
<1
<1
Infection
16
1
<1
Alopecia
15
<1
0
Stomatitis
11
<1
0
Somnolence
11
<1
<1
Paresthesias
10
<1
0
 
All Patientsb
All Grades (%)
Grade 3
(%)
Grade 4
(%)
Laboratory Abnormalityc
Hematologic
 
 
 
Anemia
68
7
1
Neutropenia
63
19
6
Thrombocytopenia
24
4
1
Hepatic
Increased ALT
68
8
2
Increased AST
67
6
2
Increased Alkaline Phosphatase
55
7
2
Hyperbilirubinemia
13
2
<1
Renal
Proteinuria
45
<1
0
Hematuria
35
<1
0
Increased BUN
16
0
0
Increased Creatinine
8
<1
0
 
Gemcitabine  with Cisplatinb
(%)
Cisplatinc
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Adverse Reactiond
 
 
 
 
 
 
Nausea
93
25
2
87
20
<1
Vomiting
78
11
12
71
10
9
Alopecia
53
1
0
33
0
0
Neuro Motor
35
12
0
15
3
0
Diarrhea
24
2
2
13
0
0
Neuro Sensory
23
1
0
18
1
0
Infection
18
3
2
12
1
0
Fever
16
0
0
5
0
0
Neuro Cortical
16
3
1
9
1
0
Neuro Mood
16
1
0
10
1
0
Local
15
0
0
6
0
0
Neuro Headache
14
0
0
7
0
0
Stomatitis
14
1
0
5
0
0
Hemorrhage
14
1
0
4
0
0
Hypotension
12
1
0
7
1
0
Rash
11
0
0
3
0
0
 
Gemcitabine  with Cisplatinb
(%)
Cisplatinc
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratory Abnormalityd
 
 
 
 
 
 
Hematologic
 
 
 
 
 
 
Anemia
89
22
3
67
6
1
Thrombocytopenia
85
25
25
13
3
1
Neutropenia
79
22
35
20
3
1
Lymphopenia
75
25
18
51
12
5
RBC Transfusione
39
 
 
13
 
 
Platelet Transfusionse
21
 
 
<1
 
 
Hepatic
 
 
 
 
 
 
Increased Transaminases
22
2
1
10
1
0
Increased Alkaline Phosphatase
19
1
0
13
0
0
Renal
 
 
 
 
 
 
Elevated creatinine
38
4
<1
31
2
<1
Proteinuria
23
0
0
18
0
0
Hematuria
15
0
0
13
0
0
Other Laboratory
 
 
 
 
 
 
Hyperglycemia
30
4
0
23
3
0
Hypomagnesemia
30
4
3
17
2
0
Hypocalcemia
18
2
0
7
0
<1
 
Adverse Reactiond
Gemcitabine  with Cisplatinb
(%)
Etoposide with Cisplatinc
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Nausea and Vomiting
96
35
4
86
19
7
Alopecia
77
13
0
92
51
0
Paresthesias
38
0
0
16
2
0
Infection
28
3
1
21
8
0
Stomatitis
20
4
0
18
2
0
Diarrhea
14
1
1
13
0
2
Edemae
12
-
-
2
-
-
Rash
10
0
0
3
0
0
Hemorrhage
9
0
3
3
0
3
Fever
6
0
0
3
0
0
Flu-like Syndromee
3
-
-
0
-
-
Somnolence
3
0
0
3
2
0
Dyspnea
1
0
1
3
0
0
 
Gemcitabine  with Cisplatinb
(%)
Etoposide with Cisplatinc
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratory Abnormalityd
 
 
 
 
 
 
       Hematologic
  
 
 
 
 
 
Anemia
88
22
0
77
13
2
Neutropenia
88
36
28
87
20
56
Thrombocytopenia
81
39
16
45
8
5
RBC Transfusionse
29
-
-
21
-
-
Platelet Transfusionse
3
-
-
8
-
-
      Hepatic
 
 
 
 
 
 
Increased Alkaline Phosphatase
16
0
0
11
0
0
Increased ALT
6
0
0
12
0
0
Increased AST
3
0
0
11
0
0
Bilirubin
0
0
0
0
0
0
     Renal
 
 
 
 
 
 
Hematuria
22
0
0
10
0
0
Proteinuria
12
0
0
5
0
0
BUN
6
0
0
4
0
0
Creatinine
2
0
0
2
0
0
 
Gemcitabine  with Paclitaxel
(N=262)
(%)
Paclitaxel
(N=259)
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Adverse Reactionb
 
 
 
 
 
 
Alopecia
90
14
4
92
19
3
Neuropathy-sensory
64
5
<1
58
3
0
Nausea
50
1
0
31
2
0
Fatigue
40
6
<1
28
1
<1
Vomiting
29
2
0
15
2
0
Diarrhea
20
3
0
13
2
0
Anorexia
17
0
0
12
<1
0
Neuropathy-motor
15
2
<1
10
<1
0
Stomatitis/pharyngitis
13
1
<1
8
<1
0
Fever
13
<1
0
3
0
0
Rash/desquamation
11
<1
<1
5
0
0
Febrile neutropenia
6
5
<1
2
1
0
 
Gemcitabine  with Paclitaxel
(N=262)
(%)
Paclitaxel
(N=259)
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratory Abnormalityb
 
 
 
 
 
 
  Hematologic
 
 
 
 
 
 
Anemia
69
6
1
51
3
<1
Neutropenia
69
31
17
31
4
7
Thrombocytopenia
26
5
<1
7
<1
<1
  Hepatobiliary
 
 
 
 
 
 
Increased ALT
18
5
<1
6
<1
0
Increased AST
16
2
0
5
<1
0
 
Gemcitabine  with Carboplatin
(N=175)
(%)
Carboplatin
(N=174)
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Adverse Reactionb
 
 
 
 
 
 
Nausea
69
6
0
61
3
0
Alopecia
49
0
0
17
0
0
Vomiting
46
6
0
36
2
<1
Constipation
42
6
1
37
3
0
Fatigue
40
3
<1
32
5
0
Diarrhea
25
3
0
14
<1
0
Stomatitis/pharyngitis
22
<1
0
13
0
0
 
Gemcitabine plus Carboplatin
(N=175)
(%)
Carboplatin
(N=174)
(%)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratory Abnormalityb
 
 
 
 
 
 
Hematologic
 
 
 
 
 
 
Neutropenia
90
42
29
58
11
1
Anemia
86
22
6
75
9
2
Thrombocytopenia
78
30
5
57
10
1
RBC Transfusionsc
38
 
 
15
 
 
Platelet Transfusionsc
9
 
 
3
 
 

The following adverse reactions have been identified during post-approval use of gemcitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular - Congestive heart failure, myocardial infarction, arrhythmias, and supraventricular arrhythmias

Vascular Disorders - Peripheral vasculitis, gangrene, and capillary leak syndrome

Skin - Cellulitis, pseudocellulitis, severe skin reactions, including desquamation and bullous skin eruptions

Hepatic - Hepatic failure, hepatic veno-occlusive disease

Pulmonary - Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS)

Nervous System - Posterior reversible encephalopathy syndrome (PRES)

Risk Summary

Based on animal data and its mechanism of action, INFUGEM can cause fetal harm when administered to a pregnant woman. There are no available data on the use of gemcitabine in pregnant women. In animal reproductive studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of  fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day (approximately 0.005 times the 1000 mg/m clinical dose on body surface area (BSA)). Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m clinical dose based on BSA).

Risk Summary

There is no information regarding the presence of gemcitabine or its metabolites in human milk, or their effects on the breastfed infant or milk production. Due to the potential for serious adverse reactions in nursing infants from INFUGEM, advise woman not to breastfeed during treatment with INFUGEM and for at least one week after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating INFUGEM [see Use in Specific Populations (8.1)].

Contraception

INFUGEM can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. 

Females

Advise females of reproductive potential to use effective contraception during treatment with INFUGEM and for 6 months after the last dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during and for 3 months following the last dose of INFUGEM [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on animal studies, INFUGEM may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of INFUGEM have not been established in pediatric patients. The safety and pharmacokinetics ofgemcitabine were evaluated in a trial in pediatric patients with  refractory leukemia. The maximum tolerated dose was 10 mg/m/min for 360 minutes weekly for three weeks followed by a one-week rest period. The safety and activity of  gemcitabine were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m/min administered over 360 minutes weekly for three weeks followed by a one-week rest period. Patients with M1 or M2 bone marrow on Day 28 who did not experience unacceptable toxicity were eligible to receive a maximum of one additional four-week course. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this trial.

In clinical studies of gemcitabine enrolling 979 patients with various cancers who received gemcitabine as a single agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a randomized trial in women with ovarian cancer, 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older. 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 [see Dosage and Administration (2.1-2.4)].

Gemcitabine clearance is decreased in females [see Clinical Pharmacology (12.3)]. In single-agent studies of gemcitabine, women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia [see Dosage and Administration (2.1-2.4)].

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

Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine hydrochloride is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer) with the following structural formula:

Gemcitabine hydrochloride is a white to off-white crystalline powder. The empirical formula for gemcitabine hydrochloride is CHFNO• HCl. It has a molecular weight of 299.66 g/mol. Gemcitabine hydrochloride is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

INFUGEM (gemcitabine in 0.9% sodium chloride injection) is a clear, colorless, sterile solution that is provided as a single-dose, premixed intravenous infusion bag (10 mg/mL) for intravenous use and does not require any further preparation.

Each 100 mL contains 1000 mg of gemcitabine (equivalent to 1138 mg of gemcitabine hydrochloride, USP), 900 mg of sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. 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, which eventually results in the initiation of apoptotic cell death.

The pharmacokinetics of gemcitabine were examined in 353 patients, 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 gemcitabine dose varied from 500 to 3600 mg/m. Distribution

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m. 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. Gemcitabine plasma protein binding is negligible. Elimination Metabolism 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. Excretion Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m/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. Specific Populations Geriatric Patients  

Clearance of gemcitabine was affected by age. The lower clearance in the elderly results in higher concentrations of gemcitabine for any given dose. 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 17 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender. Table 17: Gemcitabine Clearance and Half-Life for the “Typical” Patient

Half-life for patients receiving <70 minute infusion. 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. Male and Female Patients Clearance of gemcitabine was affected by gender. Female patients have lower clearance and longer half-lives than male patients as described in Table 17. Patients with Renal Impairment

No clinical studies have been conducted with gemcitabine in patients with decreased renal function. Patients with Hepatic Impairment

No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function. Drug Interactions

When gemcitabine (1250 mg/m on Days 1 and 8) and cisplatin (75 mg/m on Day 1) were administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m and on Day 8 was 107 L/hr/m. Analysis of data from metastatic breast cancer patients shows that, on average, gemcitabine 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 gemcitabine. Data from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

Age
Clearance Men (L/hr/m2)
Clearance Women (L/hr/m2)
Half-Lifea Men
(min)
Half-Lifea Women
(min)
29
92.2
69.4
42
49
45
75.7
57
48
57
65
55.1
41.5
61
73
79
40.7
30.7
79
94

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been conducted. Gemcitabine was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine intraperitoneal doses of 0.5 mg/kg/day (about 1/700 the 1000 mg/m clinical dose based on BSA) in male mice resulted in 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 administered intravenously (about 1/200 the 1000 mg/m clinical dose based on BSA) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the 1000 mg/m clinical dose based on BSA).

The safety and efficacy of gemcitabine were studied in a randomized trial (Study 1) of 356 women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine hydrochloride 1000 mg/m on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after gemcitabine hydrochloride infusion on Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary efficacy outcome measure was progression free survival (PFS).

Baseline demographics and disease characteristics in gemcitabine plus carboplatin arm were: median age of 59 (range: 36 to 78), 94% ECOG PS 0-1. 8% had evaluable disease and 92% had bidimensionally measurable disease. 40% had 6 to 12 months of platinum free interval, 59% had greater than 12 months platinum free interval; and as first-line therapy, 70% had platinum-taxane combination, 29% had platinum-non-taxane combination and 1% had platinum monotherapy. 

Baseline demographics and disease characteristics in the carboplatin arm were: median age of 58 (range 21 to 81), 95% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; 3% had evaluable disease and 96% had bidimensionally measurable disease; 40% had a 6 to 12 month platinum-free interval and 60% had a greater than 12 month platinum-free interval; and as first-line therapy, 71% had a platinum-taxane combination, 28% had platinum-non-taxane combination, and 1% had platinum monotherapy.

The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS and overall response rate as shown in Table 18 and Figure 1. Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms.

Table 18: Efficacy Results for Study 1

Figure 1: Kaplan-Meier Curve of Progression Free Survival for Study 1

 
Gemcitabine/Carboplatin
(N=178)
Carboplatin
(N=178)
Progression-free Survival
Median (95% CICI=confidence interval) months
Hazard Ratio (95% CI)
 
8.6 (8, 9.7)
 
5.8 (5.2, 7.1)
0.72 (0.57, 0.9)
p-valueLog rank, unadjusted
p=0.0038
Overall Survival
Median (95% CI) months
Hazard Ratio (95% CI)
p-value
 
18 (16.2, 20.3)
 
17.3 (15.2, 19.3)
0.98 (0.78, 1.24)
p=0.8977
Investigator Assessed
Overall Response Rate
 
47.2%
 
30.9%
p-valueChi square
p=0.0016
CRCR=Complete response
14.6%
6.2%
PR plus PRNMPR plus PRNM=Partial response plus partial response, non-measurable disease
32.6%
24.7%
Independently Assessed
Overall Response RateIndependently reviewed cohort – gemcitabine hydrochloride/carboplatin (n=121), carboplatin (n=101); independent reviewers were unable to measure disease detected by sonography or physical exam.
 
46.3%
 
35.6%
p-value
p=0.11
CR
9.1%
4%
PR plus PRNM
37.2%
31.7%

The safety and efficacy of gemcitabine were evaluated in a randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and in women who had received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive gemcitabine 1250 mg/m on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m administered prior to gemcitabine on Day 1 of each cycle (n=267) or to receive paclitaxel 175 mg/m on Day 1 of each 21-day cycle (n=262). The primary efficacy outcome measure was time to documented disease progression.

A total of 529 patients were enrolled. Baseline demographics and disease characteristics in the gemcitabine with  paclitaxel arm were: median age of 53 (range 26 to 83); 97% had metastatic disease; 70% had baseline Karnofsky Performance Status (KPS) greater than or equal to 90%; 57% had 1 to 2 tumor sites and 43% had 3 or more tumor sites; 73% had visceral disease and 97% had prior anthracycline.

Efficacy results are presented in Table 19 and Figure 2. The addition of gemcitabine to paclitaxel resulted in a statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant difference in overall survival.

Table 19: Efficacy Results for Study 2

Karnofsky Performance Status

 
                            Gemcitabine  /Paclitaxel
(N=267)
Paclitaxel
(N=262)
Efficacy Outcomes
Time to Documented Disease
 
 
ProgressionThese represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.
 
 
Median in months
5.2
2.9
(95% CI)
(4.2, 5.6)
(2.6, 3.7)
Hazard Ratio (95% CI)
0.65 (0.524, 0.805)
p-value
p<0.0001
Overall SurvivalBased on the ITT population
 
 
Median Survival in months
18.6
15.8
(95% CI)
(16.5, 20.7)
(14.1, 17.3)
Hazard Ratio (95% CI)
0.86 (0.71, 1.04)
p-value
Not Significant
Overall Response Rate
40.8%
22.1%
(95% CI)
(34.9, 46.7)
(17.1, 27.2)
p-value
p<0.0001

The safety and efficacy of gemcitabine were evaluated in two randomized, multicenter trials.

Study 3: 28-Day Schedule

A randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive gemcitabine 1000 mg/m on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m administered on Day 1 of each cycle or to receive cisplatin 100 mg/m on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall survival. A total of 522 patients were enrolled. Patient demographics and baseline characteristics were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma. Efficacy results are presented in Table 20 and Figure 3 for overall survival.

Study 4: 21-Day Schedule

A randomized (1:1), multicenter trial (Study 4) was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were randomized to receive gemcitabine 1250 mg/m on Days 1 and 8, and cisplatin 100 mg/m on Day 1 of a 21-day cycle or to receive etoposide 100 mg/m intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m on Day 1 of a 21-day cycle. A total of 135 patients were enrolled. Patient demographics and baseline characteristics in gemcitabine with cisplatin arm were: 93% males, median age 58 years (range 33 to 76); 48% in stage IIIB and 52% stage IV, 45 %; Baseline KPS 70 to 80, 55% Baseline KPS 90 to 100. Patient demographics and baseline characteristics in cisplatin arm were: 92% males, median age 60 years (range 35 to 75), 52% in stage IIIB and 49% stage IV NSCLC, 52% Baseline KPS 70 to 80, 49% Baseline KPS 90 to 100.

There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided, see Table 20). The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide with cisplatin arm (Fisher’s Exact p=0.01, two-sided).

Table 20: Randomized Trials of Gemcitabine with Cisplatin in Patients with NSCLC Efficacy Results for Studies 3 and 4

28-day schedule – gemcitabine with cisplatin: gemcitabine 1000 mg/mon Days 1, 8, and 15 and cisplatin 100 mg/m on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m on Day 1 every 28 days

21-day schedule – gemcitabine with cisplatin: gemcitabine 1250 mg/mon Days 1 and 8 and cisplatin 100 mg/m on Day 1 every 21 days; etoposide with cisplatin: cisplatin 100 mg/m on Day 1 and intravenous etoposide 100 mg/m on Days 1, 2, and 3 every 21 days

N/A Not applicable

Karnofsky Performance Status

CI=confidence intervals

p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses

Trial
28-day Schedule (Study 3)a
21-day Schedule (Study 4)b
Treatment Arm
Gemcitabine  with Cisplatin
(N=260)
Cisplatin
(N=262)
Gemcitabine  with Cisplatin
(N=69)
Etoposide with
Cisplatin
(N=66)
Efficacy Outcomes
 
 
 
 
Survival
 
 
 
 
Median in months
9
7.6
8.7
7
(95% CIe) months
8.2, 11
6.6, 8.8
7.8, 10.1
6, 9.7
p-valuef
p=0.008
p=0.18
Time to Disease
 
 
 
 
 
 
 
 
Progression
Median in months
5.2
3.7
5
4.1
(95% CIe) months
4.2, 5.7
3, 4.3
4.2, 6.4
2.4, 4.5
p-valuef
p=0.009
p=0.015
Tumor Response
p-valuef
26%
10%
33%
14%
p<0.0001
p=0.01

The safety and efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. Study 5 randomized patients to receive gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28 days in subsequent cycles (n=63) or to fluorouracil 600 mg/m intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 consecutive weeks every 28 days in subsequent cycles.

The primary efficacy outcome measure in both trials was "clinical benefit response". A patient was considered to have had a clinical benefit response if either of the following occurred:

OR

Study 5 enrolled 126 patients. The demographic and entry characteristics were similar between the arms. The efficacy outcome results are shown in Table 21 and for overall survival in Figure 4. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm.

Table 21: Efficacy Results for Study 5

Karnofsky Performance Status

p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other p-values are calculated using log rank test.

 

 
Gemcitabine 
(N=63)
Fluorouracil
(N=63)
Efficacy Outcomes
Clinical benefit response
p-valueb
22.2%
4.8%
p=0.004
Survival
Median
(95% CI)
p-valueb
 
5.7 months
(4.7, 6.9)
 
4.2 months
(3.1, 5.1)
p=0.0009
Time to Disease Progression
Median
(95% CI)
p-valueb
 
2.1 months
(1.9, 3.4)
 
0.9 months
(0.9, 1.1)
p=0.0013

1.“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

INFUGEM (gemcitabine in 0.9% sodium chloride injection) is a clear, colorless, sterile solution in a single-dose, premixed intravenous infusion bag with an aluminum overwrap. The container closure is not made with natural rubber latex and is tamper evident. It is available in presentations as described in Table 22.

Table 22: INFUGEM Available Presentations

Strength
Package
NDC number
1200 mg in 120 mL
1 single-dose bag per carton
62756-073-60
1300 mg in 130 mL
1 single-dose bag per carton
62756-008-60
1400 mg in 140 mL
1 single-dose bag per carton
62756-102-60
1500 mg in 150 mL
1 single-dose bag per carton
62756-219-60
1600 mg in 160 mL
1 single-dose bag per carton
62756-321-60
1700 mg in 170 mL
1 single-dose bag per carton
62756-438-60
1800 mg in 180 mL
1 single-dose bag per carton
62756-533-60
1900 mg in 190 mL
1 single-dose bag per carton
62756-614-60
2000 mg in 200 mL
1 single-dose bag per carton
62756-746-60
2200 mg in 220 mL
1 single-dose bag per carton
62756-974-60

INFUGEM is a cytotoxic drug. Follow applicable special handling and disposal procedures.  

Unopened infusion bags of INFUGEM are stable until the expiration date indicated on the package when stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [see USP Controlled Room Temperature].

Do not freeze as crystallization can occur.

Myelosuppression

Advise patients of the risks of myelosuppression and instruct them to immediately contact their healthcare provider should any signs of infection develop, including fever or if bleeding or symptoms of anemia occur [see Warnings and Precautions (5.2)].

Pulmonary Toxicity

Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough [see Warnings and Precautions (5.3)].

Hemolytic-Uremic Syndrome and Renal Failure

Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to immediately contact their healthcare provider for changes in the color or volume of urine output or for increased bruising or bleeding [see Warnings and Precautions (5.4)].

Hepatic Toxicity

Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal quadrant [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise females and males of reproductive potential that INFUGEM can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the final dose of INFUGEM. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with and for 3 months after the final dose of INFUGEM [see Warnings and Precaution (5.6), Use in Specific Populations (8.1), (8.3)].

Lactation

Advise women not to breastfeed during treatment with and for at least one week after the last dose of INFUGEM [see Use in Specific Populations (8.2)].

Fertility Effects

Advise males of reproductive potential of the potential for reduced fertility with INFUGEM use [see Use in Specific Populations (8.3)].

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Ind. Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India

(gemcitabine in 0.9% sodium chloride injection), 10 mg/mL

These instructions contain information on how to:

  

Select the Correct INFUGEM Bag(s)

Spike the Infusion Bag

INFUGEM for intravenous use is a clear, colorless, pre-mixed sterile solution that is available in single-dose ready to infuse bags. Do NOT remove or add medication. The bag closures are tamper evident and do not allow contamination.

Understanding the INFUGEM Dose Ranges

INFUGEM (gemcitabine) in 0.9% Sodium Chloride Injection (10 mg/mL) provides predefined dose ranges (in premixed bags) that correspond to BSA-calculated and prescribed doses. Select the INFUGEM premixed bag(s) that allow for a variance of up to 5% of the BSA-calculated dose as described in Table 1 and Table 2.

Use another formulation of gemcitabine for patients that require a dose that is less than those listed in the tables below (i.e. <1150 mg).

Selecting the Correct INFUGEM INFUSION Bag(s)

1         Use Table 1 for Gemcitabine doses of 1000 mg/m2 (non-small cell lung cancer, ovarian cancer, pancreatic cancer). Use Table 2 for Gemcitabine doses of 1250 mg/m2 (breast cancer and non-small cell lung cancer).

2         Identify the appropriate INFUGEM Infusion Bag(s)* based on the BSA-calculated dose range.

*Combinations of bags listed below are suggested combinations. Other possible combinations of bags can be used to reach the appropriate dose.

  

Make sure to select the correct target dose table in order to determine the appropriate INFUGEM infusion bag(s).

  

Based on the calculated dose, one or two INFUGEM bags may be needed.

How to Spike the INFUGEM Infusion Bag(s)

To achieve the prescribed dose two bags can be administered sequentially.

1         Inspect the integrity of the overwrap before removing the overwrap pouch. Do not use the product if the overwrap has been previously opened or damaged.

2         Remove the overwrap pouch by tearing at the notch at the bottom of the overwrap and pulling across the infusion bag. (Figure A, B and C)

3         Check for leaks by squeezing the bag firmly. Inspect bag and contents for damage, discoloration or particulate matter. (Figure D)

4         Break the tamper evident cap on the infusion port by applying pressure on one side with thumb. (Figure E)

5         Using aseptic technique, remove the cover from the spike of the infusion set. (Figure F)

6         Holding the bag with the port side up, insert the spike straight down into the infusion port. (Figure G)

NOTE: DO NOT spike the bag while the bag is hanging on the IV pole.

7         Twist and push the spike through the diaphragm.(Figure H)

NOTE: Follow the instructions for use for the infusion set.

8         Please follow your institution’s procedures for administration and disposal.

For more information, call 1-800-818-4555.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

NDC 62756-073-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,200 mg per 120 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-008-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,300 mg per 130 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-102-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,400 mg per 140 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-219-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,500 mg per 150 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-321-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,600 mg per 160 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-438-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,700 mg per 170 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-533-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,800 mg per 180 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-614-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 1,900 mg per 190 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-746-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 2,000 mg per 200 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

NDC 62756-974-60 Rx only Infugem Gemcitabine in 0.9% sodium chloride injection 2,200 mg per 220 mL (10 mg/mL) For Intravenous Use Only Caution: Cytotoxic Agent SUN PHARMA

Manufacturer

Sun Pharmaceutical Industries, Inc.

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