Gemcitabin

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Gemcitabin uses


1 INDICATIONS AND USAGE

Gemcitabin is a nucleoside metabolic inhibitor indicated for:

1.1 Ovarian Cancer

Gemcitabin Injection 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.

1.2 Breast Cancer

Gemcitabin Injection 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.

1.3 Non-Small Cell Lung Cancer

Gemcitabin Injection is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced, or metastatic (Stage IV) non-small cell lung cancer.

1.4 Pancreatic Cancer

Gemcitabin Injection 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. Gemcitabin Injection is indicated for patients previously treated with 5-FU.

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2 DOSAGE AND ADMINISTRATION

Gemcitabin Injection is for intravenous use only. Gemcitabin Injection may be administered on an outpatient basis.

Gemcitabin Injection is for intravenous use only.

2.1 Ovarian Cancer

Gemcitabin Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after Gemcitabin Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

Gemcitabin Injection dosage adjustments for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabin Injection 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 Gemcitabin Injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer’s prescribing information.

Dose adjustment for Gemcitabin Injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemcitabin Injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:


If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, Gemcitabin Injection should be given on Day 1 only at 800 mg/m2.

2.2 Breast Cancer

Gemcitabin Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before Gemcitabin Injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

Gemcitabin Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemcitabin Injection dosage should be modified according to the guidelines in Table 2.


Absolute granulocyte count





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 Gemcitabin Injection should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.

2.3 Non-Small Cell Lung Cancer

Two schedules have been investigated and the optimum schedule has not been determined [ see Clinical Studies (14.3) ]. With the 4-week schedule, Gemcitabin Injection should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabin Injection. With the 3-week schedule, Gemcitabin Injection should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of Gemcitabin Injection on Day 1. See prescribing information for cisplatin administration and hydration guidelines.

Dose Modifications

Dosage adjustments for hematologic toxicity may be required for Gemcitabin Injection and for cisplatin. Gemcitabin Injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemcitabin Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemcitabin Injection plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for Gemcitabin Injection plus cisplatin was 5% versus 2% for cisplatin alone).

2.4 Pancreatic Cancer

Gemcitabin Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks, 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 Gemcitabin Injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.


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. Gemcitabin Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

Patients treated with Gemcitabin Injection who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemcitabin Injection at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue Gemcitabin for any of the following


Withhold Gemcitabin or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation and Administration Precautions

Caution should be exercised in handling and preparing Gemcitabin Injection and diluted solution. The use of gloves is recommended. If Gemcitabin Injection and diluted solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities due to dermal absorption.

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published [ see References (15) ].

2.7 Preparation for Intravenous Infusion Administration

Each vial contains a Gemcitabin concentration of 38 mg/mL. Hence, withdrawing 5.26 mL, 26.3 mL, or 52.6 mL of the vial contents will provide 200 mg, 1 g, or 2 g of Gemcitabin, respectively. The appropriate amount of drug should be further diluted with 0.9% Sodium Chloride Injection to concentrations as low as 0.1 mg/mL.

After dilution with 0.9% Sodium Chloride Injection the solution should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution or container permits. If particulate matter or discoloration is found, do not administer.

When prepared as directed, diluted Gemcitabin solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F). Discard unused portion.

The compatibility of Gemcitabin Injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

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3 DOSAGE FORMS AND STRENGTHS

Gemcitabin Injection is a clear and colorless to light straw-colored solution available in sterile single-use vials containing:

4 CONTRAINDICATIONS

Gemcitabin Injection is contraindicated in those patients with a known hypersensitivity to the drug.

Patients with a known hypersensitivity to Gemcitabin (4)

5 WARNINGS AND PRECAUTIONS

Patients receiving therapy with Gemcitabin Injection should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

5.1 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) ].

5.2 Hematology

Gemcitabin can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [ see Adverse Reactions ], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [ see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

5.3 Pulmonary

Pulmonary toxicity has been reported with the use of Gemcitabin. In cases of severe lung toxicity, Gemcitabin Injection therapy should be discontinued immediately and appropriate supportive care measures instituted [ see Adverse Reactions (6.1 and 6.2)].

5.4 Renal

Hemolytic Uremic Syndrome and/or renal failure have been reported following one or more doses of Gemcitabin. 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)] .

Gemcitabin Injection 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) ] .

5.5 Hepatic

Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemcitabin alone or in combination with other potentially hepatotoxic drugs [ see Adverse Reactions (6.1 and 6.2)] .

Gemcitabin Injection 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 Gemcitabin Injection 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) ] .

5.6 Pregnancy

Gemcitabin can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, Gemcitabin was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of Gemcitabin 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 ] .

5.7 Laboratory Tests

Patients receiving Gemcitabin Injection 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) ] .

5.8 Radiation Therapy

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

Non-concurrent - Analysis of the data does not indicate enhanced toxicity when Gemcitabin is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemcitabin 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 Gemcitabin has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemcitabin, frequency of Gemcitabin administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemcitabin 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 Gemcitabin administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemcitabin with therapeutic doses of radiation has not yet been determined in all tumor types.

5.9 Capillary Leak Syndrome

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

5.10 Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemcitabin 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 discontinue Gemcitabin if PRES develops during therapy.

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6 ADVERSE REACTIONS

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


The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPPGemcitabinhospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

Gemcitabin 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 Gemcitabin 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 Gemcitabin as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemcitabin 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 Gemcitabin therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the Gemcitabin 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.

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.


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


Hematologic - In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with Gemcitabin, 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 Gemcitabin 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, Gemcitabin 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 Gemcitabin or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemcitabin 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 Gemcitabin in clinical trials. Four patients developed HUS on Gemcitabin 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). Gemcitabin 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 Gemcitabin 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 Gemcitabin therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of Gemcitabin [ see Adverse Reactions (6.2) ] . The etiology of these effects is unknown. If such effects develop, Gemcitabin 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. Gemcitabin is not a vesicant.

Allergic - Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of Gemcitabin injections and 16% of cisplatin injections in the Gemcitabin 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 Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with Gemcitabin plus cisplatin treatment (~90%) compared to that with the Gemcitabin monotherapy (~60%). With combination therapy Gemcitabin 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 Gemcitabin 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 Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued Gemcitabin plus cisplatin use.

Nausea and vomiting despite the use of antiemetics occurred more often with Gemcitabin plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent Gemcitabin, 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 Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin combination arm.

Table 6 presents data from the randomized study of Gemcitabin plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin arm. RBC transfusions were given to 29% of the patients who received Gemcitabin plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received Gemcitabin plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemcitabin plus cisplatin arm. On the Gemcitabin 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 Gemcitabin 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 Gemcitabin plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the Gemcitabin plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm.

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 Gemcitabin plus cisplatin patients with laboratory or non-laboratory data. Gemcitabin 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.


Gemcitabin 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 criteria from the World Health Organization (WHO).

b N=67-69; all Gemcitabin plus cisplatin patients with laboratory or non-laboratory data. Gemcitabin at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.

c N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.

d Regardless of causality.

e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events.

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

g Pain data were not collected.


Gemcitabin plus Cisplatinb


Etoposide plus Cisplatinc


All Grades


Grade 3


Grade 4


All Grades


Grade 3


Grade 4


Laboratoryd

Hematologic

Anemia

RBC Transfusionse

Leukopenia

Neutropenia

Thrombocytopenia

Platelet Transfusionse




88

29

86

88

81

3




22


26

36

39





0


3

28

16





77

21

87

87

45

8




13


36

20

8





2


7

56

5



Hepatic

ALT

AST

Alkaline Phosphatase

Bilirubin



6

3

16

0



0

0

0

0



0

0

0

0



12

11

11

0



0

0

0

0



0

0

0

0


Renal

Proteinuria

Hematuria

BUN

Creatinine



12

22

6

2



0

0

0

0



0

0

0

0



5

10

4

2



0

0

0

0



0

0

0

0


Non-laboratoryf,g

Nausea and Vomiting

Fever

Rash

Dyspnea

Diarrhea

Hemorrhage

Infection

Alopecia

Stomatitis

Somnolence

Paresthesias



96

6

10

1

14

9

28

77

20

3

38



35

0

0

0

1

0

3

13

4

0

0



4

0

0

1

1

3

1

0

0

0

0



86

3

3

3

13

3

21

92

18

3

16



19

0

0

0

0

0

8

51

2

2

2



7

0

0

0

2

3

0

0

0

0

0


Combination Use in Breast Cancer

In the Gemcitabin plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of Gemcitabin injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of Gemcitabin doses were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the Gemcitabin plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm. Table 7 presents the safety data occurrences of ≥10% (all grades) from the Gemcitabin plus paclitaxel versus paclitaxel study in breast cancer.

a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%).

b Regardless of causality.

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


Gemcitabin plus Paclitaxel

(N=262)


Paclitaxel

(N=259)


All Grades


Grade 3


Grade 4


All Grades


Grade 3


Grade 4


Laboratoryb

Hematologic

Anemia

Neutropenia

Thrombocytopenia

Leukopenia


69

69

26

21


6

31

5

10


1

17

<1

1


51

31

7

12


3

4

<1

2


<1

7

<1

0


Hepatobiliary

ALT

AST


18

16


5

2


<1

0


6

5


<1

<1


0

0


Non-laboratoryc

Alopecia

Neuropathy-sensory

Nausea

Fatigue

Myalgia

Vomiting

Arthralgia

Diarrhea

Anorexia

Neuropathy-motor

Stomatitis/pharyngitis

Fever

Rash/desquamation


90

64

50

40

33

29

24

20

17

15

13

13

11


14

5

1

6

4

2

3

3

0

2

1

<1

<1


4

<1

0

<1

0

0

0

0

0

<1

<1

0

<1


92

58

31

28

33

15

22

13

12

10

8

3

5


19

3

2

1

3

2

2

2

<1

<1

<1

0

0


3

0

0

<1

<1

0

<1

0

0

0

0

0

0


The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus paclitaxel versus paclitaxel): febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Combination Use in Ovarian Cancer

In the Gemcitabin plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemcitabin injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemcitabin doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively).

Table 8 presents the adverse reactions (all grades) occurring in ≥10% of patients in the ovarian cancer study.

a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%).

b Regardless of causality.

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


Gemcitabin plus Carboplatin

(N=175)


Carboplatin

(N=174)


All Grades


Grade 3


Grade 4


All Grades


Grade 3


Grade 4


Laboratoryb

Hematologic

Neutropenia

Anemia

Leukopenia

Thrombocytopenia

RBC Transfusionsc

Platelet Transfusionsc


90

86

86

78

38

9


42

22

48

30


29

6

5

5


58

75

70

57

15

3


11

9

6

10


1

2

<1

1


Non-laboratoryb

Nausea

Alopecia

Vomiting

Constipation

Fatigue

Neuropathy-sensory

Diarrhea

Stomatitis/pharyngitis

Anorexia


69

49

46

42

40

29

25

22

16


6

0

6

6

3

1

3

<1

1


0

0

0

1

<1

0

0

0

0


61

17

36

37

32

27

14

13

13


3

0

2

3

5

2

<1

0

0


0

0

<1

0

0

0

0

0

0


In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively).

The following are the clinically relevant adverse reactions, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (gemcitabine plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Gemcitabin. 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.

These adverse reactions have occurred after Gemcitabin single-agent use and Gemcitabin in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemcitabin.

Nervous System – Posterior reversible encephalopathy syndrome (PRES) [ see Warnings and Precautions (5.10) ].

Cardiovascular - Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemcitabin. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disorders - Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skin - Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepatic - Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemcitabin alone or in combination with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported.

Pulmonary - Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemcitabin administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemcitabin dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renal - Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemcitabin. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Injury, Poisoning, and Procedural Complications - Radiation recall reactions have been reported [ see Warnings and Precautions (5.8) ] .

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7 DRUG INTERACTIONS

No specific drug interaction studies have been conducted. Information is available on the pharmacodynamics and pharmacokinetics of Gemcitabin in combination with cisplatin, paclitaxel, or carboplatin [ see Clinical Pharmacology (12.2 and 12.3)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. [ See Warnings and Precautions . ]

Gemcitabin can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Gemcitabin is expected to result in adverse reproductive effects. There are no adequate and well-controlled studies of Gemcitabin in pregnant women. Gemcitabin is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabin is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. 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 Warnings and Precautions (5.6) ] .

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gemcitabin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Gemcitabin in pediatric patients has not been established. Gemcitabin was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemcitabin was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.

8.5 Geriatric Use

Gemcitabin clearance is affected by age [ see Clinical Pharmacology (12.3) ]. There is no evidence, however, that unusual dose adjustments [ see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)] are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial of Gemcitabin in combination with carboplatin for recurrent ovarian cancer [ see Clinical Studies (14.1) ], 125 women treated with Gemcitabin plus carboplatin were <65 years and 50 were ≥65 years. Similar effectiveness was observed between older and younger women. There was significantly higher Grade 3/4 neutropenia in women 65 years of age or older. Overall, there were no other substantial differences in toxicity profile of Gemcitabin plus carboplatin based on age.

8.6 Renal

Hemolytic Uremic Syndrome and/or renal failure have been reported following one or more doses of Gemcitabin. 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)] .

Gemcitabin Injection 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 Warnings and Precautions (5.4) ] .

8.7 Hepatic

Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemcitabin alone or in combination with other potentially hepatotoxic drugs [ see Adverse Reactions (6.1 and 6.2)] .

Gemcitabin Injection 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 Gemcitabin Injection 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 Warnings and Precautions (5.5) ] .

8.8 Gender

Gemcitabin clearance is affected by gender [ see Clinical Pharmacology (12.3) ] . In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments [ see Dosage and Administration (2) ] are necessary in women. In general, in single-agent studies of Gemcitabin, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. There was a greater tendency in women, especially older women, not to proceed to the next cycle.

10 OVERDOSAGE

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

11 DESCRIPTION

Gemcitabin is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabin HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).

The structural formula is as follows:

The empirical formula for Gemcitabin HCl is C9H11F2N3O4 - HCl. It has a molecular weight of 299.66.

Gemcitabin HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

The clinical formulation is supplied as a sterile solution for intravenous single vial use only. Vials of Gemcitabin Injection contain either 200 mg, 1 g, or 2 g of Gemcitabin HCl (expressed as free base). Each mL contains equivalent of 38 mg of Gemcitabin in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

structural formula Gemcitabin

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gemcitabin exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis and also blocking the progression of cells through the G1/S-phase boundary. Gemcitabin is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of Gemcitabin is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, Gemcitabin diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotides, including dCTP. Second, Gemcitabin 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 Gemcitabin triphosphate into DNA (self-potentiation). After the Gemcitabin nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the Gemcitabin nucleotide and repair the growing DNA strands (masked chain termination). In CEM T lymphoblastoid cells, Gemcitabin induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.

12.2 Pharmacodynamics

Gemcitabin demonstrated dose-dependent synergistic activity with cisplatin in vitro. No effect of cisplatin on Gemcitabin triphosphate accumulation or DNA double-strand breaks was observed. In vivo, Gemcitabin showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gemcitabin was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to Gemcitabin 4 hours before cisplatin produced the greatest interaction.

12.3 Pharmacokinetics

Absorption and Distribution

The pharmacokinetics of Gemcitabin 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 Gemcitabin dose varied from 500 to 3600 mg/m2.

The volume of distribution was increased with infusion length. Volume of distribution of Gemcitabin was 50 L/m2 following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.

Gemcitabin 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 Gemcitabin was significantly influenced by duration of infusion and gender. Gemcitabin plasma protein binding is negligible.

Metabolism

Gemcitabin disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabin (<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.

The active metabolite, Gemcitabin triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for Gemcitabin triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.

Excretion

Clearance of Gemcitabin was affected by age and gender. The lower clearance in women and the elderly results in higher concentrations of Gemcitabin 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 9 shows plasma clearance and half-life of Gemcitabin following short infusions for typical patients by age and gender.

a Half-life for patients receiving a short infusion (<70 min).

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


57.0


48


57


65


55.1


41.5


61


73


79


40.7


30.7


79


94


Gemcitabin 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.

Drug Interactions

When Gemcitabin (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC patients, the clearance of Gemcitabin on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. The clearance of cisplatin in the same study was reported to be 3.94 mL/min/m2 with a corresponding half-life of 134 hours [ see Drug Interactions (7) ]. Analysis of data from metastatic breast cancer patients shows that, on average, Gemcitabin 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 Gemcitabin. Data from NSCLC patients demonstrate that Gemcitabin and carboplatin given in combination does not alter the pharmacokinetics of Gemcitabin or carboplatin compared to administration of either single-agent. However, due to wide confidence intervals and small sample size, interpatient variability may be observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Gemcitabin have not been conducted. Gemcitabin induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabin was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Gemcitabin IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day administered intravenously (about 1/1300 the human dose on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Ovarian Cancer

Gemcitabin was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemcitabin 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemcitabin on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival.

Patient characteristics are shown in Table 10. The addition of Gemcitabin to carboplatin resulted in statistically significant improvement in PFS and overall response rate as shown in Table 11 and Figure 1. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemcitabin after progression. There was not a significant difference in overall survival between arms.

a Nine patients (5 on the Gemcitabin plus carboplatin arm and 4 on the carboplatin arm) did not have baseline Eastern Cooperative Oncology Group (ECOG) performance status recorded.

b Three patients (2 on the Gemcitabin plus carboplatin arm and 1 on the carboplatin arm) had a platinum-free interval of less than 6 months.


Gemcitabine/Carboplatin


Carboplatin


Number of randomized patients


178


178


Median age, years

Range


59

36 to 78


58

21 to 81


Baseline ECOG performance status 0-1a


94%


95%


Disease Status

Evaluable

Bidimensionally measurable



7.9%

91.6%



2.8%

95.5%


Platinum-free intervalb

6-12 months

>12 months



39.9%

59.0%



39.9%

59.6%


First-line therapy

Platinum-taxane combination

Platinum-non-taxane combination

Platinum monotherapy



70.2%

28.7%

1.1%



71.3%

27.5%

1.1%

a Treatment adjusted for performance status, tumor area, and platinum-free interval.

b Partial response non-measurable disease

c Independent reviewers could not evaluate disease demonstrated by sonography or physical exam.

d Log Rank, unadjusted

e Chi Square

f Independently reviewed cohort - Gemcitabine/Carboplatin N=121, Carboplatin N=101




Gemcitabine/Carboplatin

(N=178)


Carboplatin

(N=178)


PFS

Median (95%, C.I.) months



8.6 (8.0, 9.7)



5.8 (5.2, 7.1)



p=0.0038d


Hazard Ratio (95%, C.I.)


0.72 (0.57, 0.90)




Overall Survival


Median (95%, C.I.) months


18.0 (16.2, 20.3)


17.3 (15.2, 19.3)


p=0.8977d


Hazard Ratio (95%, C.I.)


0.98 (0.78, 1.24)


Adjusteda Hazard Ratio (95%, C.I.)


0.86 (0.67, 1.10)


Investigator Reviewed

Overall Response Rate

CR

PR+PRNMb



47.2%

14.6%

32.6%



30.9%

6.2%

24.7%


p=0.0016e


Independently Reviewed

Overall Response Ratec,f

CR

PR+PRNM



46.3%

9.1%

37.2%



35.6%

4.0%

31.7%


p=0.11e


Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabin Plus Carboplatin Versus Carboplatin in Ovarian Cancer (N=356)

Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemcitabin Plus Carboplatin Versus Carboplatin in Ovarian Cancer

14.2 Breast Cancer

Data from a multi-national, randomized Phase 3 study (529 patients) support the use of Gemcitabin in combination with paclitaxel for treatment of breast cancer patients who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Gemcitabin 1250 mg/m2 was administered on Days 1 and 8 of a 21-day cycle with paclitaxel 175 mg/m2 administered prior to Gemcitabin on Day 1 of each cycle. Single-agent paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle as the control arm.

The addition of Gemcitabin to paclitaxel resulted in statistically significant improvement in time to documented disease progression and overall response rate compared to monotherapy with paclitaxel as shown in Table 12 and Figure 2. Final survival analysis results at 440 events were Hazard Ratio of 0.86 (95%, CI: 0.71 – 1.04) for the ITT population, as shown in Table 12.

a Karnofsky Performance Status.

b Based on the ITT population

c These represent reconciliation of investigator and Independent Review Committee assessments according to a predefined algorithm.


Gemcitabine/Paclitaxel


Paclitaxel


Number of patients


267


262


Median age, years

Range


53

26 to 83


52

26 to 75




Metastatic disease


97.0%


96.9%




Baseline KPSa ≥90


70.4%


74.4%




Number of tumor sites

1-2

≥3



56.6%

43.4%



58.8%

41.2%




Visceral disease


73.4%


72.9%


Prior anthracycline


96.6%


95.8%


Overall Survivalb


Median (95%, CI)


18.6 (16.5, 20.7)


15.8 (14.1, 17.3)


Hazard Ratio (95%, CI)


0.86 (0.71, 1.04)


Time to Documented Disease








Progressionc


5.2 (4.2, 5.6)


2.9 (2.6, 3.7)


p<0.0001


Median (95%, C.I.), months








Hazard Ratio (95%, C.I.)


0.650 (0.524, 0.805)


p<0.0001


Overall Response Ratec (95%, C.I.)


40.8% (34.9, 46.7)


22.1% (17.1, 27.2)


p<0.0001


Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemcitabin Plus Paclitaxel Versus Paclitaxel Breast Cancer Study (N=529)

graph figure 2: kaplan-meier curve of time to Documented disease progression in Gemcitabin plus paclitaxel versus paclitaxel breast cancer study

14.3 Non-Small Cell Lung Cancer

Data from 2 randomized clinical studies (657 patients) support the use of Gemcitabin in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC.

Gemcitabin plus cisplatin versus cisplatin: This study was conducted in Europe, the US, and Canada in 522 patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Gemcitabin 1000 mg/m2 was administered on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle. Single-agent cisplatin 100 mg/m2 was administered on Day 1 of each 28-day cycle. The primary endpoint was survival. Patient demographics are shown in Table 13. An imbalance with regard to histology was observed with 48% of patients on the cisplatin arm and 37% of patients on the Gemcitabin plus cisplatin arm having adenocarcinoma.

The Kaplan-Meier survival curve is shown in Figure 3. Median survival time on the Gemcitabin plus cisplatin arm was 9.0 months compared to 7.6 months on the single-agent cisplatin arm (Log rank p=0.008, two-sided). Median time to disease progression was 5.2 months on the Gemcitabin plus cisplatin arm compared to 3.7 months on the cisplatin arm (Log rank p=0.009, two-sided). The objective response rate on the Gemcitabin plus cisplatin arm was 26% compared to 10% with cisplatin (Fisher’s Exact p<0.0001, two-sided). No difference between treatment arms with regard to duration of response was observed.

Gemcitabin plus cisplatin versus etoposide plus cisplatin: A second, multicenter, study in Stage IIIB or IV NSCLC randomized 135 patients to Gemcitabin 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle (Table 13).

There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two-sided). The median survival was 8.7 months for the Gemcitabin plus cisplatin arm versus 7.0 months for the etoposide plus cisplatin arm. Median time to disease progression for the Gemcitabin plus cisplatin arm was 5.0 months compared to 4.1 months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemcitabin plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided).

Figure 3: Kaplan-Meier Survival Curve in Gemcitabin Plus Cisplatin Versus Cisplatin NSCLC Study (N=522)


a 28-day schedule - Gemcitabin plus cisplatin: Gemcitabin 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days.

b 21-day schedule - Gemcitabin plus cisplatin: Gemcitabin 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 1, 2, and 3 every 21 days.

c N/A Not applicable.

d Karnofsky Performance Status.

e p-value for tumor response was calculated using the two-sided Fisher’s Exact test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.


Trial


28-day Schedulea


21-day Scheduleb


Treatment Arm


Gemcitabine/

Cisplatin


Cisplatin




Gemcitabine/

Cisplatin


Cisplatin




Number of patients

Male

Female


260

182

78


262

186

76




69

64

5


66

61

5




Median age, years

Range


62

36 to 88


63

35 to 79




58

33 to 76


60

35 to 75




Stage IIIA

Stage IIIB

Stage IV


7%

26%

67%


7%

23%

70%




N/Ac

48%

52%


N/Ac

52%

49%




Baseline KPSd 70 to 80

Baseline KPSd 90 to 100


41%

57%


44%

55%




45%

55%


52%

49%






Survival

Median, months

(95%, C.I.) months



9.0

8.2, 11.0



7.6

6.6, 8.8


p=0.008





8.7

7.8, 10.1



7.0

6.0, 9.7


p=0.18




Time to Disease Progression

Median, months

(95%, C.I.) months



5.2

4.2, 5.7



3.7

3.0, 4.3


p=0.009





5.0

4.2, 6.4



4.1

2.4, 4.5


p=0.015




Tumor Response


26%


10%


p<0.0001e


33%


14%


p=0.01e

graph figure 3: kaplan-meier survival curve in Gemcitabin Plus cisplatin versus cisplatin nsclc study

14.4 Pancreatic Cancer

Data from 2 clinical trials evaluated the use of Gemcitabin in patients with locally advanced or metastatic pancreatic cancer. The first trial compared Gemcitabin to 5-Fluorouracil in patients who had received no prior chemotherapy. A second trial studied the use of Gemcitabin in pancreatic cancer patients previously treated with 5-FU or a 5-FU-containing regimen. In both studies, the first cycle of Gemcitabin was administered intravenously at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitated holding a dose) followed by a week of rest from treatment with Gemcitabin. Subsequent cycles consisted of injections once weekly for 3 consecutive weeks out of every 4 weeks.

The primary efficacy parameter in these studies was “clinical benefit response,” which is a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change. Definitions for improvement in these variables were formulated prospectively during the design of the 2 trials. A patient was considered a clinical benefit responder if either:


The first study was a multicenter (17 sites in US and Canada), prospective, single-blinded, two-arm, randomized, comparison of Gemcitabin and 5-FU in patients with locally advanced or metastatic pancreatic cancer who had received no prior treatment with chemotherapy. 5-FU was administered intravenously at a weekly dose of 600 mg/m2 for 30 minutes. The results from this randomized trial are shown in Table 14. Patients treated with Gemcitabin had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to 5-FU. The Kaplan-Meier curve for survival is shown in Figure 4. No confirmed objective tumor responses were observed with either treatment.

a Karnofsky Performance Status.

b Kaplan-Meier estimates.

c N=number of patients.

d No progression at last visit; remains alive.

e The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All other p-values were calculated using the Log rank test for difference in overall time to an event.


Gemcitabin


5-FU


Number of patients

Male

Female


63

34

29


63

34

29


Median age

Range


62 years

37 to 79


61 years

36 to 77


Stage IV disease


71.4%


76.2%


Baseline KPSa ≤70


69.8%


68.3%




Clinical benefit response


22.2%

(Nc=14)


4.8%

(Nc=3)


p=0.004e


Survival

Median

6-month probabilityb

9-month probabilityb

1-year probabilityb

Range

95% C.I. of the median



5.7 months

(N=30) 46%

(N=14) 24%

(N=9) 18%

0.2 to 18.6 months

4.7 to 6.9 months



4.2 months

(N=19) 29%

(N=4) 5%

(N=2) 2%

0.4 to 15.1+d months

3.1 to 5.1 months


p=0.0009


Time to Disease Progression

Median

Range

95% C.I. of the median



2.1 months

0.1+d to 9.4 months

1.9 to 3.4 months



0.9 months

0.1 to 12.0+d months

0.9 to 1.1 months


p=0.0013


Clinical benefit response was achieved by 14 patients treated with Gemcitabin and 3 patients treated with 5-FU. One patient on the Gemcitabin arm showed improvement in all 3 primary parameters (pain intensity, analgesic consumption, and performance status). Eleven patients on the Gemcitabin arm and 2 patients on the 5-FU arm showed improvement in analgesic consumption and/or pain intensity with stable performance status. Two patients on the Gemcitabin arm showed improvement in analgesic consumption or pain intensity with improvement in performance status. One patient on the 5-FU arm was stable with regard to pain intensity and analgesic consumption with improvement in performance status. No patient on either arm achieved a clinical benefit response based on weight gain.

Figure 4: Kaplan-Meier Survival Curve


The second trial was a multicenter (17 US and Canadian centers), open-label study of Gemcitabin in 63 patients with advanced pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The study showed a clinical benefit response rate of 27% and median survival of 3.9 months.

Figure 4: Kaplan-Meier Survival Curve

14.5 Other Clinical Studies

When Gemcitabin was administered more frequently than once weekly or with infusions longer than 60 minutes, increased toxicity was observed. Results of a Phase 1 study of Gemcitabin to assess the maximum tolerated dose (MTD) on a daily x 5 schedule showed that patients developed significant hypotension and severe flu-like symptoms that were intolerable at doses above 10 mg/m2. The incidence and severity of these events were dose-related. Other Phase 1 studies using a twice-weekly schedule reached MTDs of only 65 mg/m2 (30-minute infusion) and 150 mg/m2 (5-minute bolus). The dose-limiting toxicities were thrombocytopenia and flu-like symptoms, particularly asthenia. In a Phase 1 study to assess the maximum tolerated infusion time, clinically significant toxicity, defined as myelosuppression, was seen with weekly doses of 300 mg/m2 at or above a 270-minute infusion time. The half-life of Gemcitabin is influenced by the length of the infusion [ see Clinical Pharmacology (12.3) ] and the toxicity appears to be increased if Gemcitabin is administered more frequently than once weekly or with infusions longer than 60 minutes [ see Warnings and Precautions (5.1) ].

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Gemcitabin Injection is available in sterile single-use vials individually packaged in a carton as follows:

16.2 Storage and Handling

Unopened vials of Gemcitabin Injection are stable until the expiration date indicated on the package when stored at 2° to 8°C (36° to 46°F). Do not freeze [ see Dosage and Administration ( 2.6 and 2.7 ) ] .

17 PATIENT COUNSELING INFORMATION

17.1 Low Blood Cell Counts

Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur [ see Warnings and Precautions ] .

17.2 Pregnancy

There are no adequate and well-controlled studies of Gemcitabin in pregnant women. Based on animal studies Gemcitabin can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the risks to the fetus need to be discussed with their physician [ see Warnings and Precautions (5.6) and Use in Specific Populations (8.1) ] .

17.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Gemcitabin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [ see Use in Specific Populations (8.3) ] .



EN-3523

Manufactured by:

Zydus Hospira Oncology Private Ltd.

Ahmedabad 382-213, Gujarat, India.

for Hospira, Inc.

Lake Forest, IL 60045 USA

Product of India

Hospira Logo

CA-2915

Carton NDC 0409-0181-01

CA-2916

Carton NDC 0409-0182-01

CA-2917

Carton NDC 0409-0183-01

Gemcitabin pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Gemcitabin available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Gemcitabin destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Gemcitabin Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Gemcitabin pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."GEMCITABINE HYDROCHLORIDE INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION GEMCITABINE HYDROCHLORIDE INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION [ACTAVIS ". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "gemcitabine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "gemcitabine". http://www.drugbank.ca/drugs/DB0044... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Gemcitabin?

Depending on the reaction of the Gemcitabin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Gemcitabin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Gemcitabin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Gemcitabin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Gemcitabin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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