GEMCITABINE SOL IMGSA

Gemcitabine is a nucleoside metabolic inhibitor.

The chemical name of gemcitabine

HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (β-isomer).

The structural formula is as follows

Gemcitabine HCl, USP is a white to off-white solid with a molecular formula of C 9 H 11 F 2 N 3 O 4.

• HCl and a molecular weight of 299.66 g/mol.

It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents.

Injection is a sterile solution in single-dose vials for intravenous use.

Each vial contains 200 mg, 1 g, or 2 g of gemcitabine equivalent to 227.7 mg, 1.139 g, or 2.277 g of gemcitabine HCl, USP.

Each mL contains 38 mg of gemcitabine free base in Water for Injection equivalent to 43.27 mg of gemcitabine HCl.

Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.

• in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

• in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

• in combination with cisplatin for the treatment of non-small cell lung cancer.

• as a single agent for the treatment of pancreatic cancer. 1.1 Ovarian Cancer Gemcitabine 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 Gemcitabine 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 Gemcitabine Injection in combination with cisplatin is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). 1.4 Pancreatic Cancer Gemcitabine 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.

Injection is indicated for patients previously treated with fluorouracil.

History of alcoholism History of hepatitis History of hepatic cirrhosis History of cardiovascular disease Combined chemotherapy Female likely to be pregnant Pregnancy Male of childbearing age Hepatic impairment Malmedal failure Renal impairment Liver metastasis Pregnant or likely partner Presence of anti-HBc antibodies Radiotherapy Negative hepatitis B serology Subject under 18 Live vaccines.

Mechanism of Action 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. 12.3 Pharmacokinetics 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 mg/m to 3600 mg/m 2.

The volume of distribution was increased with infusion length.

Volume of distribution of gemcitabine was 50 L/m 2 following infusions lasting <70 minutes.

For long infusions, the volume of distribution rose to 370 L/m 2.

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 sex.

Gemcitabine plasma protein binding is negligible.

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.

Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m of radiolabeled drug as a 30-minute infusion.

Within one 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.

Clearance of gemcitabine was affected by age.

The lower clearance in geriatric patients results in higher concentrations of gemcitabine for any given dose.

Differences in either clearance or volume of distribution based on or the duration of infusion result in changes in half-life and plasma concentrations.

Table 15 shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and sex.

Gemcitabine half-life for short infusions ranged from to 94 minutes, and for long infusions varied from to 638 minutes, depending on age and sex, reflecting a greatly increased volume of distribution with longer infusions.

Females have lower clearance and longer half-lives than male patients as described in Table 15.

Table 15: Gemcitabine Clearance and Half-Life for the “Typical” Patient Age Clearance Men (L/hr/m 2 ) Clearance Women (L/hr/m 2 ) Half-Life Half-life for patients receiving a <70 minute infusion.

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

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

When gemcitabine (1250 mg/m on Days and 8) and cisplatin (75 mg/m on Day 1) were administered in patients with NSCLC, the clearance of gemcitabine on Day was 128 L/hr/m and on Day was 107 L/hr/m 2.

Data from patients with

NSCLC 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.

Data from patients with metastatic breast cancer shows that 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.

Mechanism of action

Gemcitabine has significant cytotoxic activity on various human murine and tumour cells in culture.

Gemcitabine is an antimetabolic specific to the S phase of the cell cycle, a phase of DNA synthesis (deoxyribonucleic acid).

It blocks, in certain circumstances, the cell progression beyond the G1/S phase.

In vitro, the cytotoxic action of gemcitabine depends on both its concentration and time.

In tumour models in animals, the antitumor activity of gemcitabine depends on the regimen of administration.

Administered daily, gemcitabine causes death of animals with minimal antitumor activity.

However, when the enzyme of the enzyme is reduced by the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the enzyme of the cytotabine (dPCP) is metabolised in nonlethal doses provided with an excellent antitumoral action on a large number of tumours in the mouse.

• Neutropenia (Very common)
• Hyperbilirubinaemia (Common)
• Proteinuria (Very common)
• Alkaline phosphates (increase) (Very common)
• Granulopenia (Very common)
• Transaminases (increase) (Very common)
• Gamma GT (increase) (Rare)
• Radic reactivation Allergic dermatitis (Very common)
• Hypersudation (Common)
• Pruritus (Common)
• Alopecia (Very common)
• Skin desquamation (Rare)
• Skin ulcer (Rare)
• Bully dermatosis (Very rare)
• Vesicular rash (Rare)
• Severe skin reaction (Rare)
• Generalised acute exanthemous pusulosis
• Musculoskeletal ulcer Stevens-Johnson Syndrome Pseudocellulite Lyell's syndrome Frisher (Common)
• Edema (Very common)
• Fever (Common)
• Peripheral edema (Very common)
• Fatigue (Common)
• Deaths (Very rare)
• Asthenia Feeling drunk Irflu pseudo-influenza syndrome Face edema
• Leucopenia (Very common)
• Cardiac aplasia (Very common)
• Thrombocytopenia (Very common)
• Febrile neutropenia (Common)
• Anemia (Very common)
• Thrombocytosis (Very rare)
• Haemorrhage
• Severe hepatitis (Uncommon)
• Hepatic impairment (Very rare)
• Hepatitis Anaphylactic reaction (Very rare)
• Anaphylactoid reaction (Very rare)
• Infection (Common)
• Sepsis Injection site reaction (Very rare)
• Anorexia (Common)
• Oral ulceration (Common)
• Stomatitis (Common)
• Rhinite (Common)
• Insomnia (Common)
• Heart failure (Rare)
• Vasculitis (Very rare)
• Myocardial infarction (Rare)
• Gangrene (Very rare)
• Hypotension (Rare)
• Hair Leak Syndrome (Very rare) supraventricular arrhythmia (Rare)
• Thrombotic microangiopathy (Very rare)
• Arrhythmia Malaise Constipation (Common)
• Nausea (Very common)
• Diarrhoea (Common)
• Vomiting (Very common)
• Ischemic colitis Sleeping (Common)
• Muscle pain (Common)
• Polymyositis Headache (Common)
• Difficult to sleep (Very common)
• Somnolence (Common)
• Reversible posterior encephalopathy syndrome (Very rare)
• Peripheral sensory neuropathy
• Stroke Multifocal motor neuropathy Pulmonary edema (Uncommon)
• Dyspnoea (Very common)
• Bronchospasm (Uncommon)
• Cough (Common)
• Acute respiratory distress syndrome (Rare)
• Pulmonary eosinophilia Interstitial pneumopathy Haematuria (Very common)
• Renal impairment (Rare)
• Hemolytic and uremic syndrome (Rare).

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, monitor with appropriate blood counts and provide supportive therapy, as necessary.

Injection is contraindicated in patients with a known hypersensitivity to gemcitabine.

Reactions include anaphylaxis.

Patients with a known hypersensitivity to gemcitabine.

Injection is for intravenous use only.

• Ovarian Cancer: 1000 mg/m 2 over 30 minutes on Days and 8 of each 21-day cycle.

• Breast Cancer: 1250 mg/m 2 over 30 minutes on Days and 8 of each 21-day cycle.

• Non-Small Cell Lung Cancer: 1000 mg/m 2 over 30 minutes on Days 1, 8, and of each 28-day cycle or 1250 mg/m 2 over 30 minutes on Days and 8 of each 21-day cycle.

• Pancreatic Cancer: 1000 mg/m 2 over 30 minutes once weekly for the first 7 weeks, then one-week rest, then once weekly for 3 weeks of each 28-day cycle. 2.1 Ovarian Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 intravenously over 30 minutes on Days and 8 of each 21-day cycle, in combination with carboplatin AUC 4 administered intravenously on Day 1 after Gemcitabine Injection administration.

Refer to carboplatin prescribing information for additional information.

Dosage Modifications Recommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Tables and 2.

Refer to the recommended dosage modifications for non-hematologic adverse reactions.

Table 1: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Ovarian Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 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 And Greater than or equal to 100,000 None to 1499 Or to 99,999 50% of full dose Less than 1000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dosage Modification Initial Occurrence.

• Absolute neutrophil count less than 500 x 10 6 /L for more than 5 days or.

• Absolute neutrophil count less than 100 x 10 6 /L for more than 3 days or.

• Febrile neutropenia or.

• Platelets less than 25,000 x 10 6 /L.

• Cycle delay for more than one week due to toxicity Permanently reduce Gemcitabine Injection to 800 mg/m on Days and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce Gemcitabine Injection dose to 800 mg/m on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine Injection is 1250 mg/m 2 intravenously over 30 minutes on Days and 8 of each 21-day cycle in combination with paclitaxel 175 mg/m 2 administered as a 3-hour intravenous infusion on Day 1 before Gemcitabine Injection administration.

Refer to paclitaxel prescribing information for additional information.

Dosage Modifications Recommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Table 3.

Table 3: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Day 1 Greater than or equal to 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 And Greater than 75,000 None to 1199 Or to 75,000 75% of full dose to 999 And Greater than or equal to 50,000 50% of full dose Less than 700 Or Less than 50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule 28-day schedule The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 intravenously over 30 minutes on Days 1, 8, and of each 28-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after Gemcitabine Injection administration. 21-day schedule The recommended dosage of Gemcitabine Injection is 1250 mg/m 2 intravenously over 30 minutes on Days and 8 of each 21-day cycle in combination with cisplatin 100 mg/m 2 administered intravenously on Day 1 after Gemcitabine Injection administration.

Refer to cisplatin prescribing information for additional information.

Dosage Modifications Recommended dosage modifications for Gemcitabine Injection myelosuppression are described in Table 4.

Refer to the recommended dosage modifications for non-hematologic adverse reactions. 2.4 Pancreatic Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine Injection is 1000 mg/m 2 intravenously over 30 minutes.

• Weeks to 8: weekly dosing for the first 7 weeks followed by one-week rest.

• After week 8: weekly dosing on Days 1, 8, and of each 28-day cycle.

Dosage Modifications Recommended dosage modifications for Gemcitabine Injection for myelosuppression are described in Table 4.

Table 4: Recommended Dosage Modifications for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute Neutrophil Count (x 10 6 /L) Platelet Count (x 10 6 /L) Dosage Modification Greater than or equal to And Greater than or equal to 100,000 None to 999 Or to 99,999 75% of full dose Less than 500 Or Less than 50,000 Hold 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions Permanently discontinue Gemcitabine Injection for any of the following:

• Severe Cutaneous Adverse Reactions (SCARs).

• Unexplained dyspnea or evidence of severe pulmonary toxicity.

• Hemolytic uremic syndrome (HUS) or severe renal impairment.

• Severe hepatic toxicity.

• Capillary leak syndrome (CLS).

• Posterior reversible encephalopathy syndrome (PRES) Withhold Gemcitabine Injection or reduce dose by 50% for other Grade 3 or 4 non-hematological adverse reactions until resolved.

No dose modifications are recommended for alopecia, nausea, or vomiting. 2.6 Preparation Gemcitabine Injection is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

Exercise caution and wear gloves when preparing Gemcitabine Injection solutions.

Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine Injection contacts the skin or mucus membranes.

Death has occurred in animal studies due to dermal absorption.

• Withdraw the calculated dose from the vial and discard any unused portion.

• Prior to administration, dilute the appropriate amount of drug with 0.9% Sodium Chloride Injection to a minimum final concentration of at least 0.1 mg/mL.

• Store diluted Gemcitabine Injection solution for no more than 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F) .

Discard if not used within 24 hours after dilution.

• Visually inspect for particulate matter or discoloration prior to administration and discard if particulate matter or discoloration is observed.

• No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

Injection appears as a clear and colorless to light straw-colored solution.

• 200 mg/5.26 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-616-10.

• 1 g/26.3 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-617-30.

• 2 g/52.6 mL (38 mg/mL), sterile solution in a single-dose glass vial per package, NDC 67457-618-10 Store at 2° to 8°C (36° to 46°F).

Do not freeze.

Injection is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

Based on animal data and its mechanism of action, Gemcitabine Injection 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 reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits.

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 miscarriages in clinically recognized pregnancies is to 4% and to 20%, respectively.

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 [about 0.005 times the 1000 mg/m 2 clinical dose based on body surface area (BSA).

Gemcitabine is 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 (about 0.002 times the 1000 mg/m 2 clinical dose based on BSA).

The safety and effectiveness of gemcitabine have not been established in pediatric patients.

The safety and pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia.

The maximum tolerated dose was 10 mg/m 2 /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 2 /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 myelosuppression, febrile neutropenia, increased serum transaminases, nausea, and rash/desquamation.

No meaningful clinical activity was observed in this trial.

In clinical studies which enrolled 979 patients with various malignancies who received single agent gemcitabine, no overall differences in safety were observed between patients aged and older and younger patients, with the exception of a higher rate of Grade to 4 thrombocytopenia in older patients as compared to younger patients.

In a randomized trial in women with ovarian cancer (Study 1), 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 to 4 neutropenia in women 65 years of age or older.

Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients' age.