MECITABINE

Gemcitabine is a nucleoside analog and a chemotherapeutic agent.

It was originally investigated for its antiviral effects, but it is now used as an anticancer therapy for various cancers.

Gemcitabine is a cytidine analog with two fluorine atoms replacing the hydroxyl on the ribose.

As a prodrug, gemcitabine is transformed into its active metabolites that work by replacing the building blocks of nucleic acids during DNA elongation, arresting tumour growth and promoting apoptosis of malignant cells.

The structure, metabolism, and mechanism of action of gemcitabine are similar to cytarabine, but gemcitabine has a wider spectrum of antitumour activity.

Gemcitabine is marketed as

Gemzar and it is available as intravenous injection.

It is approved by the

FDA to treat advanced ovarian cancer in combination with carboplatin, metastatic breast cancer in combination with paclitaxel, non-small cell lung cancer in combination with cisplatin, and pancreatic cancer as monotherapy.

It is also being investigated in other cancer and tumour types.

Gemcitabine is a chemotherapeutic agent used as monotherapy or in combination with other anticancer agents: In combination with carboplatin, it is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

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

In combination with cisplatin, gemcitabine is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage Intravenous) non-small cell lung cancer (NSCLC) .

Dual therapy with cisplatin is also used to treat patients with Stage Intravenous (locally advanced or metastatic) transitional cell carcinoma (TCC) of the bladder.

Gemcitabine is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage Intravenous) adenocarcinoma of the pancreas.

Gemcitabine is indicated for patients previously treated with fluorouracil.

Intravesical system of gemcitabine is used to treat adults with Bacillus Calmette-Guérin (BCG)-unresponsive, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) , with or without papillary tumours.

Gemcitabine is a nucleoside analog that mediates its antitumour effects by promoting apoptosis of malignant cells undergoing DNA synthesis.

More specifically, it blocks the progression of cells through the G1/S-phase boundary.

Gemcitabine demonstrated cytotoxic effects against a broad range of cancer cell lines in vitro.

It displayed schedule-dependent antitumour activity in various animal models and xenografts from human non-small cell lung cancer (NSCLC) and pancreatic cancer.

Therefore, the antineoplastic effects of gemcitabine are enhanced through prolonged infusion time rather than higher dosage.

Gemcitabine inhibited the growth of human xenografts from carcinoma of the lung, pancreas, ovaries, head and neck, and breast.

In mice, gemcitabine inhibited the growth of human tumour xenografts from the breast, colon, lung or pancreas by 69-99%.

In clinical trials of advanced

NSCLC, gemcitabine monotherapy produced objective response rates ranging from 18-26%, with a median duration of response ranging from 3.3-12.7 months.

Overall median survival time was 6.2-12.3 months.

The combined use of cisplatin and gemcitabine produced better objective response rates compared to monotherapy.

In patients with advanced pancreatic cancer, objective response rates in patients ranged from 5.to 12%, with a median survival duration of 3.9-6.3 months.

II trials involving patients with metastatic breast cancer, treatment with gemcitabine alone or with adjuvant chemotherapies resulted in response rate ranging from 13-42% and median survival duration ranging from 11.5-17.8 months.

In metastatic bladder cancer, gemcitabine has a response rate 20-28%.

II trials of advanced ovarian cancer, patients treated with gemcitabine had response rate of 57.1%, with progression free survival of 13.4 months and median survival of 24 months.

Gemcitabine causes dose-limiting myelosuppression, such as anemia, leukopenia, neutropenia, and thrombocytopenia; however, events leading to discontinuation tend to occur less than 1% of the patients.

Gemcitabine can elevate

ALT, AST and alkaline phosphatase levels.

Cross-linking/alkylation Ribonucleoside-diphosphate reductase large subunit Inhibitor Ribonucleoside-diphosphate reductase subunit M2 Inhibitor + 1 more target.

Peak plasma concentrations of gemcitabine range from 10-40 mg/L following a 30-minute intravenous infusion, and are reached at 15-30 minutes.

One study showed that steady-state concentrations of gemcitabine showed a linear relationship to dose over the dose range 53-1000 mg/m 2.

Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells.

In one study, the C max of gemcitabine triphosphate in peripheral blood mononuclear cells occurred within 30 minutes of the end of the infusion period and increased increased proportionally with gemcitabine doses of up to 350 mg/m 2.

In patients with various solid tumours, the volume of distribution increased with infusion length.

The volume of distribution of gemcitabine was 50 L/m 2 following infusions lasting less than 70 minutes.

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

Gemcitabine triphosphate, the active metabolite of gemcitabine, accumulates and retains in solid tumour cells in vitro and in vivo.

It is not extensively distributed to tissues after short infusions that last less than 70 minutes.

It is not known whether gemcitabine crosses the blood-brain barrier, but gemcitabine is widely distributed into tissues, including ascitic fluid.

In rats, placental and lacteal transfer occurred rapidly at five to 15 minutes following drug administration.

Following administration and uptake into cancer cells, gemcitabine is initially phosphorylated by deoxycytidine kinase (dCK), and to a lower extent, the extra-mitochondrial thymidine kinase to form gemcitabine monophosphate (dFdCMP). dFdCMP is subsequently phosphorylated by nucleoside kinases to form active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP).

Gemcitabine is also deaminated intracellularly and extracellularly by cytidine deaminase to its inactive metabolite 2′,2′-difluorodeoxyuridine or 2'-deoxy-2',2'-difluorouridine (dFdU).

Deamination occurs in the blood, liver, kidneys, and other tissues, 1 and this metabolic pathway accounts for most of drug clearance. 3, 6 Hover over products below to view reaction partners Gemcitabine Gemcitabine Monophosphate Gemcitabine diphosphate Gemcitabine triphosphate 2′,2′-difluorodeoxyuridine monophosphate 2',2'-Difluorodeoxyuridine.

Gemcitabine mainly undergoes renal excretion.

Within a week following administration of a single dose of 1000 mg/m 2 infused over 30 minutes, about 92-98% of the dose was recovered in urine where 89% of the recovered dose was excreted as difluorodeoxyuridine (dFdU) and less than 10% as gemcitabine.

Monophosphate, diphosphate, or triphosphate metabolites of gemcitabine are not detectable in urine.

In a single-dose study, about 1% of the administered dose was recovered in the feces.

Following intravenous infusions lasting less than 70 minutes, the terminal half-life ranged from 0.7-1.6 hours.

Following infusions ranging from 70-285 minutes, the terminal half-life ranged from 4.1-10.6 hours.

Females tend to have longer half-lives than male patients.

Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells.

The terminal half-life of gemcitabine triphosphate, the active metabolite, from mononuclear cells ranges from 1.7-19.4 hours.

Following intravenous infusions lasting less than 70 minutes, clearance ranged from 41-92 L/h/m in males and ranged from 31-69 L/h/m in females.

Clearance decreases with age.

Females have about 30% lower clearance than male patients.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

The oral

LD is 333 mg/kg in mice and >500 mg/kg in rats.

The dermal

LD in rabbits is >1000 mg/kg.

There is no known antidote for gemcitabine overdose.

In a dose-escalation study, patients were administered a single dose of gemcitabine as high as 5700 mg/m 2 administered by intravenous infusion over 30 minutes every two weeks: main observed toxicities were myelosuppression, paresthesia, and severe rash.

In the event of a suspected drug overdose, blood counts should be monitored, and patients should be provided with 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.