Gemcitabine Form

U.S. Food and Drug Administration (FDA)-Approved Indications

Compendial Uses

Hodgkin lymphoma

T-Cell lymphomas

Gemcitabine (brand name Gemzar) is a nucleoside metabolic inhibitor that 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

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The FDA has approved gemcitabine for the following indications:

Breast Cancer

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either gemcitabine 1250 mg/m

on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m

administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m

on Day 1 of each 21-day cycle (n=262). The major efficacy outcome measure was time to documented disease progression. A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in median time to documented disease progression (5.2 months in the gemcitabine/paclitaxel group compared with 2.9 months in the paclitaxel group; p < 0.0001) and overall response rate (40.8% in the gemcitabine/paclitaxel group compared with 22.1% in the paclitaxel group; p < 0.0001) compared to paclitaxel alone. There was no significant difference in overall survival (18.6 months in the gemcitabine/paclitaxel group compared with 15.8 months in the paclitaxel group)

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Non-Small Cell Lung Cancer

The efficacy of gemcitabine was evaluated in two randomized, multicenter trials

Study 3: 28-Day Schedule A multinational, randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive either gemcitabine 1000 mg/m

on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m

on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m

on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival. A total of 522 patients were enrolled. Demographics and baseline characteristics were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma. The median survival was 9.0 months in the gemcitabine/cisplatin group compared with 7.6 months in the cisplatin group for Study 3; p = 0.008. The tumor response rate was 26% in the gemcitabine/cisplatin group compared with 10% in the cisplatin group for Study 3; p < 0.0001.

Study 4: 21-Day Schedule A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive either gemcitabine 1250 mg/m

on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m

on Day 1 after gemcitabine administration or etoposide 100 mg/m

intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m

on Day 1 of each 21 -day cycle. The major efficacy outcome measure was response rate. A total of 135 patients were enrolled. There was no significant difference in survival between the two treatment arms (8.7 months in the gemcitabine/cisplatin group compared with 7.0 months in the etoposide/cisplatin group for Study 4; p = 0.18). The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm was 33% compared to 14% on the etoposide e with cisplatin arm (Fisher’s Exact p=0.01, two-sided). The tumor response rate was 33% in the gemcitabine/cisplatin group compared with 14% in the etoposide/cisplatin group for Study 4; p = 0.01.

Ovarian Cancer

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m

on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n=178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n=178). The major efficacy outcome measure was progression-free survival (PFS). A total of 356 patients were enrolled. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS (8.6 months in the gemcitabine/carboplatin group compared with 5.8 months in the carboplatin group; p = 0.0038) and overall response rate by investigator review (46.2% in the gemcitabine/carboplatin group compared with 30.9% in the carboplatin group; p = 0.0016). Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms (18 months in the gemcitabine/carboplatin group compared with 17.3 months in the carboplatin group; p = 0.8977) (Eli Lilly 2019).

Pancreatic Cancer

The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles. The major efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to have had a clinical benefit response if either of the following occurred: The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR the patient was stable on all of the aforementioned parameters and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm (Eli Lilly 2019).

Gemcitabine with Pazopanib or Gemcitabine with Docetaxel for the Treatment of Soft-Tissue Sarcoma

Somaiah et al (2021) noted that therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. In an open-label, randomized, multi-center, phase- II clinical trial, these researchers examined the safety and effectiveness of combined gemcitabine plus pazopanib, a multi-tyrosine kinase inhibitor (TKI) with activity in STS. This trial enrolled patients with advanced non-adipocytic STS who had received prior anthracycline-based therapy. Subjects were assigned 1:1 to receive gemcitabine at a dose of 1,000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Cross-over was allowed at the time of disease progression. This trial employed a non-comparative statistical design based on the precision of 95 % confidence intervals (CIs) for reporting the primary endpoints of median PFS and rate of grade 3 or worse adverse events (AEs) for these 2 regimens based on the intent-to-treat (ITT) patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (p = 0.3, log-rank test). The best overall response of stable disease (SD) or better (complete response [CR] + partial response [PR] + SD) was the same for both treatment arms (64 % for both the G+T and G+P arms). The rate of related grade 3 or worse AEs was 82 % for the G+T arm and 78 % for the G+P arm. Related grade 3 or worse AEs occurring in 10 % or more of patients in the G+T and G+P arms were anemia (36 % and 20 %, respectively), fatigue (29 % and 13 %, respectively), thrombocytopenia (53 % and 49 %, respectively), neutropenia (20 % and 49 %, respectively), lymphopenia (13 % and 11 %, respectively), and hypertension (2 % and 20 %, respectively). The authors concluded that the findings of this trial suggested the similarity of the G+P regimen compared with G+T with regard to effectiveness and tolerability. In patients who are unsuitable for treatment with G+T (because of a contraindication or intolerance to docetaxel), G+P would be a reasonable alternate regimen for the 2nd-line treatment of those with metastatic non-adipocytic sarcomas.

Nivolumab, Gemcitabine, and Cisplatin or Nivolumab and Ipilimumab in Previously Untreated Advanced Biliary Cancer

Sahai et al (2022) stated that gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC). The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors. In a phase-II clinical trial, patients 18 years of age or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 1 were randomized across 6 academic centers. Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks. Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks. Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5 % women with a median age of 62.5 years. The observed primary outcome of 6-month PFS rates in the evaluable population was 59.4 % in Arm A and 21.2 % in Arm B. The median PFS and OS in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment. The most common treatment-related grade-3 or higher hematologic AE was neutropenia in 34.3 % (Arm A) and non-hematologic AEs were fatigue (8.6 % Arm A) and elevated transaminases (9.1 % Arm B). The authors concluded that the addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS. Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggested benefit in a small cohort of patients.

Criteria for Initial Approval

Aetna considers gemcitabine (Gemzar, Infugem, or generic gemcitabine) medically necessary for the following indications:

Aetna considers gemcitabine experimental and investigational for all other indications.

Continuation of Therapy

Aetna considers continuation of gemcitabine (Gemzar, Infugem, or generic gemcitabine) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Gemcitabine (Gemzar) is supplied as 200 mg or 1 gram lyophilized powder in single-dose vials for reconstitution for intravenous infusion. Additionally, gemcitabine (Infugem) is supplied as single-dose premixed infusion bags containing 10 mg/mL of gemcitabine in 0.9% sodium chloride: 1200 mg in 120 mL, 1300 mg in 130 mL, 1400 mg in 140 mL, 1500 mg in 150 mL, 1600 mg in 160 mL, 1700 mg in 170 mL, 1800 mg in 180 mL, 1900 mg in 190 mL, 2000 mg in 200 mL, and 2200 mg in 220 mL for intravenous infusion.

The recommended dosing is as follows:

Ovarian Cancer

Administer 1000 mg/m

over 30 minutes on Days 1 and 8 of each 21-day cycle.

Breast Cancer

Administer 1250 mg/m

over 30 minutes on Days 1 and 8 of each 21-day cycle.

Non-Small Cell Lung Cancer

Administer 1000 mg/m

over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m

over 30 minutes on Days 1 and 8 of each 21-day cycle.

Pancreatic Cancer

Administer 1000 mg/m

over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly

ays 1, 8, and 15 of each 28-day cycle.

Source: Eli Lilly, 2019; Meitheal Pharmaceuticals, 2019

Gemcitabine is also available as a generic formulation.