Gemcitabine hydrochloride

Dosage and Administration, Dosage Modifications for Non-Hematologic Adverse Reactions ( 2.5 ) 8/2024 Warnings and Precautions, Severe Cutaneous Adverse Reactions (SCARs) ( 5.3 ) 8/2024

1 INDICATIONS AND USAGE Gemcitabine for Injection is a nucleoside metabolic inhibitor indicated: • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. ( 1.1 ) • 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. ( 1.2 ) • in combination with cisplatin, for the treatment of non-small cell lung cancer. ( 1.3 ) • as a single agent for the treatment of pancreatic cancer. ( 1.4 ) 1.1 Ovarian Cancer Gemcitabine for 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 for 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 for 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 for 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. Gemcitabine for Injection is indicated for patients previously treated with fluorouracil.

2 DOSAGE AND ADMINISTRATION Gemcitabine for Injection is for intravenous use only. • Ovarian Cancer: 1000 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.1 ) • Breast Cancer: 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.2 ) • Non-Small Cell Lung Cancer: 1000 mg/m 2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m 2 over 30 minutes on Days 1 and 8 of each 21-day cycle. ( 2.3 ) • 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. ( 2.4 ) 2.1 Ovarian Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine for Injection is 1000 mg/m 2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle in combination with carboplatin AUC 4 administered intravenously on Day 1 after Gemcitabine for Injection administration. Refer to carboplatin prescribing information for additional information. Dosage Modifications Recommended Gemcitabine for Injection dosage modifications for myelosuppression are described in Tables 1 and 2 [see Warnings and Precautions (5.2) ] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ]. Table 1: Recommended Dosage Modifications for Gemcitabine for 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 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Delay Treatment Cycle Day 8 Greater than or equal to 1500 And Greater than or equal to 100,000 None 1000 to 1499 Or 75,000 to 99,999 50% of full dose Less than 1000 Or Less than 75,000 Hold Table 2: Recommended Dosage Modifications for Gemcitabine for 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 or Cycle delay for more than one week due to toxicity Permanently reduce Gemcitabine for Injection to 800 mg/m 2 on Days 1 and 8 Subsequent Occurrence If any of the above toxicities occur after the initial dose reduction: Permanently reduce Gemcitabine for Injection to 800 mg/m 2 on Day 1 only 2.2 Breast Cancer Recommended Dose and Schedule The recommended dosage of Gemcitabine for Injection is 1250 mg/m 2 intravenously over 30 minutes on Days 1 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 for Injection administration. Refer to paclitaxel prescribing information for additional information. Dosage Modifications Recommended Gemcitabine for Injection dosage modifications for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2) ] . Refer to the recommended dosage modifications for non-hematologic adverse reactions [see Dosage and Administration (2.5) ]. Table 3: Recommended Dosage Modifications for Gemcitabine for 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 1500 And Greater than or equal to 100,000 None Less than 1500 Or Less than 100,000 Hold Day 8 Greater than or equal to 1200 And Greater than 75,000 None 1000 to 1199 Or 50,000 to 75,000 75% of full dose 700 to 999 And Greater than or equal to 50,000 50% of full dose Less than 700 Or Less than 50,000 Hold 2.3 Non-Small Cell Lung Cancer Recommended Dose and Schedule 28-day schedule The recommended dosage of Gemcitabine for Injection is 1000 mg/m 2 intravenously over 30 minutes on Days 1, 8, and 15 of each 28-d …

3 DOSAGE FORMS AND STRENGTHS Gemcitabine for Injection, USP is a white to off-white lyophilized powder available in sterile single-dose vials containing 200 mg or 1 gram gemcitabine. Gemcitabine for Injection is a white to off-white lyophilized powder available in sterile single-dose vials containing 200 mg or 1 gram gemcitabine. ( 3 )

4 CONTRAINDICATIONS Gemcitabine for Injection is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis [see Adverse Reactions (6.1) ] . Patients with a known hypersensitivity to gemcitabine. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4) ] Schedule-Dependent Toxicity [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3) ] Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.4) ] Hemolytic Uremic Syndrome [see Warnings and Precautions (5.5) ] Hepatic Toxicity [see Warnings and Precautions (5.6) ] Exacerbation of Radiation Therapy Toxicity [see Warnings and Precautions (5.8) ] Capillary Leak Syndrome [see Warnings and Precautions (5.9) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10) ] The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, anemia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teyro Labs Private Limited at 1800-726-4148 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. Single Agent The data described below reflect exposure to Gemcitabine for Injection as a single agent administered at doses between 800 mg/m 2 to 1250 mg/m 2 intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent Gemcitabine for Injection are nausea/vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting, increased ALT, increased alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemcitabine for Injection due to adverse reactions. Adverse reactions resulting in discontinuation of Gemcitabine for Injection in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemcitabine for Injection in 10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 1 a Adverse Reactions b Gemcitabine for Injection /Carboplatin (N=175) Carboplatin(N=174) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades(%) Grade 3 (%) Grade 4 (%) Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] in Study 2 a Laboratory Abnormality b Gemcitabine for Injection /Paclitaxel (N=262) Paclitaxel (N=259) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Anemia 69 6 1 51 3 90% versus 16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher for patients receiving Gemcitabine for Injection with cisplatin compared to those receiving cisplatin alone. The incidence of febrile neutropenia (3% versus10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin [Between Arm Difference of ≥5% (All Grades) o …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, Gemcitabine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of Gemcitabine for Injection in pregnant women. In animal reproduction studies, gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits (see Data) . Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3) ]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. Data Animal Data Gemcitabine is embryotoxic in mice. Daily dosing of gemcitabine to pregnant mice increased the incidence of fetal malformation (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day [approximately 0.005 times the 1000 mg/m 2 clinical dose based on body surface area (BSA)]. Gemcitabine was embryotoxic and fetotoxic in rabbits. Daily dosing of gemcitabine to pregnant rabbits resulted in fetotoxicity (decreased fetal viability, reduced litter sizes, and developmental delays) and increased the incidence of fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day (approximately 0.002 times the 1000 mg/m 2 clinical dose based on BSA). 8.2 Lactation Risk Summary There is no information regarding the presence of Gemcitabine for Injection or its metabolites in human milk, or their effects on the breastfed infant or on milk production. Due to the potential for serious adverse reactions in breastfed infants from Gemcitabine for Injection, advise women not to breastfeed during treatment with Gemcitabine for Injection and for at least one week following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Gemcitabine for Injection [see Use in Specific Populations (8.1) ] . Contraception Gemcitabine for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection and for 6 months after the final dose of Gemcitabine for Injection. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Gemcitabine for Injection and for 3 months after the final dose [see Nonclinical Toxicology (13.1) ] . Infertility Males Based on animal studies, Gemcitabine for Injection may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] . It is not known whether these effects on fertility are reversible. 8.4 Pediatric Use The safety and effectiveness of Gemcitabine for Injection 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 for Injection 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 w …

12.1 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.

11 DESCRIPTION Gemcitabine is a nucleoside metabolic inhibitor. Gemcitabine hydrochloride, USP is 2’- deoxy-2’, 2’-difluorocytidine monohydrochloride (β-isomer) with the following structural formula: The empirical formula for gemcitabine hydrochloride, USP is C 9 H 11 F 2 N 3 O 4 • HCl. It has a molecular weight of 299.66 g/mol. Gemcitabine hydrochloride, USP is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder and available as 200 mg and 1 gram single-dose vials for intravenous use only. Each 200 mg vial contains 200 mg gemcitabine (equivalent to 227.7 mg gemcitabine hydrochloride, USP), 200 mg mannitol and 12.5 mg sodium acetate. Each 1 gram vial contains 1 gram gemcitabine (equivalent to 1.139 gram gemcitabine hydrochloride, USP), 1 gram mannitol, and 62.5 mg sodium acetate. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. gemcitabine-spl-image1

10 OVERDOSAGE 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 2 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Gemcitabine for Injection, USP is supplied as follows: NDC Gemcitabine for Injection, USP Package Factor 68083-148-01 200 mg Single-Dose Vial 1 vial per carton 68083-149-01 1 gram Single-Dose Vial 1 vial per carton Gemcitabine for Injection, USP is a sterile white to off-white lyophilized powder. Gemcitabine for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Storage Conditions Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Sterile, Nonpyrogenic, Preservative-free, Lyophilized. The container closure is not made with natural rubber latex.