Avgemsi Drug Information

Preparation AVGEMSI is a hazardous drug

Follow applicable special handling and disposal procedures. 1 Exercise caution and wear gloves when preparing AVGEMSI solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if AVGEMSI contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption.

After first use, store the partially used multiple-dose vial in the original carton, refrigerated at 2°C to 8°C (36ºF to 46°F) for up to 14 days. Discard unused portion of the multiple-dose vial after 14 days. Preparation for Intravenous Infusion Administration Withdraw the calculated dose from the vial.

Prior to administration, dilute the appropriate amount of drug with 0.9% Sodium Chloride Injection, USP to a minimum final concentration of at least 0.1 mg/mL. Store diluted AVGEMSI solution for no more than 24 hours at controlled room temperature of 20°C to 25°C (68°F to 77°F). Discard AVGEMSI solution 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.

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 as a single agent administered at doses between intravenously over 30 minutes once weekly in 979 patients with various malignancies. The most common (≥20%) adverse reactions of single agent gemcitabine 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 due to adverse reactions. Adverse reactions resulting in discontinuation of gemcitabine in 2% of 979 patients were cardiovascular adverse reactions (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of gemcitabine in <1% of 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.

Tables 5 and 6 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 6. Table 5: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Single Agent Gemcitabine a 0 Table 6: Selected Laboratory Abnormalities Occurring in Patients Receiving Single Agent Gemcitabine a 0 Additional adverse reactions include the following: Transfusion requirements: Red blood cell transfusions, asthenia, anorexia, headache, cough, chills, myalgia, insomnia, rhinitis, sweating, and/or malaise (19%) Infection: Sepsis (<1%) Extravasation: Injection-site reactions (4%) Allergic: Bronchospasm (<2%); anaphylactoid reactions Ovarian Cancer Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with carboplatin arm, reported in a randomized trial (Study 1) of gemcitabine with carboplatin (n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy.

Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine /carboplatin arm. Breast Cancer Tables 9 and 10 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated. The requirement for dose reduction of paclitaxel were higher for patients in the gemcitabine /paclitaxel arm (5% versus 2%).

The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms. Table 9: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel in Study 2 a: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel in Study 2 a 0 Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the gemcitabine with paclitaxel arm compared with the paclitaxel arm (1.9% versus 0). Non-Small Cell Lung Cancer Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC.

Patients randomized to gemcitabine with cisplatin received a median of 4 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. 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.

Table 11: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin in Study 3 a: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Cisplatin and at Higher Incidence than in Patients Receiving Single Agent Cisplatin in Study 3 a present the incidence of selected adverse reactions and laboratory abnormalities occurring in ≥10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC. Patients in the gemcitabine/cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% in the GC arm and 68% in the EC arm.

The incidence of hospitalizations for adverse reactions was 22% in the GC arm and 27% in the EC arm. The proportion of patients who discontinued treatment for adverse reactions was higher in the GC arm (14% versus 8%). The proportion of patients who were hospitalized for febrile neutropenia was lower in the GC arm (7% versus 12%).

There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in the GC arm. Table 13: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4 a: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study Postmarketing Experience The following adverse reactions have been identified during postapproval use of gemcitabine. 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.

Blood and Lymphatic System: Thrombotic microangiopathy (TMA) Cardiovascular: Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias Vascular: Peripheral vasculitis, gangrene, capillary leak syndrome Skin: Cellulitis; pseudocellulitis; severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP); desquamation and bullous skin eruptions Hepatic: Hepatic failure, hepatic veno-occlusive disease Pulmonary: Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, adult respiratory distress syndrome (ARDS), pulmonary eosinophilia Nervous System: Posterior reversible encephalopathy syndrome (PRES)

Pregnancy Risk Summary Based on animal data and its mechanism of action, AVGEMSI 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 (see Data).

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 2-4% and 15-20% respectively. Data Animal Data 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. 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).

Pediatric Use 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.

AVGEMSI is contraindicated in patients with a known hypersensitivity to gemcitabine. Reactions include anaphylaxis. Patients with a known hypersensitivity to gemcitabine.

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.