Fetroja Drug Information

Dosage Adjustments in Patients with CLcr Less Than 60 mL/min (Including Patients Undergoing Intermittent HD or CRRT), and CLcr 120 mL/min or Greater Dosage Adjustments in Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dosage adjustment of FETROJA is recommended in patients with CLcr less than 60 mL/min (Table 1). For patients undergoing intermittent HD, start the dosing of FETROJA immediately after the completion of HD. For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly.

Table 1 Recommended Dosage of FETROJA for Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dosage Adjustments in Patients Receiving CRRT For patients receiving CRRT, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF), the dosage of FETROJA should be based on the effluent flow rate in CRRT (see Table 2 ). These recommendations are intended to provide initial dosing in patients receiving CRRT. Dosing regimens may need to be tailored based on residual renal function and patient's clinical status.

Table 2 Dosage Adjustments in Patients with CLcr 120 mL/min or Greater For patients with CLcr greater than or equal to 120 mL/min, FETROJA 2 grams administered every 6 hours by IV infusion over 3 hours is recommended.

Preparation of FETROJA Solution for Administration FETROJA is supplied as a sterile, lyophilized powder that must be reconstituted and subsequently diluted using aseptic technique prior to intravenous infusion. Preparation of Doses Reconstitute the powder for injection in the FETROJA vial with 10 mL of either 0.9% sodium chloride injection, USP or 5% dextrose injection, USP and gently shake to dissolve. Allow the vial(s) to stand until the foaming generated on the surface has disappeared (typically within 2 minutes).

The reconstituted solution will have a final volume of approximately 11.2 mL and concentration of 0.089 gram/mL. The reconstituted solution is for intravenous infusion only after dilution in an appropriate infusion solution. To prepare the required doses, withdraw the appropriate volume of reconstituted solution from the vial according to Table 3 below.

Add the withdrawn volume to a 100 mL infusion bag containing 0.9% sodium chloride injection, USP or 5% dextrose injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. FETROJA infusions are clear, colorless solutions.

Discard any unused FETROJA solution in the vial (see Table 3 ). Table 3 Preparation of

Drug Compatibility

FETROJA solution for administration is compatible with: 0.9% sodium chloride injection, USP 5% dextrose injection, USP The compatibility of FETROJA solution for administration with solutions containing other drugs or other diluents has not been established.

Storage of Reconstituted Solutions Reconstituted FETROJA

Upon reconstitution with the appropriate diluent, the reconstituted FETROJA solution in the vial should be immediately transferred and diluted into the infusion bag. Reconstituted FETROJA can be stored for up to 1 hour at room temperature in the vial. Discard any unused reconstituted solution.

Diluted FETROJA Infusion Solution The diluted FETROJA infusion solution in the infusion bag is stable for up to 6 hours at room temperature. The diluted FETROJA infusion solution in the infusion bag may also be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours, protected from light; and then the infusion should be completed within 6 hours at room temperature.

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. Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). Approximately 96% of patients were White, most were from Europe, and 55% were female.

Patients across treatment arms received treatment for a median duration of 9 days. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).

Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1. Table 4 Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 s of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritus Psychiatric disorders: insomnia, restlessness Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). Doses of study treatments were adjusted based on renal function.

Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days.

The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests. Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial. Table 5 Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 s of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2: Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of FETROJA. 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 disorders: neutropenia, eosinophilia Renal and urinary disorders: chromaturia

Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ). Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice).

No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning.

No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose.

Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.

FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA.

There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session.