DRUG INTERACTIONS

­ Use alternate testing methods to confirm positive results of dipstick tests (urine protein, ketones, or occult blood). 

WARNINGS AND PRECAUTIONS

 Increase in All-Cause Mortality in Patients With Carbapenem-Resistant Gram-Negative Bacterial Infections:

An increase in all-cause mortality was observed in -treated patients compared to those treated with best available therapy (BAT).

ADVERSE REACTIONS

­ The most frequently occurring adverse reactions in greater than or equal to 2% of patients treated with FETROJA were diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, elevations in liver tests, headache, hypokalemia, nausea, and vomiting.

WARNINGS AND PRECAUTIONS

 Increase in All-Cause Mortality in Patients With Carbapenem-Resistant Gram-Negative Bacterial Infections:

An increase in all-cause mortality was observed in FETROJA-treated patients compared to those treated with best available therapy (BAT).

Reserve FETROJA for use in patients who have limited or no alternative treatment options for the treatment of cUTI.

Closely monitor the clinical response to therapy in patients with cUTI.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving betalactam antibacterial drugs.

Hypersensitivity was observed with FETROJA.

Cross-hypersensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue FETROJA. 

Clostridioides difficile-Associated Diarrhea (CDAD):

CDAD has been reported with nearly all systemic antibacterial agents, including FETROJA. Evaluate if diarrhea occurs. 

 Seizures and Other Central Nervous System (CNS) Adverse Reactions:

CNS adverse reactions such as seizures have been reported with FETROJA. If focal tremors, myoclonus, or seizures occur, evaluate patients to determine whether FETROJA should be discontinued. 

 PATIENT COUNSELING INFORMATION

Serious Allergic Reactions-                                                                                         Advise patients and their families that allergic reactions, including serious allergic reactions, could occur with FETROJA and that serious reactions require immediate treatment.

Ask patients about any previous hypersensitivity reactions to FETROJA, other beta-lactams (including cephalosporins), or other allergens 

Potentially Serious Diarrhea-                                                                                  Advise patients and their families that diarrhea is a common problem caused by antibacterial drugs, including FETROJA. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection.

If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider 

Seizures-                                                                                                                 Counsel patients on the implication of cephalosporins in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced and in patients with a history of epilepsy 

Antibacterial Resistance-                                                                                          Patients should be counseled that antibacterial drugs including FETROJA should only be used to treat bacterial infections. They do not treat viral infections (e.g., influenza, common cold).

When FETROJA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may                                      (1) decrease the effectiveness of the immediate treatment and                                       (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FETROJA or other antibacterial drugs in the future.

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

FETROJA is an antibacterial drug.

2. Pharmacodynamics                                                                                                  The percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the minimum inhibitory concentration (MIC) against the infecting organism best correlates with antibacterial activity in neutropenic murine thigh and lung infection models with Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia.

The in vivo animal pneumonia studies showed that the antibacterial activity of cefiderocol was greater at the human equivalent dosing regimen of 3­ hour infusion compared to that of 1-hour infusion.

Cardiac Electrophysiology                                                                                             At doses 1 and 2 times the maximum recommended dosage, FETROJA does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics                                                                                                        In cUTI patients with CLcr 60 mL/min or greater, the mean cefiderocol Cmax was 138 mg/L and AUC was 394.7 mg·hr/L (as 1184 mg·hr/L of daily AUC) after multiple (every 8 hours) FETROJA 2-gram doses infused over 1 hour (1/3 of the recommended infusion duration).

In healthy volunteers, the mean cefiderocol Cmax and AUC was 89.7 mg/L and 386 mg·hr/L, respectively, after a single FETROJA 2-gram dose was infused over 3 hours. Cefiderocol Cmax and AUC increased proportionally with dose.

Distribution                                                                                                                    The geometric mean (±SD) cefiderocol volume of distribution was 18.0 (±3.36) L. Plasma protein binding, primarily to albumin, of cefiderocol is 40% to 60%.

Elimination                                                                                                               Cefiderocol terminal elimination half-life is 2 to 3 hours. The geometric mean (±SD) cefiderocol clearance is estimated to be 5.18 (±0.89) L/hr. 

Metabolism                                                                                                            Cefiderocol is minimally metabolized [less than 10% of a single radiolabeled cefiderocol dose of 1 gram (0.5 times the approved recommended dosage) infused over 1 hour].

Excretion                                                                                                                  Cefiderocol is primarily excreted by the kidneys.                                                             After a single radiolabeled cefiderocol 1-gram (0.5 times the approved recommended dosage) dose infused over 1 hour, 98.6% of the total radioactivity was excreted in urine (90.6% unchanged) and 2.8% in feces.

Specific Populations                                                                                                      No clinically significant differences in the pharmacokinetics of cefiderocol were observed based on age (18 to 93 years of age), sex, or race.                                                         

The effect of hepatic impairment on the pharmacokinetics of cefiderocol was not evaluated.

Patients with Renal Impairment                                                                       Approximately 60% of cefiderocol was removed by a 3- to 4-hour hemodialysis session.

Drug Interaction Studies- Clinical Studies.                                                                  No clinically significant differences in the pharmacokinetics of furosemide (an organic anion transporter [OAT]1 and OAT3 substrate), metformin (an organic cation transporter [OCT]1, OCT2, and multi-drug and toxin extrusion [MATE]2-K substrate), and rosuvastatin (an organic anion transporting polypeptide [OATP]1B3 substrate) were observed when co-administered with cefiderocol.

Cytochrome P450 (CYP) Enzymes:                                                                    Cefiderocol is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. 

Cefiderocol is not an inducer of CYP1A2, CYP2B6, or CYP3A4. 

Transporter Systems: Cefiderocol is not an inhibitor of OATP1B1, MATE1, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or bile salt export pump transporters.

 USE IN SPECIFIC POPULATIONS

1 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 

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 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary

It is not known whether cefiderocol is excreted into human milk; however, cefiderocol-derived radioactivity was detected in the milk of lactating rats that received the drug intravenously.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition.

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

5. Geriatric Use Of the 300 subjects treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects.

FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age.

Dosage adjustment for elderly patients should be based on renal function 

6. Renal Impairment                                                                                                    Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min.                                                         Patients with CLcr Less Than 60 mL/min Dose adjustment is required in patients with CLcr 15 to 59 mL/min, and in patients with end-stage renal disease or who are receiving hemodialysis (HD).

In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing 

Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

Patients with CLcr 120 mL/min or greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater 

Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

7 Hepatic Impairment                                                                                                   The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function.

 OVERDOSAGE

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