WARNINGS-

­ • Infusion-Related Reactions: Monitor patients for signs and symptoms. Discontinue ADAKVEO infusion for severe reactions and manage medically. 

• Interference With Automated Platelet Counts (platelet clumping): Run test as soon as possible or use citrate tubes. 

Pat Inform-

ADVERSE REACTIONS

­ Most common adverse reactions (incidence > 10%) are nausea, arthralgia, back pain, and pyrexia. 

WARNINGS AND PRECAUTIONS

­ • Infusion-Related Reactions: Monitor patients for signs and symptoms. Discontinue ADAKVEO infusion for severe reactions and manage medically. 

• Interference With Automated Platelet Counts (platelet clumping): Run test as soon as possible or use citrate tubes. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions 

Interference With Automated Platelet Counts

Advise patients to inform their healthcare provider that they are receiving ADAKVEO prior to any blood tests due to the potential interference with laboratory tests used to measure platelet counts 

Manufactured by: Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, New Jersey 07936 US License No. 1244 © Novartis

 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.

Compared to a 1-hour infusion, a 3-hour infusion increased the percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the MIC.

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. Cefiderocol AUC fold changes in subjects with renal impairment compared to subjects with CLcr 90 to 119 mL/min.

Effect of Renal Impairment on the AUC of Cefiderocola CLcr (mL/min)

Cefiderocol AUC Geometric Mean Ratios (90% CI)b 60 to 89 (N=6) 1.37 (1.15, 1.62) 30 to 59 (N=7) 2.35 (2.00, 2.77) 15 to 29 (N=4) 3.21 (2.64, 3.91) <15 (N=6) 4.69 (3.95, 5.56)

a After a single FETROJA 1-gram dose (0.5 times the approved recommended dosage) b Compared to AUC in subjects with CLcr 90 to 119 mL/min (N=12) CI=confidence interval Patients with CLcr 120 mL/min or Greater Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater.

A FETROJA 2-gram dose every 6 hours infused over 3 hours is predicted to provide cefiderocol exposures comparable to those in patients with CLcr 90 to 119 mL/min 

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.

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.

Cefiderocol is not a substrate of OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, or BCRP.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman.

There are insufficient human data on ADAKVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality.

For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.

2. Lactation Risk Summary

 There is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk.

The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ADAKVEO and any potential adverse effects on the breastfed child from ADAKVEO or from the underlying maternal condition.

4. Pediatric Use

The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN Trial).

The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO 5 mg/kg aged 16 years old 

 The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established.

5. Geriatric Use

Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.