ZERBAXA

(ceftolozane and tazobactam) is an antibacterial consisting of the cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor tazobactam sodium for intravenous administration.

Ceftolozane sulfate is a semi-synthetic antibacterial drug of the beta-lactam class for parenteral administration.

The chemical name of ceftolozane sulfate is 1 H -Pyrazolium, 5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6 R,7 R )-7-[[(2 Z )-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-,sulfate (1:1).

The molecular formula is

C 23 H 31 N 12 O 8 S 2 + ∙HSO 4.

• and the molecular weight is 764.77.

Figure 1: Chemical structure of ceftolozane sulfate Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.

Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide.

The chemical formula is

C 10 H 11 N 4 NaO 5 S and the molecular weight is 322.3.

Figure 2: Chemical structure of tazobactam sodium ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is a white to yellow sterile powder for reconstitution consisting of ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium) per vial, packaged in single-dose glass vials.

The product contains sodium chloride (487 mg/vial) as a stabilizing agent, citric acid (21 mg/vial), and L-arginine (approximately 600 mg/vial) as excipients.

Figure 1 Figure 2.

Siftoluzin and

Tazopactam are used to treat the following cases: complex abdominal infections: Polyurbial infections: Syphtoluzin and Tazopactam are effective for the treatment of complex polyurbial infections in patients over 18 years of age, including kidney pelvic infections.

The use of this diarrhoeal drug, associated with a difficult metaphor (Clostridium difficile-associated diarrhea), may cause a severe disruption of the drug and treatment of diarrhoea.

The description of powerful antibiotics like Ciftoluzen and Tazopactam causes the patient without making sure that he has an acute bacterial infection that may increase the risk of developing antibiotic resistant bacteria, and is of no use to the patient.

ZERBAXA is an antibacterial drug. 12.2 Pharmacodynamics As with other beta-lactam antibacterial agents, the percent time of dosing interval that the plasma concentration of ceftolozane exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to be the best predictor of efficacy in animal models of infection.

The percent time of dosing interval that the plasma concentration of tazobactam exceeds a threshold concentration has been determined to be the parameter that best predicts the efficacy of tazobactam in in vitro and in vivo models.

The exposure-response analyses in efficacy and safety clinical trials for cIAI, cUTI, and HABP/VABP support the recommended dose regimens of ZERBAXA.

In a randomized, positive and placebo-controlled crossover thorough QTc study, 51 healthy subjects were administered a single therapeutic dose of ZERBAXA 1.5 gram (ceftolozane 1 g and tazobactam 0.5 g) and a supratherapeutic dose of ZERBAXA 4.5 gram (ceftolozane 3 g and tazobactam 1.5 g).

No significant effects of

ZERBAXA on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. 12.3 Pharmacokinetics Ceftolozane and tazobactam pharmacokinetics are similar following single.

• and multiple-dose administrations.

The C max and

AUC of ceftolozane and tazobactam increase in proportion to dose.

The mean steady-state population pharmacokinetic parameters of ZERBAXA in patients with cIAI and cUTI receiving 1-hour intravenous infusions of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or patients with HABP/VABP receiving 1-hour intravenous infusions of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) every 8 hours are summarized in Table 9.

Table 9: Mean (SD) Steady-State Plasma Population Pharmacokinetic Parameters of ZERBAXA (ceftolozane and tazobactam) after Multiple Intravenous 1-hour Infusions of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or 3 g (ceftolozane 2 g and tazobactam 1 g) Every 8 Hours in Adult Patients with CrCl Greater than 50 mL/min PK parameters ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) in cIAI and cUTI Patients ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) in HABP/VABP Patients Ceftolozane (n=317) Tazobactam (n=244) Ceftolozane (n=247) Tazobactam (n=247) C max (mcg/mL) 65.7 17.8 105 26.4 AUC 0-8,ss (mcg∙h/mL) 186 35.8 392 73.3 Distribution The binding of ceftolozane and tazobactam to human plasma proteins is approximately 16% to 21% and 30%, respectively.

The mean (CV%) steady-state volume of distribution of ZERBAXA in healthy adult males (n = 51) following a single intravenous dose of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume.

Following 1-hour intravenous infusions of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) or adjusted based on renal function every 8 hours in ventilated patients with confirmed or suspected pneumonia (N=22), mean pulmonary epithelial lining fluid-to-free plasma AUC ratios of ceftolozane and tazobactam were approximately 50% and 62%, respectively, and are similar to those in healthy subjects (approximately 61% and 63%, respectively) receiving ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g).

Minimum ceftolozane and tazobactam epithelial lung lining fluid concentrations in ventilated subjects at the end of the dosing interval were 8.2 mcg/mL and 1.0 mcg/mL, respectively.

Ceftolozane is eliminated from the body by renal excretion with a mean half-life of approximately to 4 hours.

Tazobactam is eliminated by renal excretion and metabolism with a plasma mean half-life of approximately to 3 hours.

The elimination half-life (t 1/2 ) of ceftolozane or tazobactam is independent of dose.

Ceftolozane does not appear to be metabolized to any appreciable extent and is not a substrate for CYP enzymes.

The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1.

Ceftolozane, tazobactam and the tazobactam metabolite M1 are excreted by the kidneys.

Following administration of a single

ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) intravenous dose to healthy male adults, greater than 95% of ceftolozane was excreted in the urine as unchanged parent drug.

More than 80% of tazobactam was excreted as the parent compound with the remainder excreted as the tazobactam M1 metabolite.

After a single dose of

ZERBAXA, renal clearance of ceftolozane (3.41 – 6.69 L/h) was similar to plasma CL (4.10 to 6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration.

Tazobactam is a substrate for

OAT1 and OAT3 transporters and its elimination has been shown to be inhibited by probenecid, an inhibitor of OAT1/3.

Dose adjustment is not warranted on the basis of age (18 years and older), gender, or race/ethnicity.

No significant differences in the pharmacokinetics of ceftolozane and tazobactam were observed based on age (18 years and older), gender, weight, or race/ethnicity.

The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in subjects with CrCl 80-51 mL/min, 50-30 mL/min, and 29-15 mL/min, respectively, compared to healthy subjects with normal renal function.

The respective tazobactam dose normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold.

To maintain similar systemic exposures to those with normal renal function, dosage adjustment is required.

In subjects with ESRD on

HD, approximately two-thirds of the administered ZERBAXA dose is removed by HD.

A single loading dose of

ZERBAXA followed by a maintenance dose administered every 8 hours for the remainder of the treatment period is recommended in patients with ESRD on HD.

On HD days, administer the dose at the earliest possible time following completion of HD.

Following a single 1-hour intravenous infusion of ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) to critically-ill patients with CrCl greater than or equal to 180 mL/min (N=10), mean terminal half-life values of ceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively.

No dose adjustment of ZERBAXA is recommended for HABP/VABP patients with augmented renal function.

ZERBAXA does not undergo hepatic metabolism, the systemic clearance of ZERBAXA is not expected to be affected by hepatic impairment.

No dose adjustment is recommended for

ZERBAXA in subjects with hepatic impairment.

Geriatric Patients In a population pharmacokinetic analysis of ZERBAXA, no clinically relevant differences in exposure were observed with regard to age.

No dose adjustment of

ZERBAXA based on age is recommended.

Dosage adjustment for

ZERBAXA in geriatric patients should be based on renal function.

The pharmacokinetics of ceftolozane and tazobactam in pediatric patients (birth to <18 years) were evaluated from 3 clinical studies: patients with proven or suspected gram-negative infection, cIAI, and cUTI.

Ceftolozane exposures were numerically higher in pediatric patients with cUTI compared to pediatric patients with cIAI, however, such a difference was not observed for tazobactam (Table and Table 11) .

In patients with cIAI (Table 10) and cUTI (Table 11) total body clearance of both ceftolozane and tazobactam increases with age, with values in adolescents approaching those in the adult population.

Whereas elimination half-life tends to decrease with a decrease of age.

While ceftolozane exposures in pediatric patients with cIAI and cUTI overlap with the range of exposures seen in adults, in general they are lower than mean exposures in adults.

Tazobactam exposures are comparable between pediatric and adult patients except for patients aged birth to <3 months (Group 5) with cUTI, who had higher exposures.

Population pharmacokinetic analyses and target attainment simulations in pediatric patients with cIAI and cUTI demonstrated that the recommended pediatric dosing regimens for patients from birth to less than 18 years with eGFR greater than 50 mL/min/1.73 m 2 result in no clinically relevant differences in systemic exposure to those in adult patients given ZERBAXA 1.5 grams.

There is insufficient information to assess the exposure of ZERBAXA in the pediatric patients with eGFR ≤ 50 mL/min/1.73 m 2.

Table 10: Steady-State Plasma Population Pharmacokinetic Parameters (Mean and SD) of ZERBAXA (ceftolozane and tazobactam) in Pediatric cIAI Patients One patient was enrolled in Group in the C/T arm but discontinued before the day of PK sample collection; one participant was enrolled for Group in the C/T arm with steady-state ceftolozane PK parameter values: AUC 0-8 =173 mcgh/mL; C eoi =43.4 mcg/mL; and with tazobactam PK parameter values: AUC 0-8 =69.9 mcgh/mL; C eoi =30.5 mcg/mL.

Group 1 (12 to <18 years) Group 2 (6 to <12 years) Group 3 (2 to <6 years) AUC 0-8, area under the curve in the dosing interval to 8 hours at steady-state; C eoi, concentration at the end of infusion; CL, elimination clearance; SD, standard deviation; t 1/2, terminal half-life; V ss, steady-state volume of distribution.

N=16 N=30 N=20 Ceftolozane AUC 0-8 (mcg•h/mL) 123 116 98.8 C eoi (mcg/mL) 51.1 53.7 42.4 t 1/2 (hr) 2.2 1.8 1.7 V ss (L) 23.0 11.5 7.4 Clearance (L/h) 9.55 5.81 3.58 Tazobactam AUC 0-8 (mcg•h/mL) 31.7 30.1 23.4 C eoi (mcg/mL) 21.7 21.4 16.9 t 1/2 (hr) 1.3 1.1 1.0 V ss (L) 18.8 10.6 7.1 Clearance (L/h) 18.87 11.02 7.62 Table 11: Steady-State Plasma Population Pharmacokinetic Parameters (Mean and SD) of ZERBAXA (ceftolozane and tazobactam) in Pediatric cUTI Patients Group 1 (12 to <18 years) Group 2 (6 to <12 years) Group 3 (2 to <6 years) Group 4 (3 months to <2 years) Group 5 (Birth to <3 months) AUC 0-8, area under the curve in the dosing interval to 8 hours at steady-state; C eoi, concentration at the end of infusion; CL, elimination clearance; SD, standard deviation; t 1/2, terminal half-life; V SS, steady-state volume of distribution.

N=14 N=19 N=20 N=22 N=14 Ceftolozane AUC 0-8 (mcg•h/mL) 177 145 133 129 144 C eoi (mcg/mL) 68.7 60.8 60.3 50.3 43.1 t 1/2 (hr) 2.3 2.0 1.8 2.0 2.7 V ss (L) 15.8 10.7 5.4 3.7 2.5 Clearance (L/h) 6.31 4.84 2.59 1.53 0.75 Tazobactam AUC 0-8 (mcg•h/mL) 35.0 26.7 26.6 28.6 44.6 C eoi (mcg/mL) 22.9 19.2 19.9 18.9 25.9 t 1/2 (hr) 1.3 1.2 1.0 1.1 1.2 V ss (L) 16.0 10.6 5.1 3.7 1.5 Clearance (L/h) 15.67 12.83 6.37 3.53 1.32 For ZERBAXA dosage recommendation in pediatric cIAI and cUTI patients, refer to table 2.

No drug-drug interaction was observed between ceftolozane and tazobactam in a clinical study in 16 healthy subjects.

In vitro and in vivo data indicate that ZERBAXA is unlikely to cause clinically relevant drug-drug interactions related to CYPs and transporters at therapeutic concentrations.

In vivo data indicated t.

Siftoluzin and

Tazopactam are a combination of antibiotic drugs, as Sevolozen belongs to the Cyvalosporin Group, and Tazopactam acts as a inhibitor to bacterial enzyme beta-Lactams.

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The following serious reactions are described in greater detail in the Warnings and Precautions section: Hypersensitivity reactions Clostridioides difficile -associated diarrhea Adult cIAI, cUTI and HAB/VABP Patients: The most common adverse reactions in adult patients (≥5% in either the cIAI or cUTI indication) are nausea, diarrhea, headache, and pyrexia. .

The most common adverse reactions (≥5% in the HABP/VABP indication) are increase in hepatic transaminases, renal impairment/renal failure, and diarrhea.

Pediatric cIAI and cUTI Patients

The most common adverse reactions in pediatric patients (≥7% in either the cIAI or cUTI indication) are thrombocytosis, diarrhea, pyrexia, leukopenia, abdominal pain, vomiting, increased aspartate aminotransferase, and anemia.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 also may not reflect rates observed in practice.

Infections, Including Pyelonephritis ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with ZERBAXA (1.5 g every 8 hours, adjusted based on renal function where appropriate) and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days.

The mean age of treated patients was to 50 years (range to 92 years), across treatment arms and indications.

In both indications, about 25% of the subjects were 65 years of age or older.

Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male.

Most patients (>70%) in both trials were enrolled in Eastern Europe and were White.

The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia.

Table 6 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials.

Table 6: Adverse Reactions Occurring in 1% or Greater of Adult Patients (18 years and older) Receiving ZERBAXA in Phase 3 cIAI and cUTI Clinical Trials Adverse Reaction Complicated Intra-abdominal.

Infections, Including Pyelonephritis ZERBAXA The ZERBAXA for injection dose was 1.5 g intravenously every 8 hours, adjusted to match renal function where appropriate.

In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=482) n (%) Meropenem (N=497) n (%) ZERBAXA (N=533) n (%) Levofloxacin (N=535) n (%) Nausea 38 29 15 9 Headache 12 9 31 26 Diarrhea 30 25 10 23 Pyrexia 27 20 9 5 Constipation 9 6 21 17 Insomnia 17 11 7 14 Vomiting 16 20 6 6 Hypokalemia 16 10 4 2 ALT increased 7 5 9 5 AST increased 5 3 9 5 Anemia 7 5 2 5 Thrombocytosis 9 5 2 2 Abdominal pain 6 2 4 2 Anxiety 9 7 1 4 Dizziness 4 5 6 1 Hypotension 8 4 2 1 Atrial fibrillation 6 3 1 0 Rash 8 7 5 2 Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving ZERBAXA and 1.9% (20/1032) of patients receiving comparator drugs.

Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms.

In the cIAI trials (Phase and 3), death occurred in 2.5% (14/564) of patients receiving ZERBAXA and in 1.5% (8/536) of patients receiving meropenem.

The causes of death varied and included worsening and/or complications of infection, surgery, and underlying conditions.

Less Common Adverse Reactions in

Phase 3 cIAI and cUTI Clinical Trials The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%: Cardiac disorders: tachycardia, angina pectoris Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic General disorders and administration site conditions: infusion site reactions.

Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection.

Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs’ test Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia Nervous system disorders: ischemic stroke Renal and urinary system: renal impairment, renal failure Respiratory, thoracic, and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: urticaria Vascular disorders: venous thrombosis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) ZERBAXA was evaluated in a Phase 3 comparator-controlled clinical trial for HABP/VABP, which included a total of 361 patients treated with ZERBAXA (3 g every 8 hours, adjusted based on renal function where appropriate) and 359 patients treated with comparator (meropenem 1 g every 8 hours) for up to 14 days.

The mean age of treated patients was 60 years (range to 98 years), across treatment arms.

About 44% of the subjects were 65 years of age or older.

Most patients (71%) enrolled in the trial were male.

All subjects were mechanically ventilated at randomization and 92% were in an intensive care unit (ICU) at randomization.

The median APACHE

II score was 17, and 33% of subjects had a baseline APACHE II score of ≥20, indicating a high severity of illness for many patients enrolled in this trial.

Table 7 lists adverse reactions occurring in 2% or greater of patients receiving ZERBAXA in a Phase 3 HABP/VABP clinical trial.

Table 7: Adverse Reactions Occurring in 2% or Greater of Adult Patients (18 years and older) Receiving ZERBAXA in a Phase 3 HABP/VABP Clinical Trial Adverse Reactions ZERBAXA The ZERBAXA for injection dose was 3 g intravenously every 8 hours, adjusted to match renal function where appropriate.

N=361 n (%) Meropenem N=359 n (%) Hepatic transaminase increased Includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal. 43 26 Renal impairment/renal failure Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment. 32 22 Diarrhea 23 25 Intracranial hemorrhage Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma. 16 5 Vomiting 12 10 Clostridioides difficile colitis Includes Clostridioides difficile colitis, Clostridioides difficile infection, Clostridioides test positive. 10 2 Treatment discontinuation due to adverse reactions occurred in 1.1% (4/361) of patients receiving ZERBAXA and 1.4% (5/359) of patients receiving meropenem.

Investigations: blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Coombs direct test positive Pediatric Patients Complicated Intra-abdominal.

Infections, Including Pyelonephritis ZERBAXA was evaluated in two blinded, randomized, active-controlled clinical studies in pediatric patients from birth to less than 18 years of age, one in cIAI and the other in cUTI, which included a total of 170 pediatric patients treated with ZERBAXA and 54 pediatric patients treated with the comparator.

ZERBAXA dosing regimen was the same in each trial.

Patients were randomized 3:1 to receive ZERBAXA plus metronidazole or meropenem plus placebo in the cIAI study and ZERBAXA or meropenem in the cUTI study.

In these pediatric patients, the type of adverse reactions were generally comparable to those observed in adults.

Table 8 lists adverse reactions occurring in 4% or greater of pediatric patients receiving ZERBAXA in either the pediatric cIAI or cUTI clinical trial.

Table 8: Adverse Reactions Occurring in 4% or Greater of Pediatric Patients (birth to less than 18 years of age) Receiving ZERBAXA in either the cIAI or cUTI Clinical Trial Adverse Reaction Complicated Intra-abdominal.

Infections, Including Pyelonephritis ZERBAXA In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=70) n (%) Meropenem (N=21) n (%) ZERBAXA (N=100) n (%) Meropenem (N=33) n (%) Thrombocytosis Includes platelet count increased. 11 3 9 3 Diarrhea 12 5 7 3 Pyrexia Includes hyperthermia. 9 3 7 1 Leukopenia Includes neutropenia and neutrophil count decreased. 3 0 8 0 Abdominal pain Includes upper abdominal pain. 8 0 2 1 AST increased 5 1 4 2 Vomiting 7 1 1 1 ALT increased 4 1 4 2 Anemia 5 0 2 0 Phlebitis Includes superficial phlebitis. 4 0 1 1 Hypertension 3 0 0 1 Gastritis 3 0 0 0 Hypokalemia Includes blood potassium decreased. 3 0 0 0 Bradypnea Includes respiratory rate decreased. 3 0 0 0 Laboratory Values The development of a positive direct Coombs test may occur during treatment with ZERBAXA.

The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving ZERBAXA and 0% in patients receiving the comparator in the adult cUTI and cIAI clinical trials.

The incidence of seroconversion to a positive direct Coombs test was 31.2% in patients receiving ZERBAXA and 3.6% in patients receiving meropenem in the adult HABP/VABP clinical trial.

The incidence of seroconversion to a positive direct Coombs test was 45.3% in patients receiving ZERBAXA and 33.3% in patients receiving meropenem in the pediatric cIAI clinical trial.

The incidence of seroconversion to a positive direct Coombs test was 29.7% in patients receiving ZERBAXA and 8.7% in patients receiving meropenem in the pediatric cUTI clinical trial.

In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.

In the event of overdose, discontinue ZERBAXA and provide general supportive treatment.

ZERBAXA can be removed by hemodialysis.

Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the tazobactam metabolite M1 were removed by dialysis.

No information is available on the use of hemodialysis to treat overdosage.

is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class.

ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class.

Administer all doses of

ZERBAXA every 8 hours by intravenous infusion over 1 hour in adult and pediatric patients.

Information for instructions on the preparation of solutions.

For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table in the Full Prescribing Information), and add to the same infusion bag.

Recommended Dosage of ZERBAXA by Infection in Adult Patients (18 years or older) with Creatinine Clearance (CrCl) Greater than 50 mL/min Infection Dose Duration of Treatment Complicated Intra-abdominal.

Infections (cIAI) Used in conjunction with metronidazole 500 mg intravenously every 8 hours 1.5 g to 14 days Complicated Urinary Tract.

Infections (cUTI), Including Pyelonephritis 1.5 g 7 days Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) 3 g to 14 days Recommended Dosage of ZERBAXA by infection in Pediatric Patients (birth to less than 18 years of age) with Estimated Glomerular Filtration Rate (eGFR) Estimated GFR using an age-appropriate equation for use in the pediatric population Greater than 50 mL/min/1.73 m 2 Infection Dose Duration of Treatment Complicated Intra-abdominal.

Infections Used in conjunction with metronidazole. 30 mg/kg up to a maximum dose of 1.5 g Pediatric patients weighing greater than 50 kg should not exceed a maximum dose of 1.5g to 14 days Complicated Urinary Tract.

Infections, including Pyelonephritis 30 mg/kg up to a maximum dose of 1.5 g to 14 days Recommended Dosage of ZERBAXA in Adult Patients (18 years or older) with CrCl 50 mL/min or less Estimated CrCl (mL/min) CrCl estimated using Cockcroft-Gault formula cIAI and cUTI, including pyelonephritis HABP/VABP to 50 ZERBAXA 750 mg (500 mg and 250 mg) intravenously every 8 hours ZERBAXA 1.5 g (1 g and 0.5 g) intravenously every 8 hours to 29 ZERBAXA 375 mg (250 mg and 125 mg) intravenously every 8 hours ZERBAXA 750 mg (500 mg and 250 mg) intravenously every 8 hours End-stage renal disease (ESRD) on hemodialysis (HD) A single loading dose of ZERBAXA 750 mg (500 mg and 250 mg) followed by a ZERBAXA 150 mg (100 mg and 50 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) A single loading dose of ZERBAXA 2.25 g (1.5 g and 0.75 g) followed by a ZERBAXA 450 mg (300 mg and 150 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) 2.1 Recommended Dosage in Adult Patients The recommended dosage of ZERBAXA in adult patients 18 years and older with creatinine clearance (CrCl) greater than 50 mL/min is 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g for cIAI and cUTI and 3 g (ceftolozane 2 g and tazobactam 1 g) for HABP/VABP administered every 8 hours by intravenous infusion over 1 hour The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 1.

Table 1: Dosage of ZERBAXA by Infection in Adult Patients (18 years and older) with CrCl CrCl estimated using Cockcroft-Gault formula Greater than 50 mL/min Infection Dose Frequency Infusion Time Duration of Treatment Complicated Intra-abdominal.

Infections Used in conjunction with metronidazole 500 mg intravenously every 8 hours 1.5 g Every 8 Hours 1 hour to 14 days Complicated Urinary Tract.

Infections, Including Pyelonephritis 1.5 g Every 8 Hours 1 hour 7 days Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) 3 g Every 8 Hours 1 hour to 14 days 2.2 Recommended Dosage in Pediatric Patients with cIAI or cUTI (birth to less than 18 years of age) The recommended dosage regimen of ZERBAXA in pediatric patients from birth to less than 18 years of age with cIAI and cUTI with an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m is described in Table 2.

ZERBAXA is administered every 8 hours by intravenous infusion over 1 hour.

The duration of treatment should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress as shown in Table 2.

For the treatment of cIAI, metronidazole should be given concurrently.

ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m 2 or less.

There is insufficient information to recommend a dosage regimen for pediatric patients with HABP/VABP.

Table 2: Dosage of ZERBAXA by infection in Pediatric Patients (birth to less 18 years of age) with eGFR Estimated GFR using an age-appropriate equation for use in the pediatric population greater than 50 mL/min/1.73 m 2 Infection Dose Frequency Infusion time Duration of treatment Complicated Intra-abdominal.

Infections Used in conjunction with metronidazole. 30 mg/kg up to a maximum dose of 1.5 g Pediatric patients weighing greater than 50 kg should not exceed a maximum dose of 1.5 g Every 8 hours 1 hour to 14 days Complicated Urinary Tract.

Infections including Pyelonephritis 30 mg/kg up to a maximum dose of 1.5 g Every 8 hours 1 hour to 14 days 2.3 Dosage Adjustments in Adult Patients with Renal Impairment Dose adjustment is required for adult patients (18 years and older) with CrCl 50 mL/min or less (Table 3).

All doses of

ZERBAXA are administered over 1 hour.

For patients with changing renal function, monitor CrCl at least daily and adjust the dosage of ZERBAXA accordingly.

Table 3: Dosage of ZERBAXA in Adult Patients (18 years and older) with CrCl 50 mL/min or less Estimated CrCl (mL/min) CrCl estimated using Cockcroft-Gault formula Complicated Intra-abdominal.

Infections, Including Pyelonephritis Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) 30 to 50 750 mg (500 mg and 250 mg) intravenously every 8 hours 1.5 g (1 g and 0.5 g) intravenously every 8 hours to 29 375 mg (250 mg and 125 mg) intravenously every 8 hours 750 mg (500 mg and 250 mg) intravenously every 8 hours End-stage renal disease (ESRD) on hemodialysis (HD) A single loading dose of 750 mg (500 mg and 250 mg) followed by a 150 mg (100 mg and 50 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) A single loading dose of 2.25 g (1.5 g and 0.75 g) followed by a 450 mg (300 mg and 150 mg) maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) 2.4 Dosage Adjustments in Pediatric Patients with Renal Impairment Dosage adjustment of ZERBAXA in pediatric patients (birth to less than 18 years of age) with eGFR 50 mL/min/1.73 m 2 or less has not been determined.

ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m 2 or less. 2.5 Preparation of Solutions ZERBAXA does not contain a bacteriostatic preservative.

Aseptic technique must be followed in preparing the infusion solution.

Preparation of doses

Constitute each vial of ZERBAXA with 10 mL of sterile water for injection or 0.9% Sodium Chloride for Injection, USP and gently shake to dissolve.

The final volume is approximately 11.4 mL per vial.

The constituted solution is not for direct injection.

To prepare the required dose, withdraw the appropriate volume determined from Table from the reconstituted vial(s).

Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP.

For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table 4), and add to the same infusion bag.

Discard unused portion.

Table 4: Preparation of Doses ZERBAXA (ceftolozane and tazobactam) Dose Volume to Withdraw from Reconstituted Vial(s) 3 g (2 g and 1 g) Two vials of 11.4 mL each (entire contents from two vials) 2.25 g (1.5 g and 0.75 g) 11.4 mL from one vial (entire contents) and 5.7 mL from a second vial 1.5 g (1 g and 0.5 g) 11.4 mL (entire contents from one vial) 750 mg (500 mg and 250 mg) 5.7 mL 450 mg (300 mg and 150 mg) 3.5 mL 375 mg (250 mg and 125 mg) 2.9 mL 150 mg (100 mg and 50 mg) 1.2 mL Inspect drug products visually for particulate matter and discoloration prior to use.

ZERBAXA infusions range from clear, colorless solutions to solutions that are clear and slightly yellow.

Variations in color within this range do not affect the potency of the product. 2.6 Compatibility Compatibility of ZERBAXA with other drugs has not been established.

ZERBAXA should not be mixed with other drugs or physically added to solutions containing other drugs. 2.7 Storage of Constituted Solutions Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted ZERBAXA solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag.

Following dilution of the solution with 0.9% sodium chloride or 5% dextrose, ZERBAXA is stable for 24 hours when stored at room temperature or 7 days when stored under refrigeration at to 8°C (36 to 46°F).

Constituted ZERBAXA solution or diluted

ZERBAXA infusion should not be frozen.

ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is supplied in single-dose vials containing ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium) per vial.

Vials are supplied in cartons containing 10 vials. (NDC 67919-030-01) 16.2 Storage and Handling ZERBAXA vials should be stored refrigerated at to 8°C (36 to 46°F) and protected from light.

The reconstituted solution, once diluted, may be stored for 24 hours at room temperature or for 7 days under refrigeration at to 8° C (36 to 46°F).

Discard unused portion.

ZERBAXA vials should be stored refrigerated at to 8°C (36 to 46°F) and protected from light.

The reconstituted solution, once diluted, may be stored for 24 hours at room temperature or for 7 days under refrigeration at to 8° C (36 to 46°F).

Discard unused portion.

Risk Summary There are no data available on ZERBAXA, ceftolozane or tazobactam use in pregnant women to allow assessment of 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 have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Neither ceftolozane nor tazobactam produced embryo-fetal toxicity when administered to rodents during the period of organogenesis at ceftolozane doses approximately 3.5 times higher in mice and 2 times higher in rats than the maximum recommended human dose (MRHD) of 2 grams every 8 hours based on plasma AUC comparison or at tazobactam doses approximately 10 times higher in rats than the MRHD of 1 gram every 8 hours based on body surface area comparison.

In pre-postnatal studies, where pregnant rats were administered intravenous ceftolozane or intraperitoneal tazobactam in gestation and through the lactation period, ceftolozane was associated with a decrease in auditory startle response in first generation offspring at a dose lower than the MRHD based on AUC comparison, and tazobactam was associated with reduced maternal body weight gain and increased stillbirths at a dose equivalent to approximately 4 times the MRHD and reduced fetal body weights in first generation offspring at a dose approximately equivalent to the MRHD based on body surface area comparison.

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 to 4% and to 20%, respectively.

While available studies with multiple cephalosporins 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 of cephalosporin use during pregnancy with 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.

Embryo-fetal development studies were performed in mice administered intravenous ceftolozane at doses of 300, 1000, and 2000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 15) and in rats administered intravenous ceftolozane in doses of 100, 300, and 1000 mg/kg/day during the period of organogenesis (Gestation Day 6 through 17).

In mice, ceftolozane was not associated with maternal or embryo-fetal toxicity with doses up to the highest dose of 2000 mg/kg/ day (approximately 3.5 times the MRHD of 2 grams every 8 hours based on plasma AUC comparison).

In rats, no embryo-fetal toxicity was observed, but maternal body weight gain was reduced at a ceftolozane dose of 1000 mg/kg/day. No adverse maternal effects in rats were observed at a dose of 300 mg/kg/day and no adverse embryo-fetal effects were observed at a dose of 1000 mg/kg/day (respectively equivalent to approximately 0.7 - and 2-times the MRHD based on plasma AUC comparison).

In a pre-postnatal study in rats, intravenous ceftolozane administered during pregnancy and lactation (Gestation Day 6 through Lactation Day 20) was associated with a decrease in auditory startle response in postnatal Day 60 male pups at maternal doses greater than or equal to 300 mg/kg/day. No adverse effects were observed in rats at a dose of 100 mg/kg/day, a dose lower than the MRHD of 2 grams every 8 hours based on plasma AUC comparison.

In an embryo-fetal study in rats, tazobactam was administered intravenously during the period of organogenesis (Gestation Day 7 through 17) at doses of 125, 500, and 3000 mg/kg/day. The high dose of 3000 mg/kg/day produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity.

No adverse maternal effects were observed at a dose of 500 mg/kg/day and no adverse fetal effects were observed at a dose of 3000 mg/kg/day (respectively equivalent to approximately 2 - and 10-times the MRHD of 1 gram every 8 hours based on body surface area comparison).

In rats, tazobactam was shown to cross the placenta.

Concentrations in the fetus were less than or equal to 10% of those found in maternal plasma.

In a pre-postnatal study in rats, tazobactam administered intraperitoneally in doses of 40, 320, and 1280 mg/kg/day at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) was associated with decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths at the high dose of 1280 mg/kg/day. No effects on the physical development, neurological function, or fertility and reproductive ability of first generation (F1) pups were noted, but postnatal body weights for F1 pups delivered to dams receiving and 1280 mg/kg/day tazobactam were significantly reduced 21 days after delivery.

The second generation (F2) fetuses were normal for all doses of tazobactam.

No adverse effects on maternal reproduction were observed at doses up to 320 mg/kg/day and F1 body weights were not reduced at a dose of 40 mg/kg/day (respectively equivalent to approximately 1.0 and 0.1 times the MRHD of 1 gram every 8 hours based on body surface area comparison).

Infections (cIAI) and Complicated Urinary Tract.

Infections (cUTI), including Pyelonephritis The safety and effectiveness of ZERBAXA for the treatment of cIAI and cUTI have been established in pediatric patients aged birth to less than 18 years old.

Use of

ZERBAXA in these age groups is supported by evidence from adequate and well-controlled studies of ZERBAXA in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials.

The safety profile of

ZERBAXA in pediatric patients was similar to adults with cIAI and cUTI, treated with ZERBAXA.

There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m 2 or less.

ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m 2 or less.

Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m 2 or greater at birth or within the first few months of life.

Hospital-acquired Bacterial Pneumonia and Ventilator-associated

Bacterial Pneumonia (HABP/VABP) The safety and effectiveness of ZERBAXA in pediatric patients have not been established for the treatment of HABP and VABP.

Of the 1015 patients treated with ZERBAXA in the Phase 3 cIAI and cUTI clinical trials, 250 (24.6%) were 65 years or older, including 113 (11.1%) 75 years or older.

The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older) in the trials for both indications.

In the cIAI trial, cure rates in the elderly (aged 65 years and older) in the ZERBAXA plus metronidazole arm were 69/100 (69%) and in the comparator arm were 70/85 (82.4%).

This finding in the elderly population was not observed in the cUTI trial.

Of the 361 patients treated with ZERBAXA in the Phase 3 HABP/VABP clinical trial, 160 (44.3%) were 65 years or older, including 83 (23%) 75 years or older.

The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older).

In the trial, Day 28 all-cause mortality rates in the elderly (aged 65 years and older) were comparable between treatment arms:50/160 (31.3%) in the ZERBAXA arm and 54/160 (33.8%) in the comparator arm.

ZERBAXA is substantially excreted by the kidney and the risk of adverse reactions to ZERBAXA may be greater in patients with renal impairment.

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.

Adjust dosage for elderly patients based on renal function.