ZINFORO

Ceftaroline fosamil for injection is a sterile, semi-synthetic, prodrug of the cephalosporin antibacterial class of beta-lactams (β - lactams).

Chemically, the prodrug, ceftaroline fosamil monoacetate is (6 R,7 R )-7-{(2 Z )-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4 - yl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate monoacetate.

Its molecular weight is 744.74.

The molecular formula is

C 22 H 21 N 8 O 8 PS 4.

CH 3 COOH.

Figure 1: Chemical structure of ceftaroline fosamil Ceftaroline fosamil for injection vials contain either 600 mg or 400 mg of anhydrous ceftaroline fosamil (equivalent to 653 mg and 435 mg, respectively, of ceftaroline fosamil monoacetate).

The powder for injection is formulated from ceftaroline fosamil monoacetate, a yellow white to light yellow powder.

Each vial of 400 mg of anhydrous ceftaroline fosamil includes inactive ingredient L-arginine 264 mg/vial as buffering agent.

Each vial of 600 mg of anhydrous ceftaroline fosamil includes inactive ingredient L-arginine 396 mg/vial as buffering agent.

All references to ceftaroline activity are expressed in terms of the prodrug, ceftaroline fosamil.

The powder is constituted for

IV injection.

The pH of the constituted solution is 4.8 to 6.5.

Ceftaroline fosamil for injection is a cephalosporin antibacterial indicated in adult and pediatric patients for the treatment of the following infection caused by designated susceptible bacteria: Acute bacterial skin and skin structure infections (ABSSSI) in adult and pediatric patients (at least 34 weeks gestational age and 12 days postnatal age) Community-acquired bacterial pneumonia (CABP) in adult and pediatric patients 2 months of age and older To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftaroline fosamil for injection and other antibacterial drugs, ceftaroline fosamil for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 1.1 Acute Bacterial Skin and Skin Structure.

Infections Ceftaroline fosamil for injection is indicated in adult and pediatric patients (at least 34 weeks gestational age and 12 days postnatal age) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca. 1.2 Community-Acquired Bacterial Pneumonia Ceftaroline fosamil for injection is indicated in adult and pediatric patients 2 months of age and older for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli. 1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftaroline fosamil for injection and other antibacterial drugs, ceftaroline fosamil for injection should be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to ceftaroline.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PHARMACOLOGY 12.1 Mechanism of Action Ceftaroline is a cephalosporin antibacterial drug. 12.2 Pharmacodynamics As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with S. aureus and S. pneumoniae.

Exposure-response analysis of

Phase 2/3 ABSSSI trials supports the recommended dosage regimen of ceftaroline fosamil for injection 600 mg every 12 hours by IV infusion over 1 hour.

Phase 3 CABP trials, an exposure-response relationship could not be identified due to the limited range of ceftaroline exposures in the majority of patients.

In a randomized, positive.

• and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of ceftaroline fosamil for injection 1,500 mg, placebo, and a positive control by IV infusion over 1 hour.

At the 1,500 mg dose of ceftaroline fosamil for injection, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. 12.3 Pharmacokinetics The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized in Table 8.

Pharmacokinetic parameters were similar for single and multiple dose administration.

Table 8: Mean (Standard Deviation) Pharmacokinetic Parameters of Ceftaroline IV in Healthy Adults Parameter Single 600 mg Dose Administered as a 1-Hour Infusion (n=6) Multiple 600 mg Doses Administered Every 12 Hours as 1-Hour Infusions for 14 Days (n=6) C max (mcg/mL) 19.0 21.3 T max (h) a 1.00 0.92 AUC (mcg•h/mL) b 56.8 56.3 T 1/2 (h) 1.60 2.66 CL (L/h) 9.58 9.60 a Reported as median (range) b AUC 0-∞ , for single-dose administration; AUC 0-tau, for multiple-dose administration; C max, maximum observed concentration; T max, time of C max; AUC 0-∞ , area under concentration-time curve from time to infinity; AUC 0-tau, area under concentration-time curve over dosing interval (0-12 hours); T 1/2, terminal elimination half-life; CL, plasma clearance The C max and AUC of ceftaroline increase approximately in proportion to dose within the single dose range of to 1,000 mg. No appreciable accumulation of ceftaroline is observed following multiple IV infusions of 600 mg administered every 12 hours for up to 14 days in healthy adults with normal renal function.

The systemic exposure (AUC), T 1/2, and clearance of ceftaroline were similar following administration of 600 mg ceftaroline fosamil in a volume of 50 mL to healthy subjects every 8 hours for 5 days as a 5-minute or 60-minute infusion, and the T max of ceftaroline occurred about 5 minutes after the end of the ceftaroline fosamil infusion for both infusion durations.

The mean (SD) C max of ceftaroline was 32.5 mcg/mL for the 5-minute infusion duration (n=11) and 17.4 mcg/mL for the 60-minute infusion duration (n=12).

The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over to 50 mcg/mL (14.5 to 28%).

The median (range) steady-state volume of distribution of ceftaroline in healthy adult males (n=6) following a single 600 mg IV dose of radiolabeled ceftaroline fosamil was 20.3 L (18.3 to 21.6 L), similar to extracellular fluid volume.

Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline.

Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion.

Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1.

The mean (SD) plasma ceftaroline M-1 to ceftaroline AUC 0-∞ ratio following a single 600 mg IV infusion of ceftaroline fosamil in healthy adults (n=6) with normal renal function is 28% (3.1%).

When incubated with pooled human liver microsomes, ceftaroline was metabolically stable (< 12% metabolic turnover), indicating that ceftaroline is not a substrate for hepatic CYP450 enzymes.

Ceftaroline and its metabolites are primarily eliminated by the kidneys.

Following administration of a single 600 mg IV dose of radiolabeled ceftaroline fosamil to healthy male adults (n=6), approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours.

Of the radioactivity recovered in urine approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1.

The mean (SD) renal clearance of ceftaroline was 5.56 L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.

Specific Populations Patients with Renal Impairment

Following administration of a single 600 mg IV dose of ceftaroline fosamil for injection, the geometric mean AUC 0-∞ of ceftaroline in subjects with mild (CrCl > 50 to ≤ 80 mL/min, n=6) or moderate (CrCl > 30 to ≤ 50 mL/min, n=6) renal impairment was 19% and 52% higher, respectively, compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6).

Following administration of a single 400 mg IV dose of ceftaroline fosamil for injection, the geometric mean AUC 0-∞ of ceftaroline in subjects with severe (CrCl ≥ 15 to ≤30 mL/min, n=6) renal impairment was 115% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6).

Dosage adjustment is recommended in patients with moderate and severe renal impairment.

A single 400 mg dose of ceftaroline fosamil for injection was administered to subjects with ESRD (n=6) either 4 hours prior to or 1 hour after hemodialysis (HD).

The geometric mean ceftaroline

AUC 0-∞ following the post-HD infusion was 167% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6).

The mean recovery of ceftaroline in the dialysate following a 4-hour HD session was 76.5 mg, or 21.6% of the administered dose.

Dosage adjustment is recommended in patients with ESRD (defined as CrCL < 15 mL/min), including patients on HD.

The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.

As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment.

Following administration of a single 600 mg IV dose of ceftaroline fosamil for injection to healthy elderly subjects (≥ 65 years of age, n=16), the geometric mean AUC 0-∞ of ceftaroline was ~33% higher compared to healthy young adult subjects (18 to 45 years of age, n=16).

The difference in

AUC 0-∞ was mainly attributable to age-related changes in renal function.

Dosage adjustment for ceftaroline fosamil for injection in elderly patients should be based on renal function.

The pharmacokinetics of ceftaroline were evaluated in adolescent patients (ages to 17, n=7) with normal renal function following administration of a single 8 mg/kg IV dose of ceftaroline fosamil for injection (or 600 mg for subjects weighing > 75 kg).

The mean plasma clearance and terminal phase volume of distribution for ceftaroline in adolescent subjects were similar to healthy adults (n=6) with normal renal function in a separate study following administration of a single 600 mg IV dose.

However, the mean C max and AUC 0-∞ for ceftaroline in adolescent subjects who received a single 8 mg/kg dose were 10% and 23% less than in healthy adult subjects who received a single 600 mg IV dose.

The population pharmacokinetic analyses demonstrated that the pharmacokinetics of ceftaroline in pediatric patients from 2 months to < 18 years of age were similar to those in adult patients after accounting for weight and maturational changes.

No clinically significant differences in ceftaroline

AUC were predicted in patients from 12 days to 2 months postnatal age and with ≥34 weeks of gestational age compared to adults and pediatric patients 2 months of age and older when given the approved recommended dosage for each patient population.

Following administration of a single 600 mg IV dose of ceftaroline fosamil for injection to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean C max and AUC 0-∞ for ceftaroline were similar between males and females, although there was a trend for higher C max (17%) and AUC 0-∞ (6 to 15%) in female subjects.

Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC 0-tau based on gender in Phase 2/3 patients with ABSSSI or CABP.

No dose adjustment is recommended based on gender.

A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 adult ABSSSI and CABP trials.

No significant differences in ceftaroline

AUC 0-tau was observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients.

Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions.

No dosage adjustment is recommended based on race.

Drug Interaction s Studies

No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil for injection.

There is minimal potential for drug-drug interactions between ceftaroline fosamil for injection and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow.

In vitro studies in human liver microsomes indicate that ceftaroline does not inhibit the major cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.

In vitro studies in human hepatocytes also demonstrate that ceftaroline and its inactive open-ring metabolite are not inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5.

Therefore, ceftaroline fosamil for injection is not expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Population pharmacokinetic analysis did not identify any clinically relevant differences in ceftaroline exposure (C max and AUC 0-tau ) in Phase 2/3 patients with ABSSSI or CABP who were taking concomitant medications that are known inhibitors, inducers, or substrates of the cytochrome P450 system; anionic or cationic drugs known to undergo active renal secretion; and vasodilator or vasoconstrictor drugs that may alter renal blood flow. 12.4 Microbiology Mechanism of Action Ceftaroline is a cephalosporin antibacterial drug with in vitro activity against Gram-positive and -negative bacteria.

The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs).

Ceftaroline is bactericidal against

S. aureus due to its affinity for PBP2a and against Streptococcus pneumoniae due to its affinity for PBP2x.

Resistance Ceftaroline is not active against

Gram-negative bacteria producing extended spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases, or class C (AmpC cephalosporinases).

Although cross-resistance may occur, some isolates resistant to other.

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section Hypersensitivity Reactions Clostridioides difficile -Associated diarrhea Neurological Adverse Reactions Direct Coombs’ Test Seroconversion The most common adverse reactions occurring in >2 % of adult patients and ≥3% of pediatric patients are diarrhea, nausea, and rash.

Additional adverse reactions that occurred in ≥3% of pediatric patients include vomiting and pyrexia.

To report SUSPECTED ADVERSE

REACTIONS, contact Apotex Corp.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.

Ceftaroline fosamil for injection was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1,300 adult patients treated with ceftaroline fosamil for injection (600 mg administered by IV over 1 hour every 12h) and 1,297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for a treatment period up to 21 days.

The median age of patients treated with ceftaroline fosamil for injection was 54 years, ranging between and 99 years old.

Patients treated with ceftaroline fosamil for injection were predominantly male (63%) and Caucasian (82%).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In the four pooled adult Phase 3 clinical trials, serious adverse reactions (SARs) occurred in 98/1,300 (7.5%) of patients receiving ceftaroline fosamil for injection and 100/1,297 (7.7%) of patients receiving comparator drugs.

Treatment discontinuation due to adverse reactions occurred in 35/1,300 (2.7%) of patients receiving ceftaroline fosamil for injection and 48/1,297 (3.7%) of patients receiving comparator drugs with the most common adverse reactions leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the ceftaroline fosamil for injection group and 0.5% in comparator group.

No adverse reactions occurred in greater than 5% of adult patients receiving ceftaroline fosamil for injection.

The most common adverse reactions occurring in > 2% of patients receiving ceftaroline fosamil for injection in the pooled adult phase 3 clinical trials were diarrhea, nausea, and rash.

Table 6 lists adverse reactions occurring in ≥ 2% of patients receiving ceftaroline fosamil for injection in the pooled adult Phase 3 clinical trials.

Table 6: Adverse Reactions Occurring in ≥ 2% of Patients Receiving Ceftaroline Fosamil for Injection in the Pooled Adult Phase 3 Clinical Trials Adverse Reactions Pooled Phase 3 Clinical Trials (four trials, two in ABSSSI and two in CABP) Ceftaroline Fosamil for Injection (N=1,300) Pooled Comparators a (N=1,297) Gastrointestinal.

Disorders Diarrhea 5 % 3 % Nausea 4 % 4 % Constipation 2 % 2 % Vomiting 2 % 2 % Laboratory.

Investigations Increased transaminases 2% 3 % Metabolism and Nutrition disorders Hypokalemia 2 % 3 % Skin and Subcutaneous Tissue.

Disorders Rash 3% 2% Vascular.

Disorders Phlebitis 2% 1% a Comparators included vancomycin 1 gram IV every 12h plus aztreonam 1 gram IV every 12h in the Phase 3 ABSSSI trials, and ceftriaxone 1 gram IV every 24h in the Phase 3 CABP trials.

Other Adverse Reactions Observed During Clinical Trials of Ceftaroline Fosamil for Injection Following is a list of additional adverse reactions reported by the 1,740 adult patients who received ceftaroline fosamil for injection in any clinical trial with incidences less than 2%.

Blood and lymphatic system disorders.

• Anemia, Eosinophilia, Neutropenia, Thrombocytopenia Cardiac disorders.

• Bradycardia, Palpitations Gastrointestinal disorders.

• Abdominal pain General disorders and administration site conditions.

• Pyrexia Hepatobiliary disorders.

• Hepatitis Immune system disorders.

Infections and infestations.

• Clostridioides difficile colitis Metabolism and nutrition disorders.

• Hyperglycemia, Hyperkalemia Nervous system disorders.

• Dizziness, Convulsion Renal and urinary disorders.

• Renal failure Skin and subcutaneous tissue disorders.

• Urticaria Pediatric Patients Ceftaroline fosamil for injection was evaluated in three clinical trials (one in ABSSSI and two in CABP) which included 257 pediatric patients 2 months to < 18 years of age treated with ceftaroline fosamil for injection, and 102 patients treated with comparator agents for a treatment period up to 21 days.

In two trials, one in ABSSSI and one in CABP, the dose was selected to result in exposures comparable to adult exposure with 600 mg administered by IV infusion every 12h.

In an additional pediatric trial in complicated CABP the dose was higher.

The median age of pediatric patients treated with ceftaroline fosamil for injection was 5 years, ranging from 2 months to < 18 years of age.

Patients treated with ceftaroline fosamil for injection were predominantly male (55%) and Caucasian (92%).

A single study enrolled 11 pediatric patients with a gestational age of ≥34 weeks and a postnatal age of 12 days to less than 2 months of age.

The safety findings were similar to those observed in adult and pediatric patients 2 months of age and older.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In the three pooled pediatric clinical trials, SARs occurred in 10/257 (4%) of patients receiving ceftaroline fosamil for injection and 3/102 (3%) of patients receiving comparator drugs.

Treatment discontinuation due to adverse reactions occurred in 10/257 (3.9%) of patients receiving ceftaroline fosamil for injection and 2/102 (2%) of patients receiving comparator drugs with the most common adverse reaction leading to discontinuation being rash in 2/257 (0.8%) of patients treated with ceftaroline fosamil for injection.

No adverse reactions occurred in greater than 8% of pediatric patients receiving ceftaroline fosamil for injection.

The most common adverse reactions occurring in ≥ 3% of patients receiving ceftaroline fosamil for injection in the pooled pediatric clinical trials were diarrhea, nausea, vomiting, pyrexia and rash.

Table 7 lists adverse reactions occurring in ≥ 3% of patients receiving ceftaroline fosamil for injection in the pooled pediatric clinical trials.

Table 7: Adverse Reactions Occurring in ≥ 3% of Patients Receiving Ceftaroline Fosamil for Injection in the Pooled Pediatric Clinical Trials Adverse Reactions Pooled Pediatric Clinical Trials (three trials, one in ABSSSI and two in CABP) Ceftaroline Fosamil for Injection (N=257) Pooled Comparators a (N=102) Gastrointestinal.

Disorders Diarrhea 8 % 10 % Nausea 3 % 1 % Vomiting 5 % 12 % General and Administrative Site disorders Pyrexia 3% 2 % Skin and Subcutaneous Tissue.

Disorders Rash 7% 4% a Comparators included vancomycin or cefazolin with or without aztreonam in the ABSSSI trial and ceftriaxone alone or ceftriaxone plus vancomycin in the CABP trials Following is a list of additional adverse reactions reported by the 257 patients who received ceftaroline fosamil for injection in the pediatric clinical trials with incidences less than 3%.

Investigations – Alanine aminotransferase increased, Aspartate aminotransferase increased Nervous system disorders – Headache Skin and subcutaneous tissue disorders.

• Pruritus 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ceftaroline fosamil for injection in adult patients.

Because these adverse 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

Agranulocytosis, leukopenia, eosinophilic pneumonia.

Nervous system disorders

Encephalopathy, seizures.

Ceftaroline fosamil for injection overdosage has occurred in patients with renal impairment.

Reactions have included neurological sequelae, including encephalopathy.

In the event of overdose, ceftaroline fosamil for injection should be discontinued and general supportive treatment given.

Ceftaroline can be removed by hemodialysis.

In subjects with

ESRD administered 400 mg of ceftaroline fosamil for injection, the mean total recovery of ceftaroline in the dialysate following a 4-hour hemodialysis session started 4 hours after dosing was 76.5 mg (21.6% of the dose).

However, no information is available on the use of hemodialysis to treat overdosage.

Ceftaroline fosamil for injection is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class.

Anaphylaxis has been reported with ceftaroline.

Known serious hypersensitivity to ceftaroline or other members of the cephalosporin class.

DOSAGE AND ADMINISTRATION Dosage of Ceftaroline Fosamil for Injection by Indication in Adult and Pediatric Patients Indication Age Range Dosage Infusion Time Duration Acute Bacterial Skin and Skin Structure.

Infections (ABSSSI) 18 years and older 600 mg every 12 hours to 60 minutes to 14 days ≥2 years to <18 years (> 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours to 60 minutes to 14 days ≥2 years to <18 years (≤33kg) 12 mg/kg every 8 hours to 60 minutes to 14 days 2 months to <2 years 8 mg/kg every 8 hours to 60 minutes to 14 days 0 to <2 months 6 mg/kg every 8 hours to 60 minutes to 14 days Gestational age 34 weeks and older and postnatal age 12 days and older Indication Age Range Dosage Infusion Time Duration Community Acquired Bacterial Pneumonia (CABP) 18 years and older 600 mg every12 hours to 60 minutes to 7 days ≥2 years to < 18 years (> 33 kg) 400 mg every 8 hours OR 600 mg every12 hours to 60 minutes to 14 days ≥2 years to < 18 years (≤ 33kg) 12 mg/kg every8 hours to 60 minutes to 14 days 2 months to < 2 years 8 mg/kg every8 hours to 60 minutes to 14 days Dosage adjustment is required in adult patients with creatinine clearance (CrCl) <50 mL/min and in End-stage Renal Disease (ESRD) including hemodialysis There is insufficient information to recommend a dosage regimen for pediatric patients with CrCL <50 mL/min/1.73 m 2 2.1 Recommended Dosage in Adult Patients The recommended dosage of ceftaroline fosamil for injection is 600 mg administered every 12 hours by intravenous (IV) infusion over to 60 minutes in patients ≥18 years of age.

The duration of therapy should be guided by the severity and site of infection and the patient’s clinical and bacteriological progress.

The recommended dosage and administration by infection is described in Table 1.

Table 1: Dosage of Ceftaroline Fosamil for Injection by Indication in Adults Indication Dosage Frequency Infusion Time Recommended Duration of Treatment Acute Bacterial Skin and Skin Structure.

Infections (ABSSSI) 600 mg Every 12 hours to 60 minutes 5-14 days Community-Acquired Bacterial Pneumonia (CABP) 600 mg Every 12 hours to 60 minutes 5-7 days 2.2 Recommended Dosage in Pediatric Patients The recommended dosage of ceftaroline fosamil for injection in pediatric patients is based on the age and weight of the child.

The duration of therapy should be guided by the severity, site of infection and the patient’s clinical and bacteriological progress.

Patients 2 Months of Age and Older For pediatric patients 2 months of age and older, ceftaroline fosamil for injection is administered every 8 hours by intravenous infusion over to 60 minutes.

Ceftaroline fosamil for injection dosing regimen is dependent on the type of infection (ABSSSI, CABP).

See dosing

Table 2 below.

Table 2: Dosage of Ceftaroline Fosamil for Injection by Indication in Pediatric Patients 2 Months of Age and Older Indication Age Range Dosage and Frequency Infusion time Recommended Duration of Treatment Acute Bacterial Skin and Skin Structure.

Infections (ABSSSI) OR Community-Acquired Bacterial Pneumonia (CABP) 2 months to < 2 years 8 mg/kg every 8 hours to 60 minutes 5-14 days ≥ 2 years to < 18 years (≤ 33 kg) 12 mg/kg every 8 hours ≥ 2 years to < 18 years (> 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours Pediatric Patients Less Than 2 Months of Age Ceftaroline fosamil for injection are administered every 8 hours by intravenous infusion over to 60 minutes for patients less than 2 months of age.

Ceftaroline fosamil for injection dosing regimen is only recommended for patients with ABSSSI.

Table 3 below.

Concentrations of ceftaroline fosamil in the cerebrospinal fluid have not been evaluated.

There is no information for dosing ceftaroline fosamil for injection in infants less than 34 weeks gestational age and less than 12 days postnatal age.

Table 3: Dosage of Ceftaroline Fosamil for Injection in Pediatric Patients less Than 2 Months of Age Indication Age Range Dosage and Frequency Infusion time Recommended Duration of Treatment Acute Bacterial Skin and Skin Structure.

Infections (ABSSSI) 0 to < 2 months 6 mg/kg every 8 hours to 60 minutes 5-14 days Gestational age 34 weeks and older and postnatal age 12 days and older. 2.3 Dosage Adjustments in Patients with Renal Impairment Adults: No dosage adjustment is required in adult patients with CrCL > 50 mL/min. The dose in adult patients should be adjusted when creatinine clearance (CrCL) is < 50 mL/min as shown below.

Table 4: Dosage of Ceftaroline Fosamil for Injection in Adult Patients with Renal Impairment Estimated CrCl a (mL/min) Recommended Dosage Regimen for Ceftaroline Fosamil for Injection > 50 No dosage adjustment necessary > 30 to ≤ 50 400 mg IV (over to 60 minutes) every 12 hours ≥ 15 to ≤ 30 300 mg IV (over to 60 minutes) every 12 hours End-stage renal disease, including hemodialysis b 200 mg IV (over to 60 minutes) every 12 hours c a Creatinine clearance (CrCl) estimated using the Cockcroft-Gault formula. b End-stage renal disease is defined as CrCl < 15 mL/min. c Ceftaroline fosamil for injection is hemodialyzable; thus, ceftaroline fosamil for injection should be administered after hemodialysis on hemodialysis days.

No dosage adjustment is required in pediatric patients with CrCL > 50 mL/min/1.73 m 2, estimated using the Schwartz equation.

There is insufficient information to recommend a dosage regimen for pediatric patients with CrCL < 50 mL/min/1.73 m 2. 2.4 Preparation of Ceftaroline Fosamil for Injection for Administration Constitution of Ceftaroline Fosamil for Injection Powder for Injection Aseptic technique must be followed in preparing the infusion solution.

The contents of ceftaroline fosamil for injection vial should be constituted with 20 mL Sterile Water for Injection, USP; or 0.9% of sodium chloride injection; or 5% of dextrose injection; or lactated ringer’s injection.

Constitution time is less than 2 minutes.

Mix gently to constitute and check to see that the contents have dissolved completely.

The preparation of ceftaroline fosamil for injection solutions is summarized in Table 5.

Table 5: Preparation of Ceftaroline Fosamil for Injection for Intravenous Use Dosage Strength (mg) Volume of Diluent To Be Added (mL) Approximate Ceftaroline fosamil Concentration (mg/mL) Amount to Be Withdrawn 400 20 20 Adults: Total Volume Pediatric: Volume based on age and weight 600 20 30 Adults: Total Volume Pediatric: Volume based on age and weight * The recommended dosage of ceftaroline fosamil for injection is based on the age and weight of the child.

Table 2 Dilution of the Constituted Solution of Ceftaroline Fosamil for Injection The constituted solution must be further diluted in a range between 50 mL to 250 mL before intravenous infusion into patients.

Use the same diluent used for constitution of the powder for this further dilution, unless sterile water for injection was used earlier.

If sterile water for injection was used earlier, then appropriate infusion solutions include: 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 2.5% Dextrose Injection, USP, and 0.45% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.

Dilution of the Constituted Solution of Ceftaroline Fosamil for Injection in the 50 mL Infusion Bags Only Preparation of 600 mg of ceftaroline fosamil for injection dose in 50 mL infusion bag (for adult patients): Withdraw 20 mL of diluent from the infusion bag.

Proceed to inject entire content of the ceftaroline fosamil for injection vial into the bag to provide a total volume of 50 mL.

The resultant concentration is approximately 12 mg/mL.

Preparation of 400 mg of ceftaroline fosamil for injection dose in 50 mL infusion bag (for adult patients or pediatric patients weighing > 33 kg): Withdraw 20 mL of diluent from the infusion bag.

The resultant concentration is approximately 8 mg/mL.

Preparation of ceftaroline fosamil for injection dose in the infusion bag (for pediatric patients weighing ≤ 33 kg): The amount of solution withdrawn from the constituted ceftaroline fosamil for injection vial for pediatric patients weighing ≤ 33 kg for dilution in the infusion bag will vary according to the weight and age of the child.

The infusion solution concentration for administration should not exceed 12 mg/ml ceftaroline fosamil.

Discard unused portion.

The color of ceftaroline fosamil for injection infusion solutions ranges from clear, light to dark yellow depending on the concentration and storage conditions.

When stored as recommended, the product potency is not affected.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.5 Storage of Constituted Solutions Stability in Baxter ® Mini-Bag Plus ™ : Solutions of ceftaroline fosamil for injection in concentrations ranging from to 12 mg/mL in Baxter Mini-Bag Plus containers with 0.9% Sodium Chloride Injection may be stored for up to 6 hours at room temperature or for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF).

Stability testing in the Baxter Mini-Bag

Plus has solely been conducted on 50 mL and 100 mL containers (0.9% Sodium Chloride Injection).

Studies have shown that the constituted solution in the infusion bag should be used within 6 hours when stored at room temperature or within 24 hours when stored under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). 2.6 Drug Compatibilities The compatibility of ceftaroline fosamil for injection with other drugs has not been established.

Ceftaroline fosamil for injection should not be mixed with or physically added to solutions containing other drugs.

SUPPLIED/STORAGE AND HANDLING Ceftaroline Fosamil for Injection is supplied in single-dose, clear glass vials containing: 400 mg.

• individual vial (NDC 60505-6124-0) and carton containing 10 vials (NDC 60505-6124-1) 600 mg.

• individual vial (NDC 60505-6125-0) and carton containing 10 vials (NDC 60505-6125-1) Ceftaroline fosamil for injection vials (unreconstituted) should be stored at 25°C (77°F); excursions permitted to 15ºC to 30ºC (59°F to 86°F) .

There are no adequate studies with ceftaroline fosamil in pregnant women that informed any drug associated risks.

Th e background risk of major birth defects and miscarriage for the indicated population is unknown.

The background risk of major birth defects is to 4% and of miscarriage is to 20% of clinically recognized pregnancies within the general population.

In developmental toxicity studies conducted in animals, no malformations or other adverse developmental effects were observed in offspring of rats exposed to ceftaroline fosamil at up to 4 times the maximum recommended human dose (MRHD) during the period of organogenesis through lactation.

In rabbits exposed to ceftaroline fosamil during organogenesis at levels approximately equal to the MRHD, no drug-induced fetal malformations were observed despite maternal toxicity.

Developmental toxicity studies performed with ceftaroline fosamil in rats at IV doses up to 300 mg/kg demonstrated no maternal toxicity and no effects on the fetus.

A separate toxicokinetic study showed that ceftaroline exposure in rats (based on AUC) at this dose level was approximately 4 times the exposure in humans given 600 mg every 12 hours.

There were no drug-induced malformations in the offspring of rabbits given IV doses of 25, 50, and 100 mg/kg, despite maternal toxicity.

Signs of maternal toxicity appeared secondary to the sensitivity of the rabbit gastrointestinal system to broad-spectrum antibacterials and included changes in fecal output in all groups and dose-related reductions in body weight gain and food consumption at > 50 mg/kg; these were associated with an increase in spontaneous abortion at and 100 mg/kg. The highest dose was also associated with maternal moribundity and mortality.

An increased incidence of a common rabbit skeletal variation, angulated hyoid alae, was also observed at the maternally toxic doses of and 100 mg/kg. A separate toxicokinetic study showed that ceftaroline exposure in rabbits (based on AUC) was approximately 0.4 times the exposure in humans given 600 mg every 12 hours at 25 mg/kg and 0.7 times the human exposure at 50 mg/kg. Ceftaroline fosamil did not affect the postnatal development or reproductive performance of the offspring of rats given IV doses up to 450 mg/kg/day. Results from a toxicokinetic study conducted in pregnant rats with doses up to 300 mg/kg suggest that exposure was ≥ 4 times the exposure in humans given 600 mg every 12 hours.

No data is available regarding the presence of ceftaroline in human milk, the effects of ceftaroline on breastfed infants, or the effects on milk production.

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

The safety and effectiveness of ceftaroline fosamil for injection in the treatment of ABSSSI have been established in pediatric patients (at least 34 weeks gestational age and 12 days postnatal age).

The safety and effectiveness of ceftaroline fosamil for injection in the treatment of CABP have been established in the age groups 2 months to less than 18 years old.

Use of ceftaroline fosamil for injection in these age groups is supported by evidence from adequate and well-controlled studies of ceftaroline fosamil for injection in adults with additional pharmacokinetic and safety data in pediatric patients 2 months of age and older with ABSSSI or CABP.

Use of ceftaroline fosamil for injection in pediatric patients less than 2 months of age was supported by pharmacokinetic and safety data in 11 infants at least 34 weeks gestational age and 12 days postnatal age.

In these infants, concentrations of ceftaroline fosamil for injection in the cerebrospinal fluid were not evaluated.

Results from the clinical studies in pediatric patients show that ceftaroline fosamil for injection demonstrated a safety profile that was comparable with treatment of ABSSSI and CABP in adults at the clinical dosages studied.

Safety and effectiveness of ceftaroline fosamil for injection in pediatric patients less than 34 weeks gestational age and less than 12 days postnatal age for the treatment of ABSSSI have not been established.

Safety and effectiveness of ceftaroline fosamil for injection in pediatric patients below the age of 2 months for the treatment of CABP have not been established as no data are available.

Of the 1,300 adult patients treated with ceftaroline fosamil for injection in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age.

The clinical cure rates in the ceftaroline fosamil for injection group (Clinically Evaluable [CE] Population) were similar in patients ≥ 65 years of age compared with patients < 65 years of age in both the ABSSSI and CABP trials.

The adverse reaction profiles in patients ≥ 65 years of age and in patients < 65 years of age were similar.

The percentage of patients in the ceftaroline fosamil for injection group who had at least one adverse reaction was 52.4% in patients ≥ 65 years of age and 42.8% in patients < 65 years of age for the two indications combined.

Ceftaroline is excreted primarily by the kidney, and the risk of adverse reactions 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 in this and it may be useful to monitor renal function.

Elderly subjects had greater ceftaroline exposure relative to non-elderly subjects when administered the same single dose of ceftaroline fosamil for injection.

However, higher exposure in elderly subjects was mainly attributed to age-related changes in renal function.

Dosage adjustment for elderly patients should be based on renal function.