Teflaro

Teflaro vials contain either 600 mg or 400 mg of anhydrous ceftaroline fosamil. The powder for injection is formulated from ceftaroline fosamil monoacetate monohydrate, a pale yellowish-white to light yellow sterile powder. All references to ceftaroline activity are expressed in terms of the prodrug, ceftaroline fosamil. The powder is constituted for IV injection[see Dosage and Administration (2.3)].

Each vial of Teflaro contains ceftaroline fosamil and L-arginine, which results in a constituted solution at pH 4.8 to 6.5.

12. CLINICAL PHARMACOLOGY

Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline[ see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Ceftaroline is an antibacterial drug[ see Clinical Pharmacology (12.4)].

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 withS. aureusandS. pneumoniae.

Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of Teflaro 600 mg every 12 hours by IV infusion over 1 hour. For 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.

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of Teflaro 1500 mg, placebo, and a positive control by IV infusion over 1 hour. At the 1500 mg dose of Teflaro, 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 inTable 5. Pharmacokinetic parameters were similar for single and multiple dose administration.

The C_maxand AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 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.

Distribution

The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over 1-50 mcg/mL (14.5-28.0%). 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 (18.3-21.6 L), similar to extracellular fluid volume.

Metabolism

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.

Excretion

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 (0.20) L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.

Specific Populations

Renal Impairment

Following administration of a single 600 mg IV dose of Teflaro, 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 Teflaro, 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[see Dosage and Administration (2.2)].

A single 400 mg dose of Teflaro 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 [see Dosage and Administration (2.2)].

Hepatic Impairment

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.

Geriatric Patients

Following administration of a single 600 mg IV dose of Teflaro 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 (18-45 years of age, n=16). The difference in AUC_0-∞was mainly attributable to age-related changes in renal function. Dosage adjustment for Teflaro in elderly patients should be based on renal function [see Dosage and Administration (2.2)].

Pediatric Patients

The pharmacokinetics of ceftaroline were evaluated in adolescent patients (ages 12 to 17, n=7) with normal renal function following administration of a single 8 mg/kg IV dose of Teflaro (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) in a separate study following administration of a single 600 mg IV dose. However, the mean C_maxand 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.

Gender

Following administration of a single 600 mg IV dose of Teflaro to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean C_maxand AUC_0-∞for ceftaroline were similar between males and females, although there was a trend for higher C_max(17%) and AUC_0-∞(6-15%) in female subjects. Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC_0-taubased on gender in Phase 2/3 patients with ABSSSI or CABP. No dose adjustment is recommended based on gender.

Race

A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 ABSSSI and CABP trials. No significant differences in ceftaroline AUC_0-tauwas 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 Interactions

In vitrostudies 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 vitrostudies 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 Teflaro 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_maxand 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

Mode of Action

Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue to its affinity for PBP2x.

Mechanisms of 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).

Cross-Resistance

Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftaroline.

Interaction with Other Antimicrobials

In vitrostudies have not demonstrated any antagonism between ceftaroline or other commonly used antibacterial agents (e.g., vancomycin, linezolid, daptomycin, levofloxacin, azithromycin, amikacin, aztreonam, tigecycline, and meropenem).

Ceftaroline has been shown to be active against most of the following bacteria, bothin vitroand in clinical infections[see Indications and Usage (1)].

Skin Infections

Gram-positive bacteria

Staphylococcus aureus(including methicillin-susceptible and -resistant isolates)

Streptococcus pyogenes

Streptococcus agalactiae

Gram-negative bacteria

Escherichia coli

Klebsiella pneumoniae

Klebsiella oxytoca

Community-Acquired Bacterial Pneumonia (CABP)

Gram-positive bacteria

Streptococcus pneumoniae

Staphylococcus aureus(methicillin-susceptible isolates only)

Gram-negative bacteria

Haemophilus influenzae

Klebsiella pneumoniae

Klebsiella oxytoca

Escherichia coli

The followingin vitrodata are available, but their clinical significance is unknown. Ceftaroline exhibitsin vitroMICs of 1 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of Teflaro in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Streptococcus dysgalactiae

Gram-negative bacteria

Citrobacter koseri

Citrobacter freundii

Enterobacter cloacae

Enterobacter aerogenes

Moraxella catarrhalis

Morganella morganii

Proteus mirabilis

Haemophilus parainfluenzae

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results ofin vitrosusceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method^1,3, (broth, and/or agar). Broth dilution MICs need to be read within 18 hours due to degradation of ceftaroline activity by 24 hours. The MIC values should be interpreted according to the criteria inTable 6.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method. This procedure uses paper disks impregnated with 30 mcg of ceftaroline to test the susceptibility of bacteria to ceftaroline. The disk diffusion interpretive criteria are provided inTable 6.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.^{1, 2, 3}Standard ceftaroline powder should provide the following range of MIC values provided inTable 7. For the diffusion technique using the 30-mcg ceftaroline disk the criteria provided inTable 7should be achieved.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with ceftaroline.

Ceftaroline fosamil did not show evidence of mutagenic activity inin vitrotests that included a bacterial reverse mutation assay and the mouse lymphoma assay. Ceftaroline was not mutagenic in anin vitromammalian cell assay.In vivo, ceftaroline fosamil did not induce unscheduled DNA synthesis in rat hepatocytes and did not induce the formation of micronucleated erythrocytes in mouse or rat bone marrow. Both ceftaroline fosamil and ceftaroline were clastogenic in the absence of metabolic activation in anin vitrochromosomal aberration assays, but not in the presence of metabolic activation.

IV injection of ceftaroline fosamil had no adverse effects on fertility of male and female rats given up to 450 mg/kg. This is approximately 4-fold higher than the maximum recommended human dose based on body surface area.

14. CLINICAL TRIALS

14.1 Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

A total of 1396 adults with clinically documented complicated skin and skin structure infection were enrolled in two identical randomized, multi-center, multinational, double-blind, non-inferiority trials (Trials 1 and 2) comparing Teflaro (600 mg administered IV over 1 hour every 12 hours) to vancomycin plus aztreonam (1 g vancomycin administered IV over 1 hour followed by 1 g aztreonam administered IV over 1 hour every 12 hours). Treatment duration was 5 to 14 days. A switch to oral therapy was not allowed. The Modified Intent-to-Treat (MITT) population included all patients who received any amount of study drug according to their randomized treatment group. The CE population included patients in the MITT population who demonstrated sufficient adherence to the protocol.

To evaluate the treatment effect of ceftaroline, an analysis was conducted in 797 patients with ABSSSI (such as deep/extensive cellulitis or a wound infection [surgical or traumatic]) for whom the treatment effect of antibacterials may be supported by historical evidence. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Trial Day 3 in the following subgroup of patients:

Patients with lesion size ≥ 75 cm²and having one of the following infection types:

• Major abscess with ≥ 5 cm of surrounding erythema
• Wound infection
• Deep/extensive cellulitis

The results of this analysis are shown inTable 8.

The protocol-specified analyses included clinical cure rates at the Test of Cure (TOC) (visit 8 to 15 days after the end of therapy) in the co-primary CE and MITT populations (Table 9) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 10). However, there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at a TOC time point. Therefore, comparisons of Teflaro to vancomycin plus aztreonam based on clinical response rates at TOC can not be utilized to establish non-inferiority.

14.2 Community-Acquired Bacterial Pneumonia (CABP)

A total of 1231 adults with a diagnosis of CABP were enrolled in two randomized, multi-center, multinational, double-blind, non-inferiority trials (Trials 1 and 2) comparing Teflaro (600 mg administered IV over 1 hour every 12 hours) with ceftriaxone (1 g ceftriaxone administered IV over 30 minutes every 24 hours). In both treatment groups of CABP Trial 1, two doses of oral clarithromycin (500 mg every 12 hours), were administered as adjunctive therapy starting on Study Day 1. No adjunctive macrolide therapy was used in CABP Trial 2. Patients with known or suspected MRSA were excluded from both trials. Patients with new or progressive pulmonary infiltrate(s) on chest radiography and signs and symptoms consistent with CABP with the need for hospitalization and IV therapy were enrolled in the trials. Treatment duration was 5 to 7 days. A switch to oral therapy was not allowed. Among all subjects who received any amount of study drug in the two CABP trials, the 30-day all-cause mortality rates were 11/609 (1.8%) for the Teflaro group vs. 12/610 (2.0%) for the ceftriaxone group, and the difference in mortality rates was not statistically significant.

To evaluate the treatment effect of ceftaroline, an analysis was conducted in CABP patients for whom the treatment effect of antibacterials may be supported by historical evidence. The analysis endpoint required subjects to meet sign and symptom criteria at Day 4 of therapy: a responder had to both (a) be in stable condition according to consensus treatment guidelines of the Infectious Diseases Society of America and American Thoracic Society, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status;⁴(b) show improvement from baseline on at least one symptom of cough, dyspnea, pleuritic chest pain, or sputum production, while not worsening on any of these four symptoms. The analysis used a microbiological intent-to-treat population (mITT population) containing only subjects with a confirmed bacterial pathogen at baseline. Results for this analysis are presented inTable 11.

The protocol-specified analyses included clinical cure rates at the TOC (8 to 15 days after the end of therapy) in the co-primary Modified Intent-to-Treat Efficacy (MITTE) and CE populations (Table 12) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 13). However, there are insufficient historical data to establish the magnitude of drug effect for antibacterials drugs compared with placebo at a TOC time point. Therefore, comparisons of Teflaro to ceftriaxone based on clinical response rates at TOC cannot be utilized to establish non-inferiority. Neither trial established that Teflaro was statistically superior to ceftriaxone in terms of clinical response rates. The MITTE population included all patients who received any amount of study drug according to their randomized treatment group and were in PORT (Pneumonia Outcomes Research Team) Risk Class III or IV. The CE population included patients in the MITTE population who demonstrated sufficient adherence to the protocol.

15. REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
• Mandell, L.A., Wunderink, R.G., Anzueto, A., Bartlett, J.G., Campbell, G.D., Dean, N.C., Dowell, S.F., File, T.M., Musher, D.M., Niederman, M.S., Torres, A., Whitney, C.G. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Disease. 2007; 44:S27-72.

16. HOW SUPPLIED/STORAGE AND HANDLING

Teflaro (ceftaroline fosamil) for injection is supplied in single-use, clear glass vials containing:

• 600 mg - individual vial (NDC 0456-0600-01) and carton containing 10 vials (NDC 0456-0600-10)
• 400 mg - individual vial (NDC 0456-0400-01) and carton containing 10 vials (NDC 0456-0400-10)

Unreconstituted Teflaro vials should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

17. PATIENT COUNSELING INFORMATION

• Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to Teflaro, other beta-lactams (including cephalosporins) or other allergens.
• Patients should be counseled that antibacterial drugs including Teflaro should be used to treat only bacterial infections. They do not treat viral infections (e.g., the common cold). When Teflaro 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 Teflaro or other antibacterial drugs in the future.
• Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. 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, patients should contact their healthcare provider.
• Keep out of reach of children

Teflaro^®(ceftaroline fosamil) for injection

Distributed by:
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045, USA

Manufactured by:
Facta Farmaceutici S.p.A.
Nucleo Industriale S. Atto–S. Nicolò a Tordino
64020 Teramo, Italy

Teflaro® is a registered trademark of Forest Laboratories, Inc.

Baxter® is a registered trademark and Mini-Bag Plus™ is a trademark of Baxter International Inc.

IF95USCFR09
©2010-2013 Forest Laboratories, Inc. All rights reserved.

Principal Display Panel – 400 mg Vial Label

Rx only NDC 0456-0400-01

Teflaro^®
ceftaroline fosamil for injection
400 mg/vial

For Intravenous Infusion Only.

See package insert for dosage information.

Single use vial – Discard after use