TEFLARO™ (ceftaroline fosamil) powder, for solution

Initial U.S. Approval: 2010
DESCRIPTION
Teflaro is a sterile, semi-synthetic, broad-spectrum, prodrug antibacterial of cephalosporin class of beta-lactams (β-lactams).
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].

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

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

Mechanism of Action
Ceftaroline is an antibacterial drug.

Microbiology
Mode of Action

Ceftaroline is a cephalosporin 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.

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 vitro studies 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, both in vitro and in clinical infections [see Indications and Usage].

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 following in vitro data are available, but their clinical significance is unknown. Ceftaroline exhibits in vitro MICs 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 of in vitro susceptibility 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.

INDICATIONS AND USAGE
Teflaro™ (ceftaroline fosamil) is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms.

Acute Bacterial Skin and Skin Structure Infections
Teflaro is indicated 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.

Community-Acquired Bacterial Pneumonia
Teflaro is indicated 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.

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Teflaro and other antibacterial drugs, Teflaro should be used to treat only ABSSSI or CABP 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

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

WARNINGS AND PRECAUTIONS
Serious hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibiotics, including ceftaroline. Exercise caution in patients with known hypersensitivity to beta-lactam antibiotics.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including Teflaro. Evaluate if diarrhea occurs.

Direct Coombs' test seroconversion has been reported with Teflaro. If anemia develops during or after therapy, a diagnostic workup for drug-induced hemolytic anemia should be performed and consideration given to discontinuation of Teflaro.

USE IN SPECIFIC POPULATIONS
Dosage adjustment is required in patients with moderate or severe renal impairment and in ESRD patients, including patients on hemodialysis.

The most common adverse reactions occurring in >2 % of patients are diarrhea, nausea, and rash.

To report SUSPECTED ADVERSE REACTIONS, contact Forest Pharmaceuticals, Inc., at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

Recommended Dosage
The recommended dosage of Teflaro is 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour 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 Teflaro by Infection

Infection	Dosage	Frequency	Infusion Time (hours)	Recommended Duration of Total Antimicrobial Treatment
Acute Bacterial Skin and Skin Structure Infection (ABSSSI)	600 mg	Every 12 hours	1	5-14 days
Community-Acquired Bacterial Pneumonia (CABP)	600 mg	Every 12 hours	1	5-7 days

Patients with Renal Impairment

Table 2: Dosage of Teflaro in Patients with Renal Impairment

Estimated CrCla (mL/min)	Recommended Dosage Regimen for Teflaro
> 50	No dosage adjustment necessary
> 30 to ≤ 50	400 mg IV (over 1 hour) every 12 hours
≥ 15 to ≤30	300 mg IV (over 1 hour) every 12 hours
End-stage renal disease, including hemodialysisb	200 mg IV (over 1 hour) every 12 hoursc
a Creatinine clearance (CrCl) estimated using the Cockcroft-Gault formula.
b End-stage renal disease is defined as CrCl < 15 mL/min.
c Teflaro is hemodialyzable; thus Teflaro should be administered after hemodialysis on hemodialysis days.

Preparation of Solutions
Aseptic technique must be followed in preparing the infusion solution. The contents of Teflaro vial should be constituted with 20 mL Sterile Water for Injection, USP. The preparation of Teflaro solutions is summarized in Table 3.

Table 3: Preparation of Teflaro 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	Total Volume
600	20	30	Total Volume

The constituted solution must be further diluted in 250 mL before infusion. Appropriate infusion solutions include:  0.9% Sodium Chloride Injection, USP (normal saline); 5% Dextrose Injection, USP; 2.5% Dextrose Injection, USP, and 0.45% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP. The resulting solution should be administered over approximately 1 hour.

Constitution time is less than 2 minutes. Mix gently to constitute and check to see that the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration.

The color of Teflaro 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.

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 2 to 8º C (36 to 46º F).

The compatibility of Teflaro with other drugs has not been established. Teflaro should not be mixed with or physically added to solutions containing other drugs.

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).