Teflaro

1. INDICATIONS AND USAGE Teflaro 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) ( 1.1 ) Community-acquired bacterial pneumonia (CABP) in adult and pediatric patients 2 months of age and older ( 1.2 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Teflaro and other antibacterial drugs, Teflaro should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.3 ) 1.1 Acute Bacterial Skin and Skin Structure Infections Teflaro 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 [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.4 )] . 1.2 Community-Acquired Bacterial Pneumonia Teflaro 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 Teflaro and other antibacterial drugs, Teflaro 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.

2. DOSAGE AND ADMINISTRATION Dosage of Teflaro by Indication in Adult and Pediatric Patients ( 2.1 , 2.2 ) Indication Age Range Dosage Infusion Time Duration Acute Bacterial Skin and Skin Structure Infections (ABSSSI) 18 years and older 600 mg every 12 hours 5 to 60 minutes 5 to 14 days ≥2 years to 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours 5 to 60 minutes 5 to 14 days ≥2 years to 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours 5 to 60 minutes 5 to 14 days ≥2 years to 2 years to 2 years to 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours Pediatric Patients Less Than 2 Months of Age Teflaro is administered every 8 hours by intravenous infusion over 30 to 60 minutes for patients less than 2 months of age. Teflaro dosing regimen is only recommended for patients with ABSSSI. See dosing Table 3 below. Concentrations of Teflaro in the cerebrospinal fluid have not been evaluated [see Use in Specific Populations ( 8.4 )] . There is no information for dosing Teflaro in infants less than 34 weeks gestational age and less than 12 days postnatal age. Table 3: Dosage of Teflaro 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 50 mL/min. The dose in adult patients should be adjusted when creatinine clearance (CrCL) is 50 No dosage adjustment necessary > 30 to ≤ 50 400 mg IV (over 5 to 60 minutes) every 12 hours ≥ 15 to ≤ 30 300 mg IV (over 5 to 60 minutes) every 12 hours End-stage renal disease, including hemodialysis b 200 mg IV (over 5 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 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 33 kg) : Withdraw 20 mL of diluent from the infusion bag. Proceed to inject entire content of the Teflaro vial into the bag to provide a total volume of 50 mL. The resultant concentration is approximately 8 mg/mL. Preparation of Teflaro dose in the infusion bag (for pediatric patients weighing ≤ 33 kg): The amount of solution withdrawn from the constituted Teflaro 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 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. 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 TM : Solutions of Teflaro in concentrations ranging from 4 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 2°C to 8°C (36°F to 46°F). Stability testing in the Baxter Mini-Bag Plus has solely been conducted on 50 mL and 100 mL containers (0.9% Sodium Chloride Injection). Stability in Infusion Bag: 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). 2. 6 Drug Compatibilities 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.

3. DOSAGE FORMS AND STRENGTHS For Injection: Teflaro is supplied as 600 mg or 400 mg of pale yellowish-white to light yellow sterile ceftaroline fosamil (equivalent to 668 mg and 446 mg, respectively, of ceftaroline fosamil monoacetate monohydrate) powder in single-dose, 20 mL clear glass vials. The powder is constituted and further diluted for intravenous injection. For Injection: 600 mg or 400 mg of sterile ceftaroline fosamil powder in single-dose 20 mL vials. The powder is constituted and further diluted for intravenous injection. ( 3 )

4. CONTRAINDICATIONS Teflaro 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. ( 4 )

6. ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Clostridioides difficile -Associated diarrhea [see Warnings and Precautions ( 5.2 )] Neurological Adverse Reactions [see Warnings and Precautions ( 5.3 )] Direct Coombs’ Test Seroconversion [see Warnings and Precautions ( 5.4 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.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. Adult Patients Teflaro was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with Teflaro (600 mg administered by IV over 1 hour every 12h) and 1297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for a treatment period up to 21 days. The median age of patients treated with Teflaro was 54 years, ranging between 18 and 99 years old. Patients treated with Teflaro 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 98/1300 (7.5%) of patients receiving Teflaro and 100/1297 (7.7%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 35/1300 (2.7%) of patients receiving Teflaro and 48/1297 (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 Teflaro group and 0.5% in comparator group. Most Common Adverse Reactions No adverse reactions occurred in greater than 5% of adult patients receiving Teflaro. The most common adverse reactions occurring in > 2% of patients receiving Teflaro in the pooled adult phase 3 clinical trials were diarrhea, nausea, and rash. Table 6 lists adverse reactions occurring in ≥ 2% of patients receiving Teflaro in the pooled adult Phase 3 clinical trials. Table 6: Adverse Reactions Occurring in ≥ 2% of Patients Receiving Teflaro in the Pooled Adult Phase 3 Clinical Trials Adverse Reactions Pooled Phase 3 Clinical Trials (four trials, two in ABSSSI and two in CABP) Teflaro (N=1300) Pooled Comparators a (N=1297) Gastrointestinal D isorders Diarrhea 5 % 3 % Nausea 4 % 4 % Constipation 2 % 2 % Vomiting 2 % 2 % Laboratory Investigations Increased transaminases 2% 3 % Metabolism and N utrition disorders Hypokalemia 2 % 3 % Skin and S ubcutaneous T issue D isorders Rash 3% 2% Vascular D isorders 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 Teflaro Following is a list of additional adverse reactions reported by the 1740 adult patients who received Teflaro 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 - Hypersensitivity, Anaphylaxis Infections and infestations - Clostridioides difficil …

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate studies with Teflaro in pregnant women that informed any drug associated risks. The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% 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 Teflaro at up to 4 times the maximum recommended human dose (MRHD) during the period of organogenesis through lactation. In rabbits exposed to Teflaro during organogenesis at levels approximately equal to the MRHD, no drug-induced fetal malformations were observed despite maternal toxicity. Data Animal Data 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 50 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 50 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. 8. 2 Lactation Risk Summary 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 Teflaro and any potential adverse effects on the breastfed child from Teflaro or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Teflaro 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 Teflaro in the treatment of CABP have been established in the age groups 2 months to less than 18 years old. Use of Teflaro in these age groups is supported by evidence from adequate and well-controlled studies of Teflaro in adults with additional pharmacokinetic and safety data in pediatric patients 2 months of age and older with ABSSSI or CABP [see Clinical Studies ( 14.1 and 14.2 )] . Use of Teflaro 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 Teflaro in the cerebrospinal fluid were not evaluated [see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 ) ] . Results from the clinical studies in pediatric patients show that Teflaro demonstrat …

12.1 Mechanism of Action Ceftaroline is a cephalosporin antibacterial drug [ see Microbiology ( 12.4 )] .

11. DESCRIPTION TEFLARO (ceftaroline fosamil) for injection, is a sterile, semi-synthetic, prodrug of the cephalosporin antibacterial class of beta-lactams (β-lactams) for intravenous use. Chemically, the prodrug, ceftaroline fosamil monoacetate monohydrate 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 monohydrate. Its molecular weight is 762.75. The empirical formula is C 22 H 21 N 8 O 8 PS 4 .C 2 H 4 O 2 .H 2 O. Figure 1: Chemical structure of ceftaroline fosamil Teflaro vials contain either 600 mg or 400 mg of anhydrous ceftaroline fosamil (equivalent to 668 mg and 446 mg, respectively, of ceftaroline fosamil monoacetate monohydrate). The powder for injection is formulated from ceftaroline fosamil monoacetate monohydrate, a pale yellowish-white to light yellow sterile powder. Each vial of 400 mg of anhydrous ceftaroline fosamil includes inactive ingredient L-arginine 263.3 mg/vial as the solubilizer and alkalizing agent. Each vial of 600 mg of anhydrous ceftaroline fosamil includes inactive ingredient L-arginine 395.0 mg/vial as the solubilizer and alkalizing agent. 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 )] . The pH of the constituted solution is pH 4.8 to 6.5. Figure 1: Chemical structure of ceftaroline fosamil

10. OVERDOSAGE Teflaro overdosage has occurred in patients with renal impairment. Reactions have included neurological sequelae, including encephalopathy [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.2 )] . In the event of overdose, Teflaro should be discontinued and general supportive treatment given. Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of Teflaro, 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 [see Clinical Pharmacology ( 12.3 )] .

16. HOW SUPPLIED/STORAGE AND HANDLING Teflaro (ceftaroline fosamil) for injection, a pale yellowish-white to light yellow sterile powder, is supplied in single-dose, 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) Teflaro vials (unreconstituted) should be stored at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature].