Ceftaroline Fosamil

1. INDICATIONS AND USAGE 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) ( 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 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. ( 1.3 ) 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 [see Dosage and Administration (2.2) and Use in Specific Populations ( 8.4 )]. 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.

2. DOSAGE AND ADMINISTRATION Dosage of Ceftaroline Fosamil for Injection 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 <18 years (> 33 kg) 400 mg every 8 hours OR 600 mg every 12 hours 5 to 60 minutes 5 to 14 days ≥2 years to <18 years (≤33kg) 12 mg/kg every 8 hours 5 to 60 minutes 5 to 14 days 2 months to <2 years 8 mg/kg every 8 hours 5 to 60 minutes 5 to 14 days 0* to <2 months 6 mg/kg every 8 hours 30 to 60 minutes 5 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 5 to 60 minutes 5 to 7 days ≥2 years to < 18 years (> 33 kg) 400 mg every 8 hours OR 600 mg every12 hours 5 to 60 minutes 5 to 14 days ≥2 years to < 18 years (≤ 33kg) 12 mg/kg every8 hours 5 to 60 minutes 5 to 14 days 2 months to < 2 years 8 mg/kg every8 hours 5 to 60 minutes 5 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 ( 2.3 ) There is insufficient information to recommend a dosage regimen for pediatric patients with CrCL <50 mL/min/1.73 m 2 ( 2.3 ) 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 5 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 5 to 60 minutes 5-14 days Community-Acquired Bacterial Pneumonia (CABP) 600 mg Every 12 hours 5 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. Pediatric 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 5 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 5 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 30 to 60 minutes for patients less than 2 months of age. Ceftaroline fosamil for injection dosing regimen is only recommended for patients with ABSSSI. See dosing Table 3 below. Concentrations of ceftaroline fosamil in the cerebrospinal fluid have not been evaluated [see Use in Specific Populations ( 8.4 )]. 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 Ceft…

5. WARNINGS AND PRECAUTIONS Serious hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs, including ceftaroline. If a hypersensitivity reaction occurs, discontinue ceftaroline fosamil for injection. ( 5.1 ) Clostridiodes difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ceftaroline fosamil for injection. Evaluate if diarrhea occurs. ( 5.2 ) Neurological adverse reactions have been reported in patients treated with cephalosporins, including ceftaroline. If neurological adverse reactions occur, consider discontinuing ceftaroline fosamil for injection or making appropriate dosage adjustments in patients with renal impairment. ( 2.3 , 5.3 ) Direct Coombs’ test seroconversion has been reported with ceftaroline. If anemia develops during or after therapy, a diagnostic workup for drug- induced hemolytic anemia should be performed and consideration given to discontinuation of ceftaroline fosamil for injection. ( 5.4 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with ceftaroline fosamil for injection is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Maintain clinical supervision if this product is to be given to a penicillin- or other beta-lactam-allergic patient, because cross sensitivity among beta-lactam antibacterial agents has been clearly established. If an allergic reaction to ceftaroline fosamil for injection occurs, discontinue ceftaroline fosamil for injection and institute appropriate treatment and supportive measures. 5.2 Clostridioides difficile - Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ceftaroline fosamil for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions ( 6.1 )]. 5.3 Neurological Adverse Reactions Neurological adverse reactions have been reported during postmarketing surveillance in patients treated with cephalosporins, including ceftaroline fosamil for injection. These reactions include encephalopathy and seizures [see Adverse Reactions ( 6.2 )] . Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment. The neurological adverse reactions were reversible and resolved after discontinuation of ceftaroline fosamil for injection or after hemodialysis. If neurological adverse reactions associated with ceftaroline fosamil for injection therapy occur, consider discontinuing ceftaroline fosamil for injection or making appropriate dosage adjustments in patients with renal impairment [see Dosage and Administration ( 2.3 )] . 5.4 Direct Coombs' Test Seroconversion Seroconversion from a negative to a positive direct Coombs’ test result occurred in 120/1,114 (10.8%) o…

4. CONTRAINDICATIONS 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. ( 4 )

8.1 Pregnancy Risk Summary 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 2 to 4% and of miscarriage is 15 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. 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 ceftaroline fosamil and any potential adverse effects on the breastfed child from ceftaroline fosamil or from the underlying maternal condition.

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 Apotex Corp. at 1-800-706-5575 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 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 18 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. Most Common Adverse Reactions 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 s…