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.

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%) of adult patients receiving ceftaroline fosamil for injection and 49/1,116 (4.4%) of patients receiving comparator drugs in the four pooled adult Phase 3 trials. In the pooled adult Phase 3 CABP trials, 51/520 (9.8%) of ceftaroline fosamil for injection-treated patients compared to 24/534 (4.5%) of ceftriaxone-treated patients seroconverted from a negative to a positive direct Coombs’ test result. No adverse reactions representing hemolytic anemia were reported in any treatment group. Seroconversion from a negative to a positive direct Coombs’ test result occurred in 42/234 (17.9%) of children receiving ceftaroline fosamil for injection and 3/93 (3.2%) of patients receiving comparator drugs in the three pooled pediatric trials. No adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with ceftaroline fosamil for injection, drug-induced hemolytic anemia should be considered. Diagnostic studies including a direct Coombs’ test, should be performed. If drug-induced hemolytic anemia is suspected, discontinuation of ceftaroline fosamil for injection should be considered and supportive care should be administered to the patient (i.e. transfusion) if clinically indicated. 5.5 Development of Drug-Resistant Bacteria Prescribing ceftaroline fosamil for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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 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 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. Most Common Adverse Reactions 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 [see Warnings and Precautions (5.3)]

8. USE IN SPECIFIC POPULATIONS 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. 8.4 Pediatric Use 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 [see Clinical Studies ( 14.1 and 14.2)]. 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 [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. 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. 8.5 Geriatric Use 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 30 to ≤ 50 mL/min) or severe (CrCl ≥ 15 to ≤ 30 mL/min) renal impairment and in patients with end-stage renal disease (ESRD – defined as CrCl < 15 mL/min), including patients on hemodialysis (HD). There is insufficient information to recommend a dosage regimen for pediatric patients with CrCl < 50 mL/min [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] .

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.