Ceftaroline Fosamil Drug Information

2. DOSAGE AND ADMINISTRATION Dosage of Ceftaroline Fosamil for Injection by *Gestational age 34 weeks and older and postnatal age 12 days and older adjustment is required in adult patients with creatinine clearance (CrCl) <50 mL/min and in End-stage Renal Disease (ESRD) including hemodialysis There is insufficient information to recommend a dosage regimen for pediatric patients with CrCL <50 mL/min/1.73 m 2 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 in Pediatric Patients The recommended dosage of ceftaroline fosamil for injection in pediatric patients is based on the age and weight of the child. Ceftaroline fosamil for injection dosing regimen is dependent on the type of infection (ABSSSI, CABP).

See dosing Table 2 below. 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. 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 Ceftaroline Fosamil for Injection in Pediatric Patients less Than 2 Months of Age *Gestational age 34 weeks and older and postnatal age 12 days and older. 2.3 Dosage Adjustments in Patients with Renal Impairment Adults: No dosage adjustment is required in adult patients with CrCL > 50 mL/min.

The dose in adult patients should be adjusted when creatinine clearance (CrCL) is < 50 mL/min as shown below (see Table 4). Table 4: Dosage of Ceftaroline Fosamil for Injection in Adult Patients with Renal Impairment a Creatinine clearance (CrCl) estimated using the Cockcroft-Gault formula. b End-stage renal disease is defined as CrCl < 15 mL/min. c Ceftaroline fosamil for injection is hemodialyzable; thus, ceftaroline fosamil for injection should be administered after hemodialysis on hemodialysis days. Pediatrics: No dosage adjustment is required in pediatric patients with 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 < 50 mL/min/1.73 m 2. 2.4 Preparation of Ceftaroline Fosamil for Injection for Administration Constitution of Ceftaroline Fosamil for Injection Powder for Injection Aseptic technique must be followed in preparing the infusion solution. The contents of ceftaroline fosamil for injection vial should be constituted with 20 mL Sterile Water for Injection, USP; or 0.9% of sodium chloride injection; or 5% of dextrose injection; or lactated ringer’s injection. Constitution time is less than 2 minutes.

Mix gently to constitute and check to see that the contents have dissolved completely. The preparation of ceftaroline fosamil for injection solutions is summarized in Table 5. Table 5: Preparation of Ceftaroline Fosamil for Injection for Intravenous Use The recommended dosage of ceftaroline fosamil for injection is based on the age and weight of the child.

See Table 2 Dilution of the Constituted Solution of Ceftaroline Fosamil for Injection The constituted solution must be further diluted in a range between 50 mL to 250 mL before intravenous infusion into patients. Use the same diluent used for constitution of the powder for this further dilution, unless sterile water for injection was used earlier. If sterile water for injection was used earlier, then appropriate infusion solutions include: 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 2.5% Dextrose Injection, USP, and 0.45% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP.

Dilution of the Constituted Solution of Ceftaroline Fosamil for Injection in the 50 mL Infusion Bags Only Preparation of 600 mg of ceftaroline fosamil for injection dose in 50 mL infusion bag (for adult patients): Withdraw 20 mL of diluent from the infusion bag. Proceed to inject entire content of the ceftaroline fosamil for injection vial into the bag to provide a total volume of 50 mL. The resultant concentration is approximately 12 mg/mL.

Preparation of 400 mg of ceftaroline fosamil for injection dose in 50 mL infusion bag (for adult patients or pediatric patients weighing > 33 kg): Withdraw 20 mL of diluent from the infusion bag. The resultant concentration is approximately 8 mg/mL. Preparation of ceftaroline fosamil for injection dose in the infusion bag (for pediatric patients weighing ≤ 33 kg): The amount of solution withdrawn from the constituted ceftaroline fosamil for injection 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 ceftaroline fosamil for injection 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 ™: Solutions of ceftaroline fosamil for injection 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 2ºC to 8ºC (36ºF to 46ºF). 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 2ºC to 8ºC (36ºF to 46ºF). 2.6 Drug Compatibilities The compatibility of ceftaroline fosamil for injection with other drugs has not been established. Ceftaroline fosamil for injection should not be mixed with or physically added to solutions containing other drugs.

6. ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section Hypersensitivity Reactions Clostridioides difficile -Associated diarrhea Neurological Adverse Reactions Direct Coombs’ Test Seroconversion 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.

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%). 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. 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%). 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.

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: Adverse Reactions Occurring in ≥ 3% of Patients Receiving Ceftaroline Fosamil for Injection in the Pooled Pediatric Clinical 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

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. 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. 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.

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.

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. 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.

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.

10. OVERDOSAGE Ceftaroline fosamil for injection overdosage has occurred in patients with renal impairment. Reactions have included neurological sequelae, including encephalopathy.

In the event of overdose, ceftaroline fosamil for injection should be discontinued and general supportive treatment given. Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of ceftaroline fosamil for injection, 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.