Teflaro

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.

2.1         Recommended Dosage in Adult Patients

The recommended dosage of Teflaro 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. 

2.2        Recommended Dosage in Pediatric Patients

The recommended dosage of Teflaro 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, Teflaro is administered every 8 hours by intravenous infusion over 5 to 60 minutes.
  
• Teflaro dosing regimen is dependent on the type of infection (ABSSSI, CABP). See dosing Table 2 below.

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.

*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).

        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.

Pediatrics: No dosage adjustment is required in pediatric patients with CrCL > 50 mL/min/1.73 m2, estimated using the Schwartz equation. There is insufficient information to recommend a dosage regimen for pediatric patients with CrCL < 50 mL/min/1.73 m2. 

2.4         Preparation of Teflaro for Administration

Constitution of Teflaro Powder for Injection 

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; 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 Teflaro solutions is summarized in Table 5.

        * The recommended dosage of Teflaro is based on the age and weight of the child. See Table 2

Dilution of the Constituted Solution of Teflaro

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 Teflaro in the 50 mL Infusion Bags Only

Preparation of 600 mg of Teflaro 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 Teflaro 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 Teflaro dose in 50 mL infusion bag (for adult patients or pediatric patients weighing > 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™: 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. 

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 demonstrated a safety profile that was comparable with treatment of ABSSSI and CABP in adults at the clinical dosages studied.

Safety and effectiveness of Teflaro 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 Teflaro 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 1300 adult patients treated with Teflaro in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age. The clinical cure rates in the Teflaro 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 Teflaro group who had at least one adverse reaction was 52.4% in patients ≥ 65 years of age and 42.8% in patients < 65 years of age for the two indications combined.

Ceftaroline is excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Elderly subjects had greater ceftaroline exposure relative to non-elderly subjects when administered the same single dose of Teflaro. However, higher exposure in elderly subjects was mainly attributed to age-related changes in renal function. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)]. 

8.6         Patients with Renal Impairment

Dosage adjustment is required in adult patients with moderate (CrCl > 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)].

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 Teflaro 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 Teflaro occurs, discontinue Teflaro 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 Teflaro, 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 Teflaro. 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 Teflaro or after hemodialysis. If neurological adverse reactions associated with Teflaro therapy occur, consider discontinuing Teflaro 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 120/1114 (10.8%) of adult patients receiving Teflaro and 49/1116 (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 Teflaro-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 Teflaro 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 Teflaro, 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 Teflaro 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 Teflaro 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.