February 13, 2016
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Teflaro

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Teflaro




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Clostridium Difficile-Associated Diarrhea

Clostridium 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].

Direct Coombs' Test Seroconversion

Seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving Teflaro and 49/1116 (4.4%) of patients receiving comparator drugs in the four pooled Phase 3 trials.

In the pooled 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.

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.

Development Of Drug-Resistant Bacteria

Prescribing Teflaro in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term carcinogenicity studies have not been conducted with ceftaroline. Ceftaroline fosamil did not show evidence of mutagenic activity in in vitro tests that included a bacterial reverse mutation assay and the mouse lymphoma assay. Ceftaroline was not mutagenic in an in vitro mammalian cell assay. In vivo, ceftaroline fosamil did not induce unscheduled DNA synthesis in rat hepatocytes and did not induce the formation of micronucleated erythrocytes in mouse or rat bone marrow. Both ceftaroline fosamil and ceftaroline were clastogenic in the absence of metabolic activation in an in vitro chromosomal aberration assays, but not in the presence of metabolic activation.

IV injection of ceftaroline fosamil had no adverse effects on fertility of male and female rats given up to 450 mg/kg. This is approximately 4-fold higher than the maximum recommended human dose based on body surface area.

Clinical Trials

Acute Bacterial Skin And Skin Structure Infections (ABSSSI)

A total of 1396 adults with clinically documented complicated skin and skin structure infection were enrolled in two identical randomized, multi-center, multinational, double-blind, non-inferiority trials (Trials 1 and 2) comparing Teflaro (600 mg administered IV over 1 hour every 12 hours) to vancomycin plus aztreonam (1 g vancomycin administered IV over 1 hour followed by 1 g aztreonam administered IV over 1 hour every 12 hours). Treatment duration was 5 to 14 days. A switch to oral therapy was not allowed. The Modified Intent-to-Treat (MITT) population included all patients who received any amount of study drug according to their randomized treatment group. The Clinically Evaluable (CE) population included patients in the MITT population who demonstrated sufficient adherence to the protocol.

To evaluate the treatment effect of ceftaroline, an analysis was conducted in 797 patients with ABSSSI (such as deep/extensive cellulitis or a wound infection [surgical or traumatic]) for whom the treatment effect of antibacterials may be supported by historical evidence. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Trial Day 3 in the following subgroup of patients:

Patients with lesion size ≥ 75 cm² and having one of the following infection types:

  • Major abscess with ≥ 5 cm of surrounding erythema
  • Wound infection
  • Deep/extensive cellulitis

The results of this analysis are shown in Table 8.

Table 8: Clinical Responders at Study Day 3 from Two Phase 3 ABSSSI Trials

  Teflaro n/N (%) Vancomycin/ Aztreonam n/N (%) Treatment Difference (2-sided 95% CI)
ABSSSI Trial 1 148/200 (74.0) 135/209 (64.6) 9.4 (0.4, 18.2)
ABSSSI Trial 2 148/200 (74.0) 128/188 (68.1) 5.9 (-3.1, 14.9)

The protocol-specified analyses included clinical cure rates at the Test of Cure (TOC) (visit 8 to 15 days after the end of therapy) in the co-primary CE and MITT populations (Table 9) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 10). However, there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at a TOC time point. Therefore, comparisons of Teflaro to vancomycin plus aztreonam based on clinical response rates at TOC cannot be utilized to establish non-inferiority.

Table 9: Clinical Cure Rates at TOC from Two Phase 3 ABSSSI Trials

  Teflaro
n/N (%)
Vancomycin/ Aztreonam
n/N (%)
Treatment Difference (2-sided 95% CI)
Trial 1
CE 288/316 (91.1) 280/300 (93.3) -2.2 (-6.6, 2.1)
MITT 304/351 (86.6) 297/347 (85.6) 1.0 (-4.2, 6.2)
Trial 2
CE 271/294 (92.2) 269/292 (92.1) 0.1 (-4.4., 4.5)
MITT 291/342 (85.1) 289/338 (85.5) -0.4 (-5.8, 5.0)

Table 10: Clinical Cure Rates at TOC by Pathogen from Two Integrated Phase 3 ABSSSI Trials

  Teflaro n/N (%) Vancomycin/Aztreonam n/N (%)
Gram-positive:
MSSA (methicillin-susceptible) 212/228 (93.0%) 225/238 (94.5%)
MRSA (methicillin-resistant) 142/152 (93.4%) 115/122 (94.3%)
Streptococcus pyogenes 56/56 (100%) 56/58 (96.6%)
Streptococcus agalactiae 21/22 (95.5%) 18/18 (100%)
Gram-negative:
Escherichia coli 20/21 (95.2%) 19/21 (90.5%)
Klebsiella pneumoniae 17/18 (94.4%) 13/14 (92.9%)
Klebsiella oxytoca 10/12 (83.3%) 6/6 (100%)

Of the 693 patients in the MITT population in the Teflaro arm in the two ABSSSI trials, 20 patients had baseline S. aureus bacteremia (nine MRSA and eleven MSSA). Thirteen of these twenty patients (65%) were clinical responders for ABSSSI at study Day 3 and 18/20 (90%) were considered clinical success for ABSSSI at TOC.

Community-Acquired Bacterial Pneumonia (CABP)

A total of 1231 adults with a diagnosis of CABP were enrolled in two randomized, multi-center, multinational, double-blind, non-inferiority trials (Trials 1 and 2) comparing Teflaro (600 mg administered IV over 1 hour every 12 hours) with ceftriaxone (1 g ceftriaxone administered IV over 30 minutes every 24 hours). In both treatment groups of CABP Trial 1, two doses of oral clarithromycin (500 mg every 12 hours), were administered as adjunctive therapy starting on Study Day 1. No adjunctive macrolide therapy was used in CABP Trial 2. Patients with known or suspected MRSA were excluded from both trials. Patients with new or progressive pulmonary infiltrate(s) on chest radiography and signs and symptoms consistent with CABP with the need for hospitalization and IV therapy were enrolled in the trials. Treatment duration was 5 to 7 days. A switch to oral therapy was not allowed. Among all subjects who received any amount of study drug in the two CABP trials, the 30-day all-cause mortality rates were 11/609 (1.8%) for the Teflaro group vs. 12/610 (2.0%) for the ceftriaxone group, and the difference in mortality rates was not statistically significant.

To evaluate the treatment effect of ceftaroline, an analysis was conducted in CABP patients for whom the treatment effect of antibacterials may be supported by historical evidence. The analysis endpoint required subjects to meet sign and symptom criteria at Day 4 of therapy: a responder had to both (a) be in stable condition, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status; (b) show improvement from baseline on at least one symptom of cough, dyspnea, pleuritic chest pain, or sputum production, while not worsening on any of these four symptoms. The analysis used a microbiological intent-to-treat population (mITT population) containing only subjects with a confirmed bacterial pathogen at baseline. Results for this analysis are presented in Table 11.

Table 11: Response Rates at Study Day 4 (72-96 hours) from Two Phase 3 CABP Trials

  Teflaro n/N (%) Ceftriaxone n/N (%) Treatment Difference (2-sided 95% CI)
CABP Trial 1 48/69 (69.6%) 42/72 (58.3%) 11.2 (-4.6,26.5)
CABP Trial 2 58/84 (69.0%) 51/83 (61.4%) 7.6 (-6.8,21.8)

The protocol-specified analyses included clinical cure rates at the TOC (8 to 15 days after the end of therapy) in the co-primary Modified Intent-to-Treat Efficacy (MITTE) and CE populations (Table 12) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 13). However, there are insufficient historical data to establish the magnitude of drug effect for antibacterials drugs compared with placebo at a TOC time point. Therefore, comparisons of Teflaro to ceftriaxone based on clinical response rates at TOC cannot be utilized to establish non-inferiority. Neither trial established that Teflaro was statistically superior to ceftriaxone in terms of clinical response rates. The MITTE population included all patients who received any amount of study drug according to their randomized treatment group and were in PORT (Pneumonia Outcomes Research Team) Risk Class III or IV. The CE population included patients in the MITTE population who demonstrated sufficient adherence to the protocol. Table 12: Clinical Cure Rates at TOC from Two Phase 3 CABP Trials

Table 12: Clinical Cure Rates at TOC from Two Phase 3 CABP Trials

  Teflaro n/N (%) Ceftriaxone n/N (%) Treatment Difference (2-sided 95% CI)
CABP Trial 1
CE 194/224 (86.6%) 183/234 (78.2%) 8.4 (1.4, 15.4)
MITTE 244/291 (83.8%) 233/300 (77.7%) 6.2 (-0.2, 12.6)
CABP Trial 2
CE 191/232 (82.3%) 165/214 (77.1%) 5.2 (-2.2, 12.8)
MITTE 231/284 (81.3%) 203/269 (75.5%) 5.9 (-1.0, 12.8)

Table 13: Clinical Cure Rates at TOC by Pathogen from Two Integrated Phase 3 CABP Trials

  Teflaro n/N (%)  Ceftriaxone n/N (%) 
Gram-positive:
Streptococcus pneumoniae
 
54/63 (85.7%)  41/59 (69.5%) 
Staphylococcus aureus (methicillin-susceptible isolates only)  18/25 (72.0%)  14/25 (56.0%) 
Gram-negative:
Haemophilus influenzae
 
15/18 (83.3%)  17/20 (85.0%) 
Klebsiella pneumoniae  12/12 (100%)  10/12 (83.3%) 
Klebsiella oxytoca  5/6 (83.3%)  7/8 (87.5%) 
Escherichia coli  10/12 (83.3%)  9/12 (75.0%) 

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Use In Specific Populations

Pregnancy

Category B

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 8 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 0.8 times the exposure in humans given 600 mg every 12 hours at 25 mg/kg and 1.5 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 ≥ 8 times the exposure in humans given 600 mg every 12 hours.

There are no adequate and well-controlled trials in pregnant women. Teflaro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether ceftaroline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Teflaro is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the 1300 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 and CLINICAL PHARMACOLOGY].

Patients With Renal Impairment

Dosage adjustment is required in 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) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 9/15/2015

Warnings
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