Teflaro Drug Information
Generic name: CEFTAROLINE FOSAMIL
Uses of Teflaro
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 .
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.
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.
Dosage & Administration of Teflaro
| Acute Bacterial Skin and Skin Structure Infections (ABSSSI) | 18 years and older | |
|---|---|---|
| ≥2 years to < 18 years (> 33 kg) | 400 mg every 8 hours OR 600 mg every 12 hours | |
| ≥2 years to < 18 years (≤ 33kg) | 12 mg/kg every 8 hours | |
| 2 months to < 2 years | 8 mg/kg every 8 hours | |
| 0* to < 2 months | 6 mg/kg every 8 hours |
Side Effects of Teflaro
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 Teflaro was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with Teflaro (600 mg administered by IV over 1 hour every 12h) and 1297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for a treatment period up to 21 days. The median age of patients treated with Teflaro was 54 years, ranging between 18 and 99 years old.
Patients treated with Teflaro 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 98/1300 (7.5%) of patients receiving Teflaro and 100/1297 (7.7%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 35/1300 (2.7%) of patients receiving Teflaro and 48/1297 (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 Teflaro group and 0.5% in comparator group. Most Common Adverse Reactions No adverse reactions occurred in greater than 5% of adult patients receiving Teflaro.
The most common adverse reactions occurring in > 2% of patients receiving Teflaro in the pooled adult phase 3 clinical trials were diarrhea, nausea, and rash. Table 6 lists adverse reactions occurring in ≥ 2% of patients receiving Teflaro in the pooled adult Phase 3 clinical trials. Table 6: Adverse Reactions Occurring in ≥ 2% of Patients Receiving Teflaro in the Pooled Adult Phase 3 Clinical Trials Adverse Reactions Pooled Phase 3 Clinical Trials (four trials, two in ABSSSI and two in CABP) Teflaro (N=1300) Pooled Comparators a (N=1297) Gastrointestinal D isorders Diarrhea 5 % 3 % Nausea 4 % 4 % Constipation 2 % 2 % Vomiting 2 % 2 % Laboratory Investigations Increased transaminases 2% 3 % Metabolism and N utrition disorders Hypokalemia 2 % 3 % Skin and S ubcutaneous T issue D isorders Rash 3% 2% Vascular D isorders 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 Teflaro Following is a list of additional adverse reactions reported by the 1740 adult patients who received Teflaro 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 Teflaro 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 Teflaro, 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 Teflaro was 5 years, ranging from 2 months to < 18 years of age. Patients treated with Teflaro 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 Teflaro and 3/102 (3%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 10/257 (3.9%) of patients receiving Teflaro 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 Teflaro. Most Common Adverse Reactions No adverse reactions occurred in greater than 8% of pediatric patients receiving Teflaro.
The most common adverse reactions occurring in ≥ 3% of patients receiving Teflaro in the pooled pediatric clinical trials were diarrhea, nausea, vomiting, pyrexia and rash. Table 7 lists adverse reactions occurring in ≥ 3% of patients receiving Teflaro in the pooled pediatric clinical trials. Table 7: Adverse Reactions Occurring in ≥ 3% of Patients Receiving Teflaro in the Pooled Pediatric Clinical Trials Adverse Reactions Pooled Pediatric Clinical Trials (three trials, one in ABSSSI and two in CABP) Teflaro (N= 257 ) Pooled Comparators a (N=102 ) Gastrointestinal D isorders Diarrhea 8 % 10 % Nausea 3 % 1 % Vomiting 5 % 12 % General and Administrative Site disorders Pyrexia 3% 2 % Skin and S ubcutaneous T issue D isorders 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 Teflaro 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
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Teflaro 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
Warnings & Cautions for Teflaro
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.
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.
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 . 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 .
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.
Pregnancy Safety for Teflaro
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.
Pediatric Use of Teflaro
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 . 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 . 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.
Contraindications for Teflaro
4. CONTRAINDICATIONS Teflaro 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.
Overdosage Information for Teflaro
10. OVERDOSAGE Teflaro overdosage has occurred in patients with renal impairment. Reactions have included neurological sequelae, including encephalopathy . In the event of overdose, Teflaro should be discontinued and general supportive treatment given. Ceftaroline can be removed by hemodialysis.
In subjects with ESRD administered 400 mg of Teflaro, 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 .
Clinical Studies of Teflaro
Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Adult Patients
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 ) 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 Study Day 3 in the following subgroup of patients: Patients with lesion size ≥ 75 cm 2 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 9. Table 9: Clinical Responders at Study Day 3 from Two Adult Phase 3 ABSSSI Trials Teflaro n/N (%) Vancomycin/ Aztreonam n/N (%) Treatment Difference (2-sided 95% CI) ABSSSI Trial 1 148/200 135/209
ABSSSI Trial 2 148/200 128/188 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 10) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 11). 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 10: Clinical Cure Rates at TOC from Two Adult Phase 3 ABSSSI Trials Teflaro n/N (%) Vancomycin/ Aztreonam n/N (%) Treatment Difference (2-sided 95% CI) Trial 1 CE 288/316 280/300 -2.2 (-6.6, 2.1) MITT 304/351 297/347 1.0 (-4.2, 6.2) Trial 2 CE 271/294 269/292 0.1 (-4.4., 4.5) MITT 291/342 289/338 -0.4 (-5.8, 5.0) Table 11: Clinical Cure Rates at TOC by Pathogen from Two Adult Integrated Phase 3 ABSSSI Trials Teflaro n/N (%) Vancomycin/Aztreonam n/N (%) Gram-positive: MSSA (methicillin-susceptible) MRSA (methicillin-resistant) 212/228 (93.0%) 142/152 (93.4%) 225/238 (94.5%) 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. Pediatric Patients The ABSSSI pediatric trial was a randomized, parallel-group, active controlled trial in pediatric patients 2 months to < 18 years of age.
A total of 163 children from 2 months to < 18 years of age with clinically documented ABSSSI were enrolled in a randomized, multi-center, multinational, parallel group, active controlled trial comparing Teflaro to vancomycin or cefazolin (each with optional aztreonam). Treatment duration was 5 to 14 days. A switch to oral therapy with either cephalexin, clindamycin, or linezolid after Study Day 3 was 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 primary objective was to evaluate the safety and tolerability of Teflaro. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary. To evaluate the treatment effect of Teflaro, an analysis was conducted in 159 patients with ABSSSI in the MITT population.
This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Study Day 3. The clinical response at Study Day 3 was 80.4% (86/107) for the ceftaroline group and 75.0% (39/52) for the comparator group, with a treatment difference of 5.4% (95% CI of –7.8, 20.3). Clinical cure rates at test of cure visit (8 to 15 days after the end of therapy) for the ABSSSI pediatric trial were 94.4% (101/107) for Teflaro and 86.5% (45/52) for the comparator, with a treatment difference of 7.9 (95% CI –1.2, 20.2). Indeterminate outcomes occurred at rates of 5.6% (6/107) for the ceftaroline group and 11.5% (6/52) for the comparator group, and rates of clinical failure were 0% (0/107) for the ceftaroline group and 1.9% (1/52) for the comparator group. The safety and effectiveness of Teflaro were evaluated in a single study that 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 with known or suspected infections. The majority of patients (8 of 11) received 6 mg/kg Teflaro every 8 hours as an intravenous (IV) infusion over 60 minutes.
Community-Acquired Bacterial Pneumonia (CABP) Adult Patients
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 12. Table 12: Response Rates at Study Day 4 (72-96 hours) from Two Adult 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 13) and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population (Table 14). 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 13: Clinical Cure Rates at TOC from Two Adult 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%)
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 14: Clinical Cure Rates at TOC by Pathogen from Two Adult 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%) Pediatric Patients The CABP pediatric trial was a randomized, parallel-group, active controlled trial in pediatric patients 2 months to < 18 years of age. A total of 161 children with a diagnosis of CABP were enrolled in a randomized, multi-center, multinational, active controlled trial comparing Teflaro with ceftriaxone. Patients with new or progressive pulmonary infiltrate(s) on chest radiography and signs and symptoms consistent with CABP including acute onset or worsening symptoms of cough, tachypnea, sputum production, grunting, chest pain, cyanosis, or increased work of breathing with the need for hospitalization and IV therapy were enrolled in the trial.
Treatment duration was 5 to 14 days. A switch to oral therapy with amoxicillin clavulanate was allowed on Study Day 4. The primary objective was to evaluate the safety and tolerability of Teflaro. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary.
To evaluate the treatment effect of Teflaro, an analysis was conducted in 143 patients with CABP in the MITT population. This analysis evaluated responder rates at Study Day 4 based on achieving improvement in at least 2 out of 7 symptoms (cough, dyspnea, chest pain, sputum production, chills, feeling of warmth / feverish and exercise intolerance or lethargy) and have worsening in none of these symptoms. The clinical response at Study Day 4 was 69.2% (74/107) for Teflaro and 66.7% (24/36) for the comparator, with a treatment difference of 2.5% (95% CI of –13.9, 20.9). Clinical cure rates at test of cure were 87.9% (94/107) for Teflaro and 88.9% (32/36) for the comparator, with a treatment difference of -1.0 (95% CI –11.5, 14.1).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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