Ceftaroline fosamil: Difference between revisions
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* Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline. | * Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline. | ||
|warnings======Hypersensitivity Reactions===== | |warnings======Hypersensitivity Reactions===== | ||
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Before therapy with | Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Before therapy with ceftaroline fosamil is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established. | ||
If an allergic reaction to | If an allergic reaction to ceftaroline fosamil occurs, the drug should be discontinued. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated. | ||
=====Clostridium difficile-associated Diarrhea===== | =====Clostridium difficile-associated Diarrhea===== | ||
Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including | Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ceftaroline fosamil, 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 ofC. difficile. | Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth ofC. difficile. | ||
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=====Direct Coombs' Test Seroconversion===== | =====Direct Coombs' Test Seroconversion===== | ||
Seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving | Seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving ceftaroline fosamil 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 | In the pooled Phase 3 CABP trials, 51/520 (9.8%) of ceftaroline fosamil-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 | If anemia develops during or after treatment with ceftaroline fosamil, 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 should be considered and supportive care should be administered to the patient (i.e. transfusion) if clinically indicated. | ||
=====Development of Drug-Resistant Bacteria===== | =====Development of Drug-Resistant Bacteria===== | ||
Prescribing | Prescribing ceftaroline fosamil 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. | ||
|clinicalTrials=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. | |clinicalTrials=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. | ||
ceftaroline fosamil was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with ceftaroline fosamil (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 ceftaroline fosamil was 54 years, ranging between 18 and 99 years old. Patients treated with ceftaroline fosamil were predominantly male (63%) and Caucasian (82%). | |||
=====Serious Adverse Events and Adverse Events Leading to Discontinuation===== | =====Serious Adverse Events and Adverse Events Leading to Discontinuation===== | ||
In the four pooled Phase 3 clinical trials, serious adverse events occurred in 98/1300 (7.5%) of patients receiving | In the four pooled Phase 3 clinical trials, serious adverse events occurred in 98/1300 (7.5%) of patients receiving ceftaroline fosamil and 100/1297 (7.7%) of patients receiving comparator drugs. The most common SAEs in both the ceftaroline fosamil and comparator treatment groups were in the respiratory and infection system organ classes (SOC). Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving ceftaroline fosamil and 48/1297 (3.7%) of patients receiving comparator drugs with the most common adverse events leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the ceftaroline fosamil group and 0.5% in comparator group. | ||
=====Most Common Adverse Reactions===== | =====Most Common Adverse Reactions===== | ||
No adverse reactions occurred in greater than 5% of patients receiving | No adverse reactions occurred in greater than 5% of patients receiving ceftaroline fosamil. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline fosamil in the pooled phase 3 clinical trials were diarrhea, nausea, and rash. | ||
[[File:Ceftaroline fosamil adverse reactions.png|thumb|none|600px]] | [[File:Ceftaroline fosamil adverse reactions.png|thumb|none|600px]] | ||
=====Other Adverse Reactions Observed During Clinical Trials of | =====Other Adverse Reactions Observed During Clinical Trials of ceftaroline fosamil===== | ||
Following is a list of additional adverse reactions reported by the 1740 patients who received | Following is a list of additional adverse reactions reported by the 1740 patients who received ceftaroline fosamil in any clinical trial with incidences less than 2%. Events are categorized by System Organ Class. | ||
* Blood and lymphatic system disorders- Anemia, Eosinophilia, Neutropenia, Thrombocytopenia | * Blood and lymphatic system disorders- Anemia, Eosinophilia, Neutropenia, Thrombocytopenia | ||
* Cardiac disorders- Bradycardia, Palpitations | * Cardiac disorders- Bradycardia, Palpitations | ||
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* Renal and urinary disorders- Renal failure | * Renal and urinary disorders- Renal failure | ||
* Skin and subcutaneous tissue disorders- Urticaria | * Skin and subcutaneous tissue disorders- Urticaria | ||
|drugInteractions=No clinical drug-drug interaction studies have been conducted with | |drugInteractions=No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil. There is minimal potential for drug-drug interactions between ceftaroline fosamil and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow. | ||
|FDAPregCat=B | |FDAPregCat=B | ||
|useInPregnancyFDA=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. | |useInPregnancyFDA=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. | ||
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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. | 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. | There are no adequate and well-controlled trials in pregnant women. ceftaroline fosamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. | ||
|useInNursing=It is not known whether ceftaroline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when | |useInNursing=It is not known whether ceftaroline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftaroline fosamil is administered to a nursing woman. | ||
|useInPed=Safety and effectiveness in pediatric patients have not been established. | |useInPed=Safety and effectiveness in pediatric patients have not been established. | ||
|useInGeri=Of the 1300 patients treated with | |useInGeri=Of the 1300 patients treated with ceftaroline fosamil in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age. The clinical cure rates in the ceftaroline fosamil 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 event profiles in patients ≥ 65 years of age and in patients < 65 years of age were similar. The percentage of patients in the | The adverse event profiles in patients ≥ 65 years of age and in patients < 65 years of age were similar. The percentage of patients in the ceftaroline fosamil group who had at least one adverse event 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 | 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 ceftaroline fosamil. 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. | ||
|useInGender=Following administration of a single 600 mg IV dose of | |useInGender=Following administration of a single 600 mg IV dose of ceftaroline fosamil to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean Cmaxand AUC0-∞for ceftaroline were similar between males and females, although there was a trend for higher Cmax(17%) and AUC0-∞(6-15%) in female subjects. Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC0-taubased on gender in Phase 2/3 patients with ABSSSI or CABP. No dose adjustment is recommended based on gender. | ||
|useInRace=A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 ABSSSI and CABP trials. No significant differences in ceftaroline AUC0-tauwas observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients. Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions. No dosage adjustment is recommended based on race. | |useInRace=A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 ABSSSI and CABP trials. No significant differences in ceftaroline AUC0-tauwas observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients. Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions. No dosage adjustment is recommended based on race. | ||
|useInRenalImpair=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). | |useInRenalImpair=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). | ||
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|useInReproPotential=V 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. | |useInReproPotential=V 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. | ||
|administration=Intravenous | |administration=Intravenous | ||
|overdose=In the event of overdose, | |overdose=In the event of overdose, ceftaroline fosamil should be discontinued and general supportive treatment given. | ||
Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of | Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of ceftaroline fosamil, 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. | ||
|mechAction=Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue to its affinity for PBP2x. | |mechAction=Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue to its affinity for PBP2x. | ||
|structure=The empirical formula is C22H21N8O8PS4.C2H4O2.H2O. | |structure=The empirical formula is C22H21N8O8PS4.C2H4O2.H2O. | ||
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|PD=As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model withS. aureusandS. pneumoniae. | |PD=As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model withS. aureusandS. pneumoniae. | ||
Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of | Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of ceftaroline fosamil 600 mg every 12 hours by IV infusion over 1 hour. For Phase 3 CABP trials, an exposure-response relationship could not be identified due to the limited range of ceftaroline exposures in the majority of patients. | ||
======Cardiac Electrophysiology====== | ======Cardiac Electrophysiology====== | ||
In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of | In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of ceftaroline fosamil 1500 mg, placebo, and a positive control by IV infusion over 1 hour. At the 1500 mg dose of ceftaroline fosamil, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. | ||
|PK=The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized inTABLE 5. Pharmacokinetic parameters were similar for single and multiple dose administration. | |PK=The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized inTABLE 5. Pharmacokinetic parameters were similar for single and multiple dose administration. | ||
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Ceftaroline fosamil did not show evidence of mutagenic activity inin vitrotests that included a bacterial reverse mutation assay and the mouse lymphoma assay. Ceftaroline was not mutagenic in anin vitromammalian 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 anin vitrochromosomal aberration assays, but not in the presence of metabolic activation. | Ceftaroline fosamil did not show evidence of mutagenic activity inin vitrotests that included a bacterial reverse mutation assay and the mouse lymphoma assay. Ceftaroline was not mutagenic in anin vitromammalian 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 anin vitrochromosomal aberration assays, but not in the presence of metabolic activation. | ||
|clinicalStudies======Acute Bacterial Skin and Skin Structure Infections (ABSSSI)===== | |clinicalStudies======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 | 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 ceftaroline fosamil (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 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: | 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: | ||
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[[File:Ceftaroline fosamil Clinical Responders at Study Day 3 from Two Phase 3 ABSSSI Trials.png|thumb|none|400px]] | [[File:Ceftaroline fosamil Clinical Responders at Study Day 3 from Two Phase 3 ABSSSI Trials.png|thumb|none|400px]] | ||
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 and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population. 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 | 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 and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population. 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 ceftaroline fosamil to vancomycin plus aztreonam based on clinical response rates at TOC can not be utilized to establish non-inferiority. | ||
[[File:Ceftaroline fosamil Clinical Cure Rates at TOC.png|thumb|none|500px]] | [[File:Ceftaroline fosamil Clinical Cure Rates at TOC.png|thumb|none|500px]] | ||
=====Community-Acquired Bacterial Pneumonia (CABP)===== | =====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 | 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 ceftaroline fosamil (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 ceftaroline fosamil 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 according to consensus treatment guidelines of the Infectious Diseases Society of America and American Thoracic Society, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status;4(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 inTABLE 11. | 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 according to consensus treatment guidelines of the Infectious Diseases Society of America and American Thoracic Society, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status;4(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 inTABLE 11. | ||
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[[File:Ceftaroline fosamil Response Rates at Study Day 4 from Two Phase 3 CABP Trials.png|thumb|none|400px]] | [[File:Ceftaroline fosamil Response Rates at Study Day 4 from Two Phase 3 CABP Trials.png|thumb|none|400px]] | ||
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 | 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 ceftaroline fosamil to ceftriaxone based on clinical response rates at TOC cannot be utilized to establish non-inferiority. Neither trial established that ceftaroline fosamil 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. | ||
[[File:Ceftaroline fosamil Clinical Cure Rates at TOC from Two Phase 3 CABP Trials.png|thumb|none|600px]] | [[File:Ceftaroline fosamil Clinical Cure Rates at TOC from Two Phase 3 CABP Trials.png|thumb|none|600px]] | ||
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|packLabel=[[File:Ceftaroline fosamil 400 mg FDA package label.png|thumb|none|600px]] | |packLabel=[[File:Ceftaroline fosamil 400 mg FDA package label.png|thumb|none|600px]] | ||
[[File:Ceftaroline fosamil 600 mg FDA package label.png|thumb|none|600px]] | [[File:Ceftaroline fosamil 600 mg FDA package label.png|thumb|none|600px]] | ||
|fdaPatientInfo=* Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to | |fdaPatientInfo=* Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to ceftaroline fosamil, other beta-lactams (including cephalosporins) or other allergens. | ||
* Patients should be counseled that antibacterial drugs including | * Patients should be counseled that antibacterial drugs including ceftaroline fosamil should be used to treat only bacterial infections. They do not treat viral infections (e.g., the common cold). When ceftaroline fosamil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: | ||
# decrease the effectiveness of the immediate treatment and | # decrease the effectiveness of the immediate treatment and | ||
# increase the likelihood that bacteria will develop resistance and will not be treatable by | # increase the likelihood that bacteria will develop resistance and will not be treatable by ceftaroline fosamil or other antibacterial drugs in the future. | ||
* Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider. | * Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider. | ||
* Keep out of reach of children | * Keep out of reach of children | ||
|alcohol=Alcohol-Ceftaroline fosamil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. | |alcohol=Alcohol-Ceftaroline fosamil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. | ||
}} | }} | ||
Revision as of 20:56, 30 January 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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Overview
Ceftaroline fosamil is a 5th generation cephalosporin that is FDA approved for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia. Common adverse reactions include diarrhea, nausea and rash.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Ceftaroline fosamil is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms.
Acute Bacterial Skin and Skin Structure Infections
- 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.
- Dosage: 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour for 5-14 days.
Community-Acquired Bacterial Pneumonia
- 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,andEscherichia coli.
- Dosage: 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour for 5-7 days.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftaroline fosamil in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftaroline fosamil in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in children
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftaroline fosamil in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftaroline fosamil in pediatric patients.
Contraindications
- Ceftaroline fosamil is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class.
- Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.
Warnings
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Before therapy with ceftaroline fosamil is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established.
If an allergic reaction to ceftaroline fosamil occurs, the drug should be discontinued. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.
Clostridium difficile-associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ceftaroline fosamil, 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 ofC. difficile.
C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains ofC. difficilecause 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 againstC. difficileshould be discontinued, if possible. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment ofC. difficile, and surgical evaluation should be instituted as clinically indicated.
Direct Coombs' Test Seroconversion
Seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving ceftaroline fosamil 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 ceftaroline fosamil-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 ceftaroline fosamil, 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 should be considered and supportive care should be administered to the patient (i.e. transfusion) if clinically indicated.
Development of Drug-Resistant Bacteria
Prescribing ceftaroline fosamil 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.
Adverse Reactions
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.
ceftaroline fosamil was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with ceftaroline fosamil (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 ceftaroline fosamil was 54 years, ranging between 18 and 99 years old. Patients treated with ceftaroline fosamil were predominantly male (63%) and Caucasian (82%).
Serious Adverse Events and Adverse Events Leading to Discontinuation
In the four pooled Phase 3 clinical trials, serious adverse events occurred in 98/1300 (7.5%) of patients receiving ceftaroline fosamil and 100/1297 (7.7%) of patients receiving comparator drugs. The most common SAEs in both the ceftaroline fosamil and comparator treatment groups were in the respiratory and infection system organ classes (SOC). Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving ceftaroline fosamil and 48/1297 (3.7%) of patients receiving comparator drugs with the most common adverse events leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the ceftaroline fosamil group and 0.5% in comparator group.
Most Common Adverse Reactions
No adverse reactions occurred in greater than 5% of patients receiving ceftaroline fosamil. The most common adverse reactions occurring in > 2% of patients receiving ceftaroline fosamil in the pooled phase 3 clinical trials were diarrhea, nausea, and rash.
Other Adverse Reactions Observed During Clinical Trials of ceftaroline fosamil
Following is a list of additional adverse reactions reported by the 1740 patients who received ceftaroline fosamil in any clinical trial with incidences less than 2%. Events are categorized by System Organ Class.
- 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-Clostridium 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
Postmarketing Experience
There is limited information regarding Ceftaroline fosamil Postmarketing Experience in the drug label.
Drug Interactions
No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil. There is minimal potential for drug-drug interactions between ceftaroline fosamil and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): 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. ceftaroline fosamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceftaroline fosamil in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ceftaroline fosamil during labor and delivery.
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 ceftaroline fosamil is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
Of the 1300 patients treated with ceftaroline fosamil in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age. The clinical cure rates in the ceftaroline fosamil 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 event profiles in patients ≥ 65 years of age and in patients < 65 years of age were similar. The percentage of patients in the ceftaroline fosamil group who had at least one adverse event 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 ceftaroline fosamil. 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.
Gender
Following administration of a single 600 mg IV dose of ceftaroline fosamil to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean Cmaxand AUC0-∞for ceftaroline were similar between males and females, although there was a trend for higher Cmax(17%) and AUC0-∞(6-15%) in female subjects. Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC0-taubased on gender in Phase 2/3 patients with ABSSSI or CABP. No dose adjustment is recommended based on gender.
Race
A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 ABSSSI and CABP trials. No significant differences in ceftaroline AUC0-tauwas observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients. Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions. No dosage adjustment is recommended based on race.
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).
Hepatic Impairment
The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established. As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment.
Females of Reproductive Potential and Males
V 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.
Immunocompromised Patients
There is no FDA guidance one the use of Ceftaroline fosamil in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
There is limited information regarding Ceftaroline fosamil Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ceftaroline fosamil and IV administrations.
Overdosage
In the event of overdose, ceftaroline fosamil should be discontinued and general supportive treatment given.
Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of ceftaroline fosamil, 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.
Pharmacology
There is limited information regarding Ceftaroline fosamil Pharmacology in the drug label.
Mechanism of Action
Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue to its affinity for PBP2x.
Structure
The empirical formula is C22H21N8O8PS4.C2H4O2.H2O.
Pharmacodynamics
As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model withS. aureusandS. pneumoniae.
Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of ceftaroline fosamil 600 mg every 12 hours by IV infusion over 1 hour. For Phase 3 CABP trials, an exposure-response relationship could not be identified due to the limited range of ceftaroline exposures in the majority of patients.
Cardiac Electrophysiology
In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of ceftaroline fosamil 1500 mg, placebo, and a positive control by IV infusion over 1 hour. At the 1500 mg dose of ceftaroline fosamil, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
Pharmacokinetics
The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized inTABLE 5. Pharmacokinetic parameters were similar for single and multiple dose administration.
The Cmax and AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multiple IV infusions of 600 mg administered every 12 hours for up to 14 days in healthy adults with normal renal function.
Distribution
The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over 1-50 mcg/mL (14.5-28.0%). The median (range) steady-state volume of distribution of ceftaroline in healthy adult males (n=6) following a single 600 mg IV dose of radiolabeled ceftaroline fosamil was 20.3 L (18.3-21.6 L), similar to extracellular fluid volume.
Metabolism
Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1. The mean (SD) plasma ceftaroline M-1 to ceftaroline AUC0-∞ratio following a single 600 mg IV infusion of ceftaroline fosamil in healthy adults (n=6) with normal renal function is 28% (3.1%).
When incubated with pooled human liver microsomes, ceftaroline was metabolically stable (< 12% metabolic turnover), indicating that ceftaroline is not a substrate for hepatic CYP450 enzymes.
Excretion
Ceftaroline and its metabolites are primarily eliminated by the kidneys. Following administration of a single 600 mg IV dose of radiolabeled ceftaroline fosamil to healthy male adults (n=6), approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours. Of the radioactivity recovered in urine approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1. The mean (SD) renal clearance of ceftaroline was 5.56 (0.20) L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.
Nonclinical Toxicology
Mechanisms of Resistance
Ceftaroline is not active against Gram-negative bacteria producing extended spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases, or class C (AmpC cephalosporinases).
Cross-Resistance
Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftaroline.
Carcinogenesis and Mutagenesis
Long-term carcinogenicity studies have not been conducted with ceftaroline.
Ceftaroline fosamil did not show evidence of mutagenic activity inin vitrotests that included a bacterial reverse mutation assay and the mouse lymphoma assay. Ceftaroline was not mutagenic in anin vitromammalian 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 anin vitrochromosomal aberration assays, but not in the presence of metabolic activation.
Clinical Studies
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 ceftaroline fosamil (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 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 cm2and having one of the following infection types:
- Major abscess with ≥ 5 cm of surrounding erythema
- Wound infection
- Deep/extensive cellulitis
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 and clinical cure rates at TOC by pathogen in the Microbiologically Evaluable (ME) population. 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 ceftaroline fosamil to vancomycin plus aztreonam based on clinical response rates at TOC can not be utilized to establish non-inferiority.
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 ceftaroline fosamil (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 ceftaroline fosamil 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 according to consensus treatment guidelines of the Infectious Diseases Society of America and American Thoracic Society, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status;4(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 inTABLE 11.
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 ceftaroline fosamil to ceftriaxone based on clinical response rates at TOC cannot be utilized to establish non-inferiority. Neither trial established that ceftaroline fosamil 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.
How Supplied
- Ceftaroline fosamil 600 mg
- Individual vial (NDC 0456-0600-01)
- Ceftaroline fosamil 400 mg
- individual vial (NDC 0456-0400-01)
Storage
Stored at 25°C (77°F)
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Patient Counseling Information
- Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to ceftaroline fosamil, other beta-lactams (including cephalosporins) or other allergens.
- Patients should be counseled that antibacterial drugs including ceftaroline fosamil should be used to treat only bacterial infections. They do not treat viral infections (e.g., the common cold). When ceftaroline fosamil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may:
- decrease the effectiveness of the immediate treatment and
- increase the likelihood that bacteria will develop resistance and will not be treatable by ceftaroline fosamil or other antibacterial drugs in the future.
- Patients should be advised that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.
- Keep out of reach of children
Precautions with Alcohol
Alcohol-Ceftaroline fosamil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ceftaroline fosamil Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ceftaroline fosamil Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.