Drug Trials Snapshots: ZEVTERA

 

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the ZEVTERA Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

ZEVTERA (ceftobiprole medocaril sodium for injection)
Zev-Tair-a
Basilea Pharmaceutica International Ltd, Allschwil
Original Approval date: April 3, 2024

---

DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZEVTERA is a cephalosporin antibacterial drug used for the treatment of serious infections including Staphylococcus aureus bacteremia (SAB) in adults, acute bacterial skin and skin structure infections (ABSSSI) in adults, and community-acquired bacterial pneumonia (CABP) in adults and children aged 3 months to less than 18 years.

How is this drug used?

ZEVTERA is given by a healthcare provider directly into the bloodstream through a needle in the vein. This is known as an intravenous (IV) infusion. It is given every six to eight hours based on the infection and patient population being treated as noted below:

• SAB: Every six hours on Days 1 to 8 and every eight hours from Day 9 for up to 42 days
• ABSSSI: Every eight hours for 5 to 4 days
• CABP in adults: Every eight hours for 5 to 14 days
• CABP in children aged 3 months to less than 18 years: Every eight hours for 7 to 14 days

Who participated in the clinical trials?

The FDA approved ZEVTERA based on evidence from four clinical trials of 1,845 patients with SAB, ABSSSI, and CABP in adults and children (390 with SAB, 679 with ABSSSI, 638 with adult CABP, and 138 with pediatric CABP). The trials were conducted at 207 (60, 32, 103, and 12, respectively) sites in 26 countries in North America, South America, Europe, Africa, and Asia. Of the 1,845 patients, 510 were from trial sites in the United States and the remaining were from outside of the United States.

How were the trials designed?

There were four trials that evaluated the benefits and side effects of ZEVTERA. These trials included Trial 1 (BPR-CS-009) which treated adult patients with SAB, Trial 2 (BPR-CS-008) which treated adult patients with ABSSSI, Trial 3 (CAP-3001) which treated adult patients with CABP, and Trial 4 (BPR-PIP-002) which treated pediatric patients with CABP.

In Trial 1, adult patients with SAB were chosen at random to receive either ZEVTERA or other antibiotics (the control). Neither the patients nor the investigators knew which treatment was given. The benefit was measured by the proportion of patients achieving overall success which included the patient being alive, having improvement of the infection with no new complications, having a negative blood culture test, and not needing to take more antibiotics.

In Trial 2, adult patients with ABSSSI were chosen at random to receive either ZEVTERA or other antibiotics (the control). Neither the patients nor the investigators knew which treatment was given. The benefit was measured by the proportion of patients achieving an early clinical response 48 to 72 hours after the start of antibiotic therapy which included the patient being alive, having improvement of the infection, and not needing to change to non-study antibiotics or have unplanned surgery.

In Trial 3, adult patients with CABP were chosen at random to receive either ZEVTERA or other antibiotics (the control). Neither the patients nor the investigators knew which treatment was given. The benefit was measured by the proportion of patients achieving cure which included the patient being alive and either having resolution or improvement of the infection so that no additional antibiotics were needed.

In Trial 4, which was mainly conducted to evaluate the drug’s safety in children, children aged 3 months to younger than 18 years old with CABP were chosen at random to receive either ZEVTERA or other antibiotics (the control). The investigator did not know which treatment was given. The benefit of ZEVTERA was expected to be similar in children and adults because the signs and symptoms of CABP and the bacteria that cause CABP are similar in both adults and children aged 3 months to younger than 18 years old.

How were the trials designed?

ZEVTERA’s efficacy in treating SAB was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 1). In the trial, 390 subjects were randomly assigned to receive either ZEVTERA (192 subjects) or daptomycin plus optional aztreonam (the comparator; 198 subjects). The primary measure of efficacy for this trial was the overall success (defined as survival, symptom improvement, S. aureus bloodstream clearance, no new SAB complications, and no use of other potentially effective antibacterial drugs) at the post-treatment evaluation visit, which occurred 70 days after randomization in the modified intent-to-treat (mITT) population.

ZEVTERA’s efficacy in treating ABSSSI was evaluated in a randomized, controlled, double-blind, multinational trial (Trial 2). In the trial, 679 subjects were randomly assigned to receive either ZEVTERA (335 subjects) or vancomycin plus aztreonam (the comparator; 344 subjects). The primary measure of efficacy was early clinical response 48 to 72 hours after the start of treatment. Early clinical response was defined as a reduction of the primary skin lesion by at least 20%, survival for at least 72 hours and the absence of concomitant antibacterial drugs or additional unplanned surgery in the intent-to-treat (ITT) population.

ZEVTERA’s efficacy in treating adult patients with CABP was evaluated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 3). In the trial, 638 adults hospitalized with CABP and requiring IV antibacterial drugs for at least three days were randomly assigned to receive either ZEVTERA (314 subjects) or ceftriaxone with optional linezolid (the comparator; 324 subjects). The primary measurement of efficacy was clinical cure (defined as survival with resolution or improvement of signs and symptoms of infection and no requirement for additional antibacterial drugs) at the test-of-cure visit, which occurred 7 to 14 days after end-of-treatment in the ITT population.

ZEVTERA’s safety in treating pediatric patients with CABP was evaluated in a randomized, controlled, investigator-blind, multinational, multicenter trial (Trial 4). In the trial, 138 pediatric patients from 3 months to younger than 18 years of age hospitalized with CABP or hospital-acquired bacterial pneumonia (HABP) and requiring IV antibacterial treatment for at least three days were randomly assigned to receive either ZEVTERA (94 subjects) or a cephalosporin with optional vancomycin (the comparator; 44 subjects). The primary measurements of safety were adverse events during the first three days of treatment and at end-of-treatment, test-of-cure visit, and last-follow up visit. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary. Efficacy in the pediatric population was extrapolated from the adult trial in CABP.

DEMOGRAPHICS SNAPSHOT

Figure 1 summarizes how many male and female patients were enrolled in the combined clinical trials used to evaluate the efficacy of ZEVTERA.

Figure 1. Baseline Demographics by Sex, Intent-to-Treat Population

Source: Adapted from FDA Review

Figure 2 summarizes how many patients by race were enrolled in the combined clinical trials used to evaluate the efficacy of ZEVTERA.

Figure 2. Baseline Demographics by Race, Intent-to-Treat Population

Source: Adapted from FDA Review

Figure 3 summarizes how many patients by age were enrolled in the combined clinical trials used to evaluate the efficacy of ZEVTERA.

Figure 3. Baseline Demographics by Age, Intent-to-Treat Population

Source: Adapted from FDA Review

Figure 4 summarizes how many patients by ethnicity were enrolled in the combined clinical trials used to evaluate the efficacy of ZEVTERA.

Figure 4. Baseline Demographics by Ethnicity, Intent-to-Treat Population

Source: Adapted from FDA Review

Who participated in the trials?

Table 1. Baseline Demographics, Intent-to-Treat Population

Demographic	Total Population N=1842 n (%)
Sex
Male	1107 (60)
Female	735 (40)
Race
American Indian or Alaska Native	7 (0.4)
Asian	144 (7.8)
Black or African American	61 (3.3)
Native Hawaiian or other Pacific Islander	2 (0.1)
White	1553 (84.3)
Other	75 (4.1)
Age, years
<2	11 (0.6)
2 to 5	56 (3.0)
6 to 11	42 (2.3)
12 to 17	29 (1.6)
18 to 35	288 (15.6)
35 to 64	965 (52.4)
≥65	451 (24.5)
Ethnicity
Hispanic or Latino	403 (21.9)
Not Hispanic or Latino	1297 (70.4)
Not reported	2 (0.1)
Missing	140 (7.6)

Source: Adapted from FDA Review

What are the benefits of this drug?

In Trial 1 for adult patients with SAB, 68.9% of patients treated with ZEVTERA achieved overall success compared to 68.7% of patients treated with the control therapy.

In Trial 2 for adult patients with ABSSSI, 91.3% of patients treated with ZEVTERA achieved an early clinical response compared to 88.1% of patients treated with the control therapy.

In Trial 3 for adult patients with CABP, 76.4% of patients treated with ZEVTERA achieved clinical cure compared to 79.3% of patients treated with the control therapy. Because the majority of adults who received ZEVTERA were cured, the benefit of ZEVTERA was expected to be similar in pediatric patients because the signs and symptoms of CABP and the bacteria that cause CABP are similar in both adult and pediatric patients from 3 months to younger than 18 years of age.

What are the benefits of this drug (results of trials used to assess efficacy)?

The efficacy of ZEVTERA was established in Trial 1 for adult patients with SAB based on the primary endpoint of overall success at the post-treatment evaluation visit at Day 70 (±5 days) after randomization in the mITT population (Table 2). This trial met its primary objective of demonstrating non-inferiority of ZEVTERA to daptomycin for the primary endpoint.

Table 2. Overall Success Based on DRC Assessment at the PTE Visit, Trial 1 (Adult Patients With SAB), mITT Population

Categories	ZEVTERA N=189	Daptomycin N=198
Number of responders, n (%)	132 (69.8)	136 (68.7)
95% CIᵃ	62.8, 76.3	61.7, 75.1
Number of non-responders, n (%)	57 (30.2)	62 (31.3)
Reasons for failureᵇ
Premature discontinuation of     study treatment due to lack of efficacy	9 (15.8)	10 (16.1)
Development of new metastatic or     other complications related to SAB	11 (19.3)	11 (17.7)
SAB relapse or reinfection	2 (3.5)	4 (6.5)
Treatment of SAB with systemic non-study antibacterial treatment,     other than those permitted under the protocol	20 (35.1)	19 (30.6)
Treatment of infections other than SAB with systemic      non-study antibacterial treatment potentially effective against S. aureus	0	13 (21.0)
Death for any reason after first     administration of study drug	17 (29.8)	18 (29.0)
Indeterminate outcome, defined as any data     needed to determine whether the outcome is success or failure missing	16 (28.1)	17 (27.4)
Requirement for systemic antibacterial treatment for     SAB beyond protocol-defined maximum study treatment duration	9 (15.8)	15 (24.2)
Proportion difference % (95% CI)ᶜ	2.0 (-7.1, 11.1)

Source: Adapted from FDA Review
^a Computed using binomial exact method.
^b Denominators for percentages are based on the number of non-responders. A subject may have been counted in more than one category.
^c Proportion difference of ZEVTERA minus daptomycin. Computed using Cochran-Mantel-Haenszel (CMH) weights method adjusted for actual stratum (dialysis status and prior antibacterial treatment use).
Abbreviations: CI, confidence interval; DRC, data review committee; mITT, modified intent-to-treat; PTE, post-treatment evaluation; SAB, Staphylococcus aureus bacteremia

The efficacy of ZEVTERA was established in Trial 2 for adult patients with ABSSSI based on the primary endpoint of early clinical response at 48 to 72 hours after start of trial drug administration (Table 3). This trial met its primary objective of demonstrating non-inferiority of ZEVTERA to vancomycin plus aztreonam for the primary endpoint.

Table 3. Primary Endpoint: Proportion of Subjects With Early Clinical Response 48 to 72 Hours After Start of Therapy, Trial 2 (Adult Patients With ABSSSI)

Categories	ZEVTERA N=335	Vancomycin + Aztreonam N=344
Number of responders, n (%)	306 (91.3)	303 (88.1)
95% CI	87.8, 94.1	84.2, 91.3
Number of non-responders, n (%)	29 (8.7)	41 (11.9)
Reason for non-responders, n (%)a
Missing surface area of     primary lesion at baseline	1 (3.4)	0
48 to 72 hours after start of treatment	8 (27.6)	12 (29.3)
<20% reduction from baseline in     surface area of primary lesion	19 (65.5)	29 (70.7)
Death prior to 72 hours from time of     first dose of study drug	0	2 (4.9)
Concomitant antibacterial treatment	0	1 (2.4)
Additional unplanned     surgical procedure for ABSSSI	1 (3.4)	1 (2.4)
Proportion difference % (95% CI)b	3.3 (-1.2, 7.8)
p-value for testing superiority	0.1543

Source: Adapted from FDA Review
^a Denominators for percentages are based on the number of non-responders. A subject may be counted in more than one category.
^b ZEVTERA minus vancomycin plus aztreonam.
Abbreviations: ABSSSI, acute bacterial skin and skin structure infections; CI, confidence interval

The efficacy of ZEVTERA was established in Trial 3 for adult patients with CABP based on two co-primary endpoints analyzed in the primary efficacy analysis, which included the clinical cure rate at the test-of-cure visit in the clinically evaluable and ITT populations (Table 4). This trial met its primary objective of demonstrating non-inferiority of ZEVTERA to ceftriaxone for the primary endpoint.

Table 4. Clinical Outcome at the TOC Visit in the CE and ITT Populations, Trial 3 (Adult Patients With CABP)

Categories	ZEVTERA n/N (%)	Ceftriaxone ± Linezolid n/N (%)	Differenceb % (95% CI)c
CE population
Cure	200/231 (86.6)	208/238 (87.4)	-0.8 ( -6.9; 5.3)
Failure	31/231 (13.4)	30/238 (12.6)	NA
ITT populationa
Cure	240/314 (76.4)	257/324 (79.3)	-2.9 ( -9.3; 3.6)
Failure	74/314 (23.6)	67/324 (20.7)	NA

Source: Adapted from FDA Review
^a Subjects were counted as Cure in the ITT Analysis Set only when the subject had a clinical outcome of Cure without effective concomitant therapy, otherwise, the subject was counted as Failure.
^b ZEVTERA minus ceftriaxone ± linezolid.
^c 2-sided 95% CI is based on the normal approximation to the difference of the two proportions.
Abbreviations: CABP, community-acquired bacterial pneumonia; CE, clinically evaluable; CI, confidence interval; ITT, intent-to-treat; NA, not applicable; TOC, test-of-cure

However, as this study was designed prior to the current regulatory guidelines, post-hoc re-analyses were necessary to show the consistency of study results with these updated guidelines. These post-hoc analyses considered an earlier timepoint of clinical success at Day 3 in patients in the ITT population, based on survival and the improvement in at least two, and no worsening in any, of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, tachypnea.

Clinical success at Day 3 was also evaluated in the ITT and mITT populations, which were also defined post-hoc.

The Day 3 ITT population included 97% (618 of 638) of ITT patients who had at least two of the following symptoms at baseline: difficulty breathing, cough, production of purulent sputum, or chest pain.

The Day 3 mITT population included Day 3 ITT patients with: baseline Pneumonia Outcomes Research Team classification of Risk Class ≥III; at least two of fever, hypothermia, hypotension, tachycardia, and tachypnea; as well as at least one of new-onset hypoxemia, rales or pulmonary consolidation, and leukocytosis or leukopenia; and new radiographic infiltrates (not related to another disease process) consistent with the diagnosis of bacterial pneumonia.

The Day 3 mITT population was the subset of the Day 3 ITT patients who had a valid pathogen at baseline.

Results of early clinical success at Day 3 in the Day 3-ITT and Day 3-mITT populations are shown in Table 5. These analyses supported the original primary analysis and were consistent with the criteria outlined in the current CABP guidance.

Table 5. Early Clinical Success at Day 3 in Adult Patients With CABP Based on a Post-Hoc Analysis of Trial 3

Parameter	ZEVTERA n/N (%)	Ceftriaxone ± Linezolid n/N (%)	Between-Group Difference % (Two-Sided 95% CI)a
Day 3 ITT population
Clinical success at Day 3b	218/307 (71.0)	221/311 (71.1)	-0.1% (-7.2, 7.1)
Day 3 mITT population
Clinical success at Day 3	69/97 (71.1)	60/90 (66.7))	4.5% (−8.8, 17.7))

Source: ZEVTERA Prescribing Information
^a Between-group difference of ZEVTERA minus ceftriaxone ± linezolid. Two-sided 95% CI is based on the Normal approximation to the difference of the two proportions.
^b Clinical success based on improvement in at least two, with no worsening in any, of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, tachypnea. Seven patients in the ZEVTERA arm and 13 patients in the comparator arm did not report any of these symptoms, and were therefore not included in the ITT population for the analysis evaluating early clinical success at Day 3.
Abbreviations: CABP, community-acquired bacterial pneumonia; CI, confidence interval; ITT, intent-to-treat; mITT, modified intent-to-treat

Data from the pediatric CABP trial (Trial 4) were primarily used to support the safety of ZEVTERA in pediatric subjects with CABP with efficacy extrapolated from the adult CABP trial.

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

• Sex: ZEVTERA worked similarly in males and females.
• Race: The majority of patients were White. The number of patients in other races was limited. Differences in how well the drug worked among races could not be determined.
• Age: ZEVTERA worked similarly in patients younger and older than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 6, Table 7, and Table 8 summarize differences in how well the drug worked in each clinical trial by subgroup.

Table 6. Overall Clinical Success Based on DRC Assessment at PTE Visit by Subgroup (mITT Population), Trial 1 (Adult Patients With SAB)

Subgroup	ZEVTERA n/N (%)	Daptomycin n/N (%)	Difference % (95% CI)
Age, years
<65	98/131 (74.8)	101/135 (74.8)	0.6 (-9.8, 10.9)
≥65	34/58 (58.6)	35/63 (55.9)	6.9 (-10.5, 24.3)
Sex
Male	93/128 (72.7)	92/140 (65.7)	8.0 (-2.8, 18.8)
Female	39/61 (63.9)	44/58 (75.9)	-11.3 (-27.7, 5.1)
Race
White	127/179 (70.9)	131/192 (68.2)	3.5 (-5.8, 12.8)
Othera	5/10 (50.0)	5/6 (83.3)	-55.6 (-100.0, -10.5)
Geographic region
Europe	126/175 (72.0)	129/185 (69.7)	2.9 (-6.5, 12.2)
North America	0/5 (0)	3/5 (60.0)	-60.0 (-100.0, -17.1)
Other	6/9 (66.7)	4/8 (50.0)	5.4 (-44.7, 55.5)

Source: Adapted from FDA Review
^a Other includes Black or African American and other
Abbreviations: CI, confidence interval; DRC, Data Review Committee; mITT, modified intent-to-treat; PTE, post-treatment evaluation; SAB, Staphylococcus aureus bacteremia

Table 7. Early Clinical Response at 48 to 72 Hours by Subgroup (ITT Population), Trial 2 (Adult Patients With ABSSSI)

Subgroup	ZEVTERA n/N (%)	Vancomycin + Aztreonam n/N (%)	Difference % (95% CI)
Age, years
<65	266/294 (90.5)	258/292 (88.4)	2.1 (-2.9, 7.2)
≥65	40/ 41 (97.6)	45/ 52(86.5)	11.0 (-0.7, 23.4)
Sex
Male	179/198 (90.4)	171/201 (85.1)	4.1 (-2.2, 10.5)
Female	127/137(92.7)	132/143 (92.3)	0.9 (-5.3, 7.1)
Race
White	289/318 (90.9)	289/330 (87.6)	3.4 (-1.3, 8.1)
Black or African American	7/7 (100.0)	8/8 (100.0)	NE
Asian	0 (0)	1/1 (100.0)	NE
Other	6/6 (100.0)	2/2 (100.0)	NE
Geographic region
North America	185/ (91.1)	190/ (88.4)	2.7 (-3.1, 8.5)
Europe	121/ (91.7)	113/ (87.6)	4.3 (-2.9, 11.5)

Source: Adapted from FDA Review
Abbreviations: ABSSSI, acute bacterial skin and skin structure infections; CI, confidence interval; ITT, intent-to-treat; NE, not estimable

Table 8. Clinical Cure Rates at the TOC Visit by Subgroup (ITT Population), Trial 3 (Adult Patients With CABP)

Subgroup	ZEVTERA n/N (%)	Ceftriaxone n/N (%)	Difference % (95% CI)
Age, years
<65	150/203 (73.9)	152/198 (76.8)	-2.9 (-9.3, 2.6)
≥65	90/111 (81.1)	105/126 (83.3)	-2.3 (-12.0, 7.5)
Sex
Male	142/179 (79.3)	146/187 (78.1)	1.3 (-7.1, 9.6)
Female	98/135 (72.6)	111/ 137 (81.0)	-8.4 (-18.4, 1.6)
Race
White	150/193 (77.7)	165/204 (80.9)	-3.2 (-11.1, 4.8)
Black or African American	9/18 (50.0)	13/18 (72.2)	-22.2 (-53.2, 8.8)
Asian	51/69 (73.9)	51/72 (70.8)	3.1 (-11.7, 17.8)
Other	30/34 (88.2)	28/30 (93.3)	-5.1 (-19.1, 8.9)
Geographic region
United States	23/ 41 (56.1)	29/41 (70.7)	-14.6 (-35.2, 6.0)
Non-United States	217/273 (79.5)	228/283 (80.6)	-1.1 (-7.7, 5.6)

Source: Adapted from FDA Review
Abbreviations: CABP, community-acquired bacterial pneumonia; CI, confidence interval; ITT, intent-to-treat; TOC, test of cure

What are the possible side effects?

Common side effects observed during the clinical trials of ZEVTERA for the treatment of adult patients with SAB (Trial 1) were anemia, nausea, low levels of potassium in the blood (hypokalemia), vomiting, diarrhea, increased levels of certain liver tests (hepatic enzymes and bilirubin), increased blood creatinine, high blood pressure, low white blood cell count (leukopenia), fever, abdominal pain, fungal infection, headache, and shortness of breath (dyspnea).

Common side effects observed during the clinical trials of ZEVTERA for the treatment of adult patients with ABSSSI (Trial 2) were nausea, diarrhea, headache, injection site reaction, increased levels of hepatic enzymes, rash, vomiting, and altered taste (dysgeusia).

Common side effects observed during the clinical trials of ZEVTERA for the treatment of adult patients with CABP (Trial 3) were nausea, increased levels of hepatic enzymes, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, vein inflammation (phlebitis), high blood pressure, and dizziness.

Common side effects observed during the clinical trials of ZEVTERA for the treatment of pediatric patients (from 3 months to younger than 18 years of age) with CABP (Trial 4) were vomiting, headache, increased levels of hepatic enzymes, diarrhea, infusion site reaction, vein inflammation (phlebitis), and fever.

What are the possible side effects (results of trials used to assess safety)?

Table 9 through Table 12 summarize the most common adverse reactions observed in the trials.

Table 9. Safety Results in Trial 1^a (Adult Patients With SAB), Safety Population

Adverse Reaction	ZEVTERAb N=191 %	Daptomycinc ± Aztreonam N=198 %
Anemiad	12	13
Nausea	10	4
Hypokalemiae	9	3
Vomiting	8	2
Hepatic enzyme and bilirubin increasedf	8	10
Diarrhea	7	3
Blood creatinine increasedg	7	5
Hypertensionh	5	2
Leukopeniai	4	3
Pyrexiaj	4	3
Abdominal paink	3	1
Fungal infectionl	3	2
Headache	3	3
Dyspneam	2	1

Source: ZEVTERA Prescribing Information
^a Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the daptomycin plus or minus aztreonam treatment groups.
^b ZEVTERA 667 mg IV over 2-hours every 6 hours from Day 1 to Day 8, and every 8 hours from Day 9 onwards, with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole
^c Daptomycin 6 mg/kg up to 10 mg/kg IV over 0.5 hours every 24 hours, with dosing adjustment based on renal function.
^d Anemia includes: Anemia, Hemoglobin decreased, Hypochromic anemia, Normochromic normocytic anemia
^e Hypokalemia replaces: Blood potassium decreased
^f Hepatic enzyme increased includes: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased, blood bilirubin increased, hyperbilirubinemia
^g Blood creatinine increased includes: Acute kidney injury, Blood creatinine increased, Creatinine renal clearance decreased, Oliguria, Renal impairment
^h Hypertension includes: Hypertension, Blood pressure increased, Hypertensive crisis
ⁱ Leukopenia includes: Leukopenia, Lymphocyte count decreased, Lymphopenia, Neutropenia, Neutrophil count decreased, White blood cell count decreased
^j Pyrexia includes Hyperthermia, Pyrexia
^k Abdominal pain includes: Abdominal pain upper, Abdominal tenderness
^l Fungal infection includes: Candida infection, Candida sepsis, Fungal test positive, Oral candidiasis, Vulvovaginal candidiasis, Tinea pedis
^m Dyspnea includes: Dyspnea, Respiratory distress
Abbreviations: IV, intravenous; SAB, Staphylococcus aureus bacteremia

Table 10. Safety Results in Trial 2^a (Adult Patients With ABSSSI), Safety Population

Adverse Reaction	ZEVTERAb N=334 %	Vancomycin + Aztreonamc N=342 %
Nausea	11	6
Diarrhea	6	5
Headache	6	7
Injection site reactiond	2	3
Hepatic enzyme increasede	2	3
Rashf	2	3
Vomiting	2	2
Dysgeusia	2	0

Source: ZEVTERA Prescribing Information
^a Trial 2 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the vancomycin plus or minus aztreonam treatment groups.
^b ZEVTERA 667 mg IV over 2-hours every 8 hours with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole
^c Vancomycin IV, as fixed 1 gram or 15 mg/kg, administered over hours every 12 hours with dosing adjustment based on renal function; aztreonam IV 1 gram over 0.5 hours every 12 hours with dosing adjustment based on renal function.
^d Infusion site reaction includes: Injection site reaction, Infusion related reaction
^e Hepatic enzyme increased includes: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased
^f Rash includes Rash, Drug eruption, Dermatitis
Abbreviations: ABSSSI, acute bacterial skin and skin structure infections; IV, intravenous

Table 11. Safety Results in Trial 3 (Adult Patients With CABP), Safety Population

Adverse Reaction	ZEVTERAa N=310 %	Ceftriaxoneb ± Linezolid N=322 %
Nausea	10	4
Hepatic enzyme increasedc	10	11
Vomiting	9	3
Diarrhea	7	9
Headache	7	7
Rashd	5	2
Insomnia	5	4
Abdominal paine	4	3
Phlebitisf	4	2
Dizziness	3	2
Hypertensiong	4	4

Source: ZEVTERA Prescribing Information
^a ZEVTERA 667 mg IV over 2-hours every 8 hours with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole
^b Ceftriaxone 2 grams IV over 0.5 hours every 24 hours, with or without linezolid 600 mg IV over 1 hour every 12 hours
^c Hepatic enzyme increased includes: Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Blood alkaline phosphatase increased, Alanine aminotransferase increased, Hepatic enzyme increased, Transaminases increased, Alanine aminotransferase, Liver function test increased.
^d Rash includes: Dermatitis contact, Dermatitis allergic, Rash, Rash pruritic
^e Abdominal pain includes: Abdominal discomfort, Abdominal pain, Abdominal pain upper
^f Phlebitis includes: Phlebitis, Injection site phlebitis
^g Hypertension includes: Hypertension, Blood pressure increased, Hypertensive Crisis
Abbreviations: CABP, community-acquired bacterial pneumonia; IV, intravenous

Table 12. Safety Results in Trial 4 (Pediatric Patients With CABP), Safety Population

Adverse Reaction	ZEVTERAa N=94 %	Cephalosporinb ± Vancomycin N=44 %
Vomiting	7	2
Headache	3	0
Hepatic enzyme increasedc	3	0
Diarrhea	2	9
Infusion site reaction	2	0
Phlebitis	2	0
Pyrexia	2	0

Source: Adapted from FDA Review
^a ZEVTERA 13.3 mg/kg to 26.7 mg/kg every 8 hours, age adjusted for dose and infusion duration (2-hour or 4-hour infusion) and based on renal function
^b Cephalosporin indicates ceftriaxone 50 to 80 mg/kg IV as a single daily dose (maximum 2 grams/day) for CABP or ceftazidime 50 mg/kg IV every 8 hours (maximum 6 grams/day) for HABP, with or without vancomycin 10 to 15 mg/kg IV every 6 hours (maximum 2 grams/day)
^c Hepatic enzyme increased includes: Aspartate aminotransferase increased, Alanine aminotransferase increased
Abbreviations: CABP, community-acquired bacterial pneumonia; IV, intravenous

Were there any differences in side effects of the clinical trials among sex, race, and age?

• Sex: The side effects of ZEVTERA were similar in females and males.
• Race: The majority of patients were White. The number of subjects in racial subgroups were too small to draw definitive conclusions about racial difference in side effects.
• Age: The majority of patients were adults between 18 and 64 years of age. No overall differences in safety of ZEVTERA were observed between patients 65 years of age and older and younger adult patients. No major differences in safety of ZEVTERA were observed between adult and pediatric patients between the ages of 3 months and 18 years.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table 13 thought Table 16 summarize the differences in side effects among subgroups observed in the trials.

Table 13. Adverse Events by Subgroup, Safety Population in Trial 1 (Adult Patients With SAB)

Subgroup	ZEVTERA N=191 n/Ns (%)	Daptomycin N=198 n/Ns (%)
Sex
Female	43/61 (70.5)	40/58 (69.0)
Male	78/130 (60.0)	77/140 (55.0)
Age group, years
18 to 34	7/20 (35.0)	11/19 (57.9)
35 to 64	72/113 (63.7)	65/116 (56.0)
65 to 74	29/41 (70.7)	28/42 (66.7)
≥75	13/17 (76.5)	13/21 (61.9)
Age group ≥65, years
≥65	42/58 (72.4)	41/63 (65.1)
Race
White	113/181 (62.4)	112/192 (58.3)
Asian	1/1 (100)	1/1 (100)
Black or African American	3/4 (75.0)	4/5 (80.0)
Native Hawaiian or other Pacific Islander	0/1 (0)	0/0 (NA)
Other	4/4 (100)	0/0 (NA)
Ethnicity
Hispanic or Latino	11/14 (78.6)	14/15 (93.3)
Not Hispanic or Latino	109/176 (61.9)	102/182 (56.0)
Not reported	1/1 (100)	1/1 (100)
Geographic region
United States	3/5 (60.0)	4/5 (80.0)
Non-United States	118/186 (63.4)	113/193 (58.5)

Source: Adapted from FDA Review
Abbreviations: N, number of subjects in treatment arm; n, number of subjects with adverse event; NA, not applicable; N_s, total number of subjects for each specific subgroup and were assigned to that specific arm; SAB, Staphylococcus aureus bacteremia

Table 14. Adverse Events by Subgroup, Safety Population in Trial 2 (Adult Patients With ABSSSI)

Subgroup	ZEVTERA N=334 n/Ns (%)	Vancomycin + Aztreonam N=342 n/Ns (%)
Sex
Female	62/137 (45.3)	63/143 (44.1)
Male	86/197 (43.7)	68/199 (34.2)
Age group, years
18 to 34	34/58 (58.6)	27/67 (40.3)
35 to 64	96/235 (40.9)	86/223 (38.6)
65 to 74	13/27 (48.1)	12/36 (33.3)
≥75	5/14 (35.7)	6/16 (37.5)
Age group ≥65, years
≥65	18/41 (43.9)	18/52 (34.6)
Race
White	140/317 (44.2)	122/328 (37.2)
American Indian or Alaska Native	2/4 (50.0)	1/3 (33.3)
Asian	0/0 (NA)	1/1 (100)
Black or African American	3/7 (42.9)	5/8 (62.5)
Native Hawaiian or other Pacific Islander	1/1 (100)	0/0 (NA)
Other	2/5 (40.0)	2/2 (100)
Ethnicity
Hispanic or Latino	52/103 (50.5)	44/114 (38.6)
Not Hispanic or Latino	96/231 (41.6)	87/228 (38.2)
Geographic region
United States	109/202 (54.0)	100/213 (46.9)
Non-United States	39/132 (29.5)	31/129 (24.0)

Source: Adapted from FDA Review
Abbreviations: ABSSSI, acute bacterial skin and skin structure infections N, number of subjects in treatment arm; n, number of subjects with adverse event; NA, not applicable; N_s, total number of subjects for each specific subgroup and were assigned to that specific arm

Table 15. Adverse Events by Subgroup, Safety Population in Trial 3 (Adult Patients With CABP)

Subgroup	ZEVTERA N=310 n/Ns (%)	Ceftriaxone ± Linezolid N=322 n/Ns (%)
Sex
Female	101/133 (75.9)	92/136 (67.6)
Male	116/177 (65.5)	116/186 (62.4)
Age group ≥65, years
≥65	78/111 (70.3)	90/126 (71.4)
Age group ≥75, years
≥75	36/54 (66.7)	46/62 (74.2)
Race
Asian	50/68 (73.5)	47/72 (65.3)
Black or African American	15/16 (93.8)	14/17 (82.4)
Other	24/33 (72.7)	19/30 (63.3)
White	128/193 (66.3)	128/203 (63.1)
Ethnicity
Hispanic or Latino	57/71 (80.3)	65/83 (78.3)
Not Hispanic or Latino	160/239 (66.9)	141/237 (59.5)
Missing	0/0 (NA)	2/2 (100)
Geographic region
United States	36/40 (90.0)	33/40 (82.5)
Non-United States	181/270 (67.0)	175/282 (62.1)

Source: Adapted from FDA Review
Abbreviations: CABP, community-acquired bacterial pneumonia; N, number of subjects in treatment arm; n, number of subjects with adverse event; NA, not applicable; N_s, total number of subjects for each specific subgroup and were assigned to that specific arm

Table 16. Adverse Events by Subgroup, Safety Population in Trial 4 (Pediatric Patients With CABP)

Subgroup	ZEVTERA N=94 n/Ns (%)	Cephalosporin ± Vancomycin N=44 n/Ns (%)
Sex
Female	8/41 (19.5)	2/23 (8.7)
Male	11/53 (20.8)	6/21 (28.6)
Age group
3 months to <2 years	2/12 (16.7)	0/2 (0)
≥2 to <6 years	8/37 (21.6)	5/19 (26.3)
≥6 to <12 years	4/27 (14.8)	3/12 (25)
≥12 to <18 years	5/18 (27.8)	0/11 (0)

Source: Adapted from FDA Review
Abbreviations: CABP, community-acquired bacterial pneumonia; N, number of patients in treatment arm; n, number of patients with adverse event; N_s, total number of patients for each specific subgroup and were assigned to that specific arm

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

DRUG PACKAGE INSERT

Back to Drug Trials Snapshots