Zevtera Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZEVTERA was evaluated in adults in four controlled comparative phase 3 clinical trials (Trials 1 through 4) which included 1221 patients treated with ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered by IV infusion over 2 hours every 6 to 8 hours and 1248 patients treated with comparator for a treatment period up to 42 days. The median age of patients treated with ZEVTERA was 56 years, ranging between 18 and 95 years old.

Patients treated with ZEVTERA were predominantly male (64%) and White (82%). The safety of ZEVTERA was also evaluated in pediatric patients aged 3 months to less than 18 years in a controlled phase 3 clinical trial (Trial 5) which included 138 patients with CABP and hospital-acquired bacterial pneumonia (HABP) requiring hospitalization. Although HABP was included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP has not been established and ZEVTERA is not approved for the treatment of HABP. Adult Patients with Staphylococcus aureus Bloodstream Infection (Bacteremia) ZEVTERA was evaluated in an active-controlled randomized, double-blind, multicenter phase 3 trial (Trial 1) in patients with Staphylococcus aureus bloodstream infection (bacteremia) (SAB) including right-sided infective endocarditis . In Trial 1, 191 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered as a 2-hour IV infusion every 6 hours from Day 1 to Day 8, and ZEVTERA 667 mg every 8 hours from Day 9 onwards, and 198 patients were treated with a comparator (daptomycin administered as an IV 0.5 hour infusion, 6 mg/kg up to 10 mg/kg every 24 hours, with optional aztreonam). The dose of study drugs were adjusted based on renal function. The median age of patients treated with ZEVTERA was 57 years, ranging between 20-89 years old with approximately 30% aged greater than or equal to 65 years.

Patients treated with ZEVTERA were predominantly male (68%), White (95%), and from Europe (93%). The median duration of treatment was 21 days in both treatment arms. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 36/191 (18.8%) patients with SAB treated with ZEVTERA and 45/198 (22.7%) of patients with SAB treated with daptomycin ± aztreonam experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 18/191 (9.4%) of patients treated with ZEVTERA, and 18/198 (9.1%) of patients treated with daptomycin ± aztreonam.

In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were nausea, vomiting, rash, and urticaria, each occurring in 2/191 (1%). Deaths occurred in 17/191 (8.9%) patients treated with ZEVTERA and 18/198 (9.1%) patients treated with daptomycin ± aztreonam. Common Adverse Reactions Table 8 lists the most common adverse reactions occurring in ≥ 2% of SAB adult patients receiving ZEVTERA in Trial 1. Table 8: Selected Adverse Reactions Occurring in ≥ 2% of SAB Adult Patients Receiving ZEVTERA in Trial 1 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. Adverse Reaction ZEVTERA 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.

N = 191 Daptomycin Daptomycin 6 mg/kg up to 10 mg/kg IV over 0.5 hour every 24 hours, with dosing adjustment based on renal function. ± Aztreonam N = 198 SAB = Staphylococcus aureus bacteremia. Anemia Anemia includes the following terms: anemia, hemoglobin decreased, hypochromic anemia, and normochromic normocytic anemia. 12% 13% Nausea 10% 4% Hypokalemia Hypokalemia replaces the term blood potassium decreased. 9% 3% Vomiting 8% 2% Hepatic enzyme and bilirubin increased Hepatic enzyme increased includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood bilirubin increased, and hyperbilirubinemia. 8% 10% Diarrhea 7% 3% Blood creatinine increased Blood creatinine increased includes the following terms: acute kidney injury, blood creatinine increased, creatinine renal clearance decreased, oliguria, and renal impairment. 7% 5% Hypertension Hypertension includes the following terms: hypertension, blood pressure increased, and hypertensive crisis. 5% 2% Leukopenia Leukopenia includes the following terms: leukopenia, lymphocyte count decreased, lymphopenia, neutropenia, neutrophil count decreased, and white blood cell count decreased. 4% 3% Pyrexia Pyrexia includes the following terms: hyperthermia and pyrexia. 4% 3% Abdominal pain Abdominal pain includes the following terms: abdominal pain upper and abdominal tenderness. 3% 1% Fungal infection Fungal infection includes the following terms: candida infection, candida sepsis, fungal test positive, oral candidiasis, vulvovaginal candidiasis, and tinea pedis. 3% 2% Headache 3% 3% Dyspnea Dyspnea includes the following terms: dyspnea and respiratory distress. 2% 1% Adult Patients with Acute Bacterial Skin And Skin Structure Infections ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 trial (Trial 2) in patients with acute bacterial skin and skin structure infections (ABSSSI) . In Trial 2, 334 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) administered as a 2-hour IV infusion every 8 hours, and 342 patients were treated with vancomycin plus aztreonam. The daily dose of vancomycin was 2 grams, as a 1 gram fixed dose or 15 mg/kg, administered as a 2-hour IV infusion every 12 hours.

Aztreonam was administered as a 1 gram fixed dose as a 0.5-hour IV infusion every 12 hours and the requirement for aztreonam therapy was reassessed at the 72-hour study visit. The dose of study drugs was adjusted based on renal function. The median age of patients treated with ZEVTERA was 51 years ranging from 18–89 years old with approximately 12% aged greater than or equal to 65 years.

Patients treated with ZEVTERA were mostly male (59%), White (95%), and from the United States (60%). Patients across treatment arms received treatment for a median duration of 6 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, a total of 6/334 (1.8%) ABSSSI patients treated with ZEVTERA and 12/342 (3.5%) of ABSSSI patients treated with vancomycin plus aztreonam experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 6/334 (1.8%) of patients treated with ZEVTERA, and 10/342 (2.9%) of patients treated with vancomycin plus aztreonam.

In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were dysgeusia and both pruritus and rash, occurring in 1/334 (0.3%). Deaths occurred in 1/334 (0.3%) patients treated with ZEVTERA and 2/342 (0.6%) patients treated with vancomycin plus aztreonam. Common Adverse Reactions Table 9 lists the most common adverse reactions occurring in ≥ 2% of ABSSSI patients receiving ZEVTERA in Trial 2. Table 9: Selected Adverse Reactions Occurring in ≥ 2% of ABSSSI Adult Patients Receiving ZEVTERA in Trial 2 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. Adverse Reaction ZEVTERA 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.

N = 334 Vancomycin plus Aztreonam Vancomycin IV, as fixed 1 gram or 15 mg/kg, administered over 2 hours every 12 hours with dosing adjustment based on renal function; aztreonam IV 1 gram over 0.5 hour every 12 hours with dosing adjustment based on renal function. N = 342 ABSSSI = Acute Bacterial Skin and Skin Structure Infections. Nausea 11% 6% Diarrhea 6% 5% Headache 6% 7% Injection site reaction Infusion site reaction includes the following terms: injection site reaction and infusion-related reaction. 2% 3% Hepatic enzyme increased Hepatic enzyme increased includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, and gamma-glutamyltransferase increased. 2% 3% Rash Rash includes the following terms: rash, drug eruption, and dermatitis. 2% 3% Vomiting 2% 2% Dysgeusia 2% 0% Adult Patients with Community-Acquired Bacterial Pneumonia ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 study in adult patients with community-acquired bacterial pneumonia (CABP) . In Trial 3, 310 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) every 8 hours as a 2-hour IV infusion, and 322 patients were treated with ceftriaxone 2 grams as a 0.5 hour IV infusion with or without linezolid 600 mg every 12 hours as a 60-minute IV infusion.

The dose of ZEVTERA was adjusted based on renal function. The median age of patients treated with ZEVTERA was 56 years, ranging from 18–90 with approximately 36% aged greater than or equal to 65 years. Approximately 62% of patients were White, 45% were from outside Europe or the United States, and 57% were male.

Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 3, a total of 35/310 (11.3%) patients with CABP treated with ZEVTERA and 37/322 (11.5%) patients with CABP treated with ceftriaxone ± linezolid experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 18/310 (5.8%) of patients treated with ZEVTERA, and 12/322 (3.7%) of patients treated with ceftriaxone ± linezolid.

The most common adverse reaction leading to discontinuation in patients treated with ZEVTERA was vomiting, occurring in 4/310 (1.3%). Deaths occurred in 9/310 (2.9%) patients treated with ZEVTERA and 9/322 (2.8%) in patients treated with ceftriaxone ± linezolid. Common Adverse Reactions Table 10 lists the most common adverse reactions occurring in ≥ 2% of CABP adult patients receiving ZEVTERA in Trial 3. Table 10: Selected Adverse Reactions Occurring in ≥ 2% of CABP Adult Patients Receiving ZEVTERA in Safety Analysis Set in Trial 3 Adverse Reaction ZEVTERA 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. N = 310 Ceftriaxone Ceftriaxone 2 grams IV over 0.5 hour every 24 hours, with or without linezolid 600 mg IV over 1 hour every 12 hours. ± linezolid N = 322 CABP = Community-Acquired Bacterial Pneumonia.

Nausea 10% 4% Hepatic enzyme increased Hepatic enzyme increased includes the following terms: aspartate aminotransferase increased, gamma-glutamyltransferase increased, blood alkaline phosphatase increased, alanine aminotransferase increased, hepatic enzyme increased, transaminases increased, alanine aminotransferase, and liver function test increased. 10% 11% Vomiting 9% 3% Diarrhea 7% 9% Headache 7% 7% Rash Rash includes the following terms: dermatitis contact, dermatitis allergic, rash, and rash pruritic. 5% 2% Insomnia 5% 4% Abdominal pain Abdominal pain includes the following terms: abdominal discomfort, abdominal pain, and abdominal pain upper. 4% 3% Phlebitis Phlebitis includes the following terms: phlebitis, and injection site phlebitis. 4% 2% Hypertension Hypertension includes the following terms: hypertension, blood pressure increased, and hypertensive crisis. 4% 4% Dizziness 3% 2% Adult Patients with Unapproved Use of Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter, phase 3 trial (Trial 4) in patients with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP). Although HABP/VABP are included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP/VABP have not been established and ZEVTERA is not approved for HABP or VABP. In Trial 4, 386 patients received ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) every 8 hours as a 2-hour IV infusion, and 386 patients were treated with ceftazidime 2 grams every 8 hours as a 2-hour IV infusion with or without linezolid 600 mg every 12 hours as a 1-hr infusion. The dose of ZEVTERA and ceftazidime were adjusted based on renal function. The median age of patients treated with ZEVTERA was 62.5 years (range 18 - 95) with approximately 47% aged 65 years or older.

Approximately 81% of the patients were White, most were outside of the United States (88%) and 72% were male. Patients across treatment arms received treatment for a median duration of 8 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 4, a total of 140/386 (36.3%) HABP/VABP adult patients treated with ZEVTERA and 123/386 (31.9%) HABP/VABP adult patients treated with ceftazidime ± linezolid experienced serious adverse reactions.

Discontinuation of treatment due to any adverse reaction occurred in 54/386 (14%) of patients treated with ZEVTERA, and 40/386 (10.4%) of patients treated with ceftazidime ± linezolid. Deaths occurred in 88/386 patients (22.8%) treated with ZEVTERA and 84/386 patients (21.8%) treated with ceftazidime ± linezolid. In the subgroup of patients with VABP, 35/103 patients treated with ZEVTERA died (34.0%) versus 24/102 (23.5%) of the patients treated with ceftazidime ± linezolid.

In the subgroup of patients with HABP, 53/283 patients treated with ZEVTERA died (18.7%) versus 60/284 patients treated with ceftazidime ± linezolid (21.1%). Common Adverse Reactions Common adverse reactions occurring in >2% of HABP/VABP adult patients who received ceftobiprole in Trial 4 include diarrhea, hypokalemia, hyponatremia, hepatic enzyme increased, vomiting, anemia, rash, phlebitis, nausea, abdominal pain, and seizures. Adverse Reactions Reported in <2% of Adults Treated with ZEVTERA The following adverse reactions were reported in ZEVTERA-treated adult patients at a rate of less than 2% in Trials 1, 2, 3, and 4: Blood and lymphatic system disorders: Thrombocytosis, Thrombocytopenia Gastrointestinal disorders: Dyspepsia, Dysphagia General disorders and administration site conditions: Fatigue, Chills, Facial swelling, Infusion site pain Immune system disorders: Hypersensitivity, Angioedema, Anaphylactic shock Infections and infestations: Mucocutaneous fungal infections Investigations: Blood lactate dehydrogenase increased, Blood triglycerides increased, Prothrombin time prolonged Psychiatric disorders: Anxiety, Irritability Renal and urinary disorders: Pollakiuria Respiratory, thoracic and mediastinal disorders: Bronchospasm, Wheezing Skin and subcutaneous tissue disorders: Pruritus Vascular disorders: Thrombosis Pediatric Patients with Community-Acquired Bacterial Pneumonia ZEVTERA was evaluated in an active-controlled, randomized, investigator-blinded, multicenter phase 3 study (Trial 5) in pediatric patients aged 3 months to less than 18 years with HABP or CABP requiring hospitalization. Although patients with HABP are included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP has not been established and ZEVTERA is not approved for HABP. In Trial 5, 94 patients received ZEVTERA 13.3 mg/kg (equivalent to 10 mg/kg of ceftobiprole) to 26.7 mg/kg (equivalent to 20 mg/kg of ceftobiprole – higher than the recommended approved dose) . ZEVTERA was administered by intravenous infusion every 8 hours, age-adjusted for dose and infusion duration (2-hour or 4-hour infusion). In the comparator arm, 44 patients received either ceftriaxone 50-80 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 10-15 mg/kg IV every 6 hours (maximum 2 grams/day). The median age of study patients was 5 years, ranging from 0.6 to 17 years.

All patients were from Europe, 100% were classified as White and 56% of patients were male. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 5, a total of 7/94 (7.4%) pediatric patients treated with ZEVTERA and 2/44 (4.5%) patients in the comparator group experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 4/94 (4.3%) of patients treated with ZEVTERA and 0/44 patients treated in the comparator group.

Adverse reactions leading to treatment discontinuation in patients who received ZEVTERA included aggravated pneumonia, pleuritis, urticaria, and hypersensitivity, each occurring in 1/94 (1.1%). There were no deaths in either arm of the pediatric study. The most common adverse reactions, occurring in ≥ 2% of pediatric patients treated with ZEVTERA were vomiting (7.4%), headache (3.2%), hepatic enzyme increased (including alanine aminotransferase increased and aspartate aminotransferase increased) (3.2%), diarrhea, infusion site reaction, phlebitis, and pyrexia (all 2.1%).

Postmarketing Experience

The following adverse reactions and altered laboratory tests have been identified during post-approval use of ZEVTERA and ceftobiprole outside of the United States, or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Altered Laboratory Tests : Positive direct Coombs' test, false-positive test for urinary glucose.

Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia. Hepatobiliary disorders : Hepatic dysfunction including cholestasis. Immune system disorders : Drug fever, serum sickness-like reaction.

Nervous system disorders : Myoclonus. Renal and urinary disorders : Renal dysfunction, toxic nephropathy. Vascular disorders : Hemorrhage, hypertension.

Organic Anion Transporting Polypeptide 1B1/1B3 (OATP1B1/OATP1B3) Substrates

ZEVTERA may increase the plasma concentrations of OATP1B1 and OATP1B3 substrates. Concomitant administration is not recommended.

Drug-Laboratory Test Interactions Dipstick Tests

ZEVTERA may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests. Serological Testing Treatment with ZEVTERA has the potential to interfere with serological testing, such as the Coombs test. In clinical studies there was no evidence of hemolytic anemia in adults or children.

However, the possibility that hemolytic anemia may occur cannot be ruled out. Patients experiencing anemia during or after treatment should be investigated for this possibility.

Pregnancy Risk Summary There are no available data with use of ZEVTERA in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from published observational studies and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups, and cannot definitively establish the absence of risk.

Intravenous administration of ceftobiprole medocaril to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times, respectively, the maximum recommended human dose (MRHD). Some evidence of maternal toxicity (slight reduction in body weight and food consumption) was noted in pregnant monkeys at 0.9 times the MRHD. Intravenous administration of ceftobiprole medocaril to rats 2-weeks prior to mating, during organogenesis, and through lactation resulted in no adverse fertility or fetal development effects in offspring at doses approximately 1.4 times the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data Pregnant rats administered ceftobiprole medocaril intravenously at doses up to 360 mg/kg/day (approximately 1.4 times the MRHD based on total body surface area (BSA)-normalized comparisons) during organogenesis on gestation days (GD) 6 to 17 showed no adverse fetal development effects. Maternal body weight gain and food consumption were slightly decreased at 360 mg/kg/day. Pregnant cynomolgus monkeys were administered ceftobiprole medocaril intravenously at doses up to 120 mg/kg/day (approximately 0.9 times the MRHD based on BSA comparison) during organogenesis (GD 20 to 50). Maternal body weight gain and food consumption were slightly reduced at 120 mg/kg/day.

This dose was associated with a slight increase in abortion rate (approximately 10% above historical controls). No other fetal development adverse effects (i.e., no fetal malformations) were observed at the high dose. In a pre- and post-natal development toxicity study, ceftobiprole medocaril was administered intravenously to pregnant rats during organogenesis starting at GD 6 and continuing to lactation day 21 (L21) at doses up to 360 mg/kg (approximately 1.4 times the MRHD based on BSA comparisons). Maternal toxicity (mortality, reduced food consumption and body weight gain in surviving females during gestation) was observed at the high dose. Effects in the offspring were also observed at the high dose during the post-natal pre-weaning period (decrease in the number of pups born per litter and decreased post-natal survival up to day 4 after birth). No adverse effects were observed in surviving pups during the post-natal postweaning development period (days 5-22) at doses up to 360 mg/kg.

Pediatric Use The safety and effectiveness of ZEVTERA have been established for the treatment of CABP in pediatric patients 3 months to less than 18 years. Use of ZEVTERA in this age group is supported by evidence from an adequate and well-controlled trial of ZEVTERA in adults, with additional pharmacokinetic, safety and efficacy data from pediatric trials . The safety and effectiveness of ZEVTERA have not been established for the treatment of CABP in pediatric patients less than 3 months of age. The safety and effectiveness of ZEVTERA have not been established for the treatment of ABSSSI and SAB in pediatric patients.

is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class. ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class.

There is no information on clinical signs and symptoms associated with an overdose of ZEVTERA. For patients who receive doses greater than the recommended dosage regimen and have unexpected adverse reactions associated with ZEVTERA, discontinue ZEVTERA, treat symptomatically, and institute general supportive treatment. ZEVTERA can be removed by hemodialysis. However, no information is available on the use of hemodialysis to treat overdose .