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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Increased Mortality in Ventilator-Associated Bacterial Pneumonia Patients [ see Warnings and Precautions ( 5.1 ) ] Hypersensitivity Reactions [see Contraindications ( 4 ) and Warning and Precautions ( 5.2 )] Seizures and Other Central Nervous System Reactions [see Warnings and Precautions ( 5.3 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] SAB (adult patients): The most common adverse reactions occurring in ≥ 4% of adult patients were anemia, nausea, hypokalemia, vomiting, hepatic enzyme and bilirubin increased, diarrhea, blood creatinine increased, hypertension, leukopenia, and pyrexia ( 6.1 ). ABSSSI (adult patients): The most common adverse reactions occurring in ≥ 2% of adult patients were nausea, diarrhea, headache, injection site reaction, hepatic enzyme increased, rash, vomiting, and dysgeusia ( 6.1 ). CABP (adult and pediatric patients 3 months to less than 18 years of age): Adult Patients: The most common adverse reactions occurring in ≥ 2% of adult patients were nausea, hepatic enzyme increased, vomiting, diarrhea, headache, rash, insomnia, abdominal pain, phlebitis, hypertension, and dizziness ( 6.1 ). Pediatric Patients: The most common adverse reactions occurring in ≥ 2% of pediatric patients were vomiting, headache, hepatic enzyme increased, diarrhea, infusion site reaction, phlebitis and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Basilea Pharmaceutica International Ltd, at 1-800-460-6620 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Overview of the Safety Evaluation of ZEVTERA ZEVTERA was evaluated in four controlled comparative phase 3 clinical trials (TRIALS 1 through 4) which included 1221 adult 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%). ZEVTERA was also evaluated in a controlled phase 3 clinical trial (TRIAL 5) which included 138 pediatric patients aged from 3 months to less than 18 years 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 Clinical Trials Experience in 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 selected adverse reactions occurring in ≥ 2% of SAB patients receiving ZEVTERA in TRIAL 1. Table 8 Selected Adverse Reactions Occurring in ≥ 2% of SAB Adult Patients Receiving ZEVTERA in TRIAL 1 * SAB = Staphylococcus aureus bacteremia. * 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. ** 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 † Daptomycin 6 mg/kg up to 10 mg/kg IV over 0.5 hours every 24 hours, with dosing adjustment based on renal function. a Anemia includes: Anemia, Hemoglobin decreased, Hypochromic anemia, Normochromic normocytic anemia b Hypokalemia replaces: Blood potassium decreased c Hepatic enzyme increased includes: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased, blood bilirubin increased, hyperbilirubinemia d Blood creatinine increased includes: Acute kidney injury, Blood creatinine increased, Creatinine renal clearance decreased, Oliguria, Renal impairment f Leukopenia includes: Leukopenia, Lymphocyte count decreased, Lymphopenia, Neutropenia, Neutrophil count decreased, White blood cell count decreased g Pyrexia includes Hyperthermia, Pyrexia h Abdominal pain includes: Abdominal pain upper, Abdominal tenderness i Fungal infection includes: Candida infection, Candida sepsis, Fungal test positive, Oral candidiasis , Vulvovaginal candidiasis, Tinea pedis j Dyspnea includes: Dyspnea, Respiratory distress Adverse Reaction ZEVTERA** N = 191 Daptomycin † ± Aztreonam N = 198 Anemia a 12% 13% Nausea 10% 4% Hypokalemia b 9% 3% Vomiting 8% 2% Hepatic enzyme and bilirubin increased c 8% 10% Diarrhea 7% 3% Blood creatinine increased d 7% 5% Hypertension e 5% 2% Leukopenia f 4% 3% Pyrexia g 4% 3% Abdominal pain h 3% 1% Fungal infection i 3% 2% Headache 3% 3% Dyspnea j 2% 1% Clinical Trials Experience in 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 selected 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 * ABSSSI = Acute Bacterial Skin and Skin Structure Infections. *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. **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 † 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. a Infusion site reaction includes: Injection site reaction, Infusion related reaction b Hepatic enzyme increased includes: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased c Rash includes Rash, Drug eruption, Dermatitis Adverse Reaction ZEVTERA** N = 334 Vancomycin plus Aztreonam † N = 342 Nausea 11% 6% Diarrhea 6% 5% Headache 6% 7% Injection site reaction a 2% 3% Hepatic enzyme increased b 2% 3% Rash c 2% 3% Vomiting 2% 2% Dysgeusia 2% 0% Clinical Trials Experience in 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 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 Adult Patients 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 in Adult Patients Table 10 lists the most common selected adverse reactions occurring in ≥ 2% of CABP 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 CABP = Community-Acquired Bacterial Pneumonia. *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 † Ceftriaxone 2 grams IV over 0.5 hours every 24 hours, with or without linezolid 600 mg IV over 1 hour every 12 hours a 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. b Rash includes: Dermatitis contact, Dermatitis allergic, Rash, Rash pruritic c Abdominal pain includes: Abdominal discomfort, Abdominal pain, Abdominal pain upper d Phlebitis includes: Phlebitis, Injection site phlebitis e Hypertension includes: Hypertension, Blood pressure increased, Hypertensive Crisis Adverse Reaction ZEVTERA* N = 310 Ceftriaxone † ± linezolid N = 322 Nausea 10% 4% Hepatic enzyme increased a 10% 11% Vomiting 9% 3% Diarrhea 7% 9% Headache 7% 7% Rash b 5% 2% Insomnia 5% 4% Abdominal pain c 4% 3% Phlebitis d 4% 2% Hypertension e 4% 4% Dizziness 3% 2% Clinical Trials Experience in 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 in patients with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) [TRIAL 4]. 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 Adult Patients In TRIAL 4, a total of 140/386 (36.3%) HABP/VABP patients treated with ZEVTERA and 123/386 (31.9%) HABP/VABP 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 in Adult Patients Common adverse reactions occurring in >2% of HABP/VABP patients who received ceftobiprole in TRIAL 4 include diarrhea, hypokalemia, hyponatremia, hepatic enzyme increased, vomiting, anemia, rash, phlebitis, nausea, abdominal pain, and seizures. Selected Adverse Reactions of ZEVTERA in Adult Patients The following selected 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 Clinical Trials Experience in Pediatric Patients with Community-Acquired Bacterial Pneumonia ZEVTERA was evaluated in an active-controlled, randomized, investigator-blind, multicenter phase 3 study in pediatric patients aged from 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) [see Dosage and Administration ( 2.2 , 2.4 )]. 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 Pediatric Patients 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. Specific 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 selected adverse reactions, occurring in ≥ 2% of pediatric patients treated with ceftobiprole, 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%). 6.2 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