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adverse reactions
ADVERSE REACTIONS The safety of Synercid was evaluated in 1099 patients enrolled in 5 comparative clinical trials. Additionally, 4 non-comparative clinical trials (3 prospective and 1 retrospective in design) were conducted in which 1199 patients received Synercid for infections due to Gram-positive pathogens for which no other treatment option was available. In non-comparative trials, the patients were severely ill, often with multiple co-morbidities or physiological impairments, and may have been intolerant to or failed other antibacterial therapies. COMPARATIVE TRIALS ADVERSE REACTION SUMMARY – ALL COMPARATIVE STUDIES Safety data are available from five comparative clinical studies (n= 1099 Synercid ; n= 1095 comparator). One of the deaths in the comparative studies was assessed as possibly related to Synercid . The most frequent reasons for discontinuation due to drug-related adverse reactions were as follows: Table 3: Percent (%) of Patients Discontinuing Therapy by Reaction Type Type Synercid Comparator Venous 9.2 2.0 Non-venous 9.6 4.3 -Rash 1.0 0.5 -Nausea 0.9 0.6 -Vomiting 0.5 0.5 -Pain 0.5 0.0 -Pruritus 0.5 0.3 CLINICAL REACTIONS – ALL COMPARATIVE STUDIES Adverse reactions with an incidence of ≥1% and possibly or probably related to Synercid administration include: Table 4: Adverse Reactions with an Incidence of ≥1% and Possibly or Probably Related to Synercid Administration Adverse Reactions % of patients with adverse reactions Synercid Comparator Inflammation at infusion site 42.0 25.0 Pain at infusion site 40.0 23.7 Edema at infusion site 17.3 9.5 Infusion site reaction 13.4 10.1 Nausea 4.6 7.2 Thrombophlebitis 2.4 0.3 Diarrhea 2.7 3.2 Vomiting 2.7 3.8 Rash 2.5 1.4 Headache 1.6 0.9 Pruritus 1.5 1.1 Pain 1.5 0.1 Additional adverse reactions that were possibly or probably related to Synercid with an incidence less than 1% within each body system are listed below: Body as a Whole: abdominal pain, worsening of underlying illness, allergic reaction, chest pain, fever, infection; Cardiovascular: palpitation, phlebitis; Digestive: constipation, dyspepsia, oral moniliasis, pancreatitis, pseudomembranous enterocolitis, stomatitis; Metabolic: gout, peripheral edema; Musculoskeletal: arthralgia, myalgia, myasthenia; Nervous: anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesia, vasodilation; Respiratory: dyspnea, pleural effusion; Skin and Appendages: maculopapular rash, sweating, urticaria; Urogenital: hematuria, vaginitis CLINICAL REACTIONS – SKIN AND SKIN STRUCTURE STUDIES In two of the five comparative clinical trials Synercid (n=450) and comparator regimens ( e.g ., oxacillin/vancomycin or cefazolin/vancomycin; n=443) were studied for safety and efficacy in the treatment of complicated skin and skin structure infections. The adverse event profile seen in the Synercid patients in these two studies differed significantly from that seen in the other comparative studies. What follows is safety data from these two studies. Discontinuation of therapy was most frequently due to the following drug related events: Table 5: Drug Related Events Most Frequently Leading to Discontinuation of Therapy % of patients discontinuing therapy by reaction type Type Synercid Comparator Venous 12.0 2.0 Non-venous 11.8 4.0 -Rash 2.0 0.9 -Nausea 1.1 0.0 -Vomiting 0.9 0.0 -Pain 0.9 0.0 -Pruritus 0.9 0.5 Venous adverse events were seen predominately in patients who had peripheral infusions. The most frequently reported venous and non-venous adverse reactions possibly or probably related to study drug were: Table 6: The Most Frequently Reported Venous and Non-Venous Adverse Reactions Possibly or Probably Related to Study Drug % of patients with adverse reactions Synercid Comparator Venous 68.0 32.7 -Pain at infusion site 44.7 17.8 -Inflammation at infusion site 38.2 14.7 -Edema at infusion site 18.0 7.2 -Infusion site reaction 11.6 3.6 Non-venous 24.7 13.1 -Nausea 4.0 2.0 -Vomiting 3.7 1.0 -Rash 3.1 1.3 -Pain 3.1 0.2 There were eight (1.7%) episodes of thrombus or thrombophlebitis in the Synercid arms and none in the comparator arms. LABORATORY EVENTS-ALL COMPARATIVE STUDIES Table 7 shows the number (%) of patients exhibiting laboratory values above or below the clinically relevant "critical" values during treatment phase (with an incidence of 0.1% or greater in either treatment group). Table 7: Laboratory Events Parameter Critically High or Low Value Synercid Critically High or Low Comparator Critically High or Low AST > 10 × ULN 9 (0.9) 2 (0.2) ALT > 10 × ULN 4 (0.4) 4 (0.4) Total Bilirubin > 5 × ULN 9 (0.9) 2 (0.2) Conjugated Bilirubin > 5 × ULN 29 (3.1) 12 (1.3) LDH > 5 × ULN 10 (2.6) 8 (2.1) Alk Phosphatase > 5 × ULN 3 (0.3) 7 (0.7) Gamma-GT > 10 × ULN 19 (1.9) 10 (1.0) CPK > 10 × ULN 6 (1.6) 5 (1.4) Creatinine ≥ 440 μmoL/L 1 (0.1) 1 (0.1) BUN ≥ 35.5 mmoL/L 2 (0.3) 9 (1.2) Blood Glucose > 22.2 mmoL/L 11 (1.3) 11 (1.3) < 2.2 mmoL/L 1 (0.1) 1 (0.1) Bicarbonates > 40 mmoL/L 2 (0.3) 3 (0.5) < 10 mmoL/L 3 (0.5) 3 (0.5) CO 2 > 50 mmoL/L 0 (0.0) 0 (0.0) < 15 mmoL/L 1 (0.2) 0 (0.0) Sodium > 160 mmoL/L 0 (0.0) 0 (0.0) < 120 mmoL/L 5 (0.5) 3 (0.3) Potassium > 6.0 mmoL/L 3 (0.3) 6 (0.6) < 2.0 mmoL/L 0 (0.0) 1 (0.1) Hemoglobin < 8 g/dL 25 (2.6) 16 (1.6) Hematocrit > 60% 2 (0.2) 0 (0.0) Platelets > 1,000,000/mm 3 2 (0.2) 2 (0.2) < 50,000/mm 3 6 (0.6) 7 (0.7) NON-COMPARATIVE TRIALS CLINICAL ADVERSE REACTIONS Approximately one-third of patients discontinued therapy in these trials due to adverse events. However, the discontinuation rate due to adverse reactions assessed by the investigator as possibly or probably related to Synercid therapy was approximately 5.0%. There were three prospectively designed non-comparative clinical trials in patients (n = 972) treated with Synercid . One of these studies (301), had more complete documentation than the other two (398A and 398B). The most common events probably or possibly related to therapy are presented in Table 8: Table 8: The Most Common Events Probably or Possibly Related to Therapy Adverse Reactions % of patients with adverse reaction Study 301 Study 398A Study 398B Arthralgia 7.8 5.2 4.3 Myalgia 5.1 0.95 3.1 Arthralgia and Myalgia 7.4 3.3 6.8 Nausea 3.8 2.8 4.9 The percentage of patients who experienced severe related arthralgia and myalgia was 3.3% and 3.1%, respectively. The percentage of patients who discontinued treatment due to related arthralgia and myalgia was 2.3% and 1.8%, respectively. LABORATORY EVENTS The most frequently observed abnormalities in laboratory studies were in total and conjugated bilirubin, with increases greater than 5 times upper limit of normal, irrespective of relationship to Synercid , reported in 25.0% and 34.6% of patients, respectively. The percentage of patients who discontinued treatment due to increased total and conjugated bilirubin was 2.7% and 2.3%, respectively. Of note, 46.5% and 59.0% of patients had high baseline total and conjugated bilirubin levels before study entry. OTHER Serious adverse reactions in clinical trials, including non-comparative studies, considered possibly or probably related to Synercid administration with an incidence < 0.1% include: acidosis, anaphylactoid reaction, apnea, arrhythmia, bone pain, cerebral hemorrhage, cerebrovascular accident, coagulation disorder, convulsion, dysautonomia, encephalopathy, grand mal convulsion, hemolysis, hemolytic anemia, heart arrest, hepatitis, hypoglycemia, hyponatremia, hypoplastic anemia, hypoventilation, hypovolemia, hypoxia, jaundice, mesenteric arterial occlusion, neck rigidity, neuropathy, pancytopenia, paraplegia, pericardial effusion, pericarditis, respiratory distress syndrome, shock, skin ulcer, supraventricular tachycardia, syncope, tremor, ventricular extrasystoles and ventricular fibrillation. Cases of hypotension and gastrointestinal hemorrhage were reported in less than 0.2% of patients. Post-marketing Experiences In addition to adverse events reported from clinical trials, reports of angioedema and anaphylactic shock have been identified during post approval use of Synercid .