Synercid Side Effects
Please note - some side effects for Synercid may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).
Side Effects of Synercid - for the Consumer
Synercid
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Synercid:
Seek medical attention right away if any of these SEVERE side effects occur when using Synercid:Joint pain; muscle pain; nausea; pain, swelling, itching, or burning at the injection site; secondary infection.
TopSevere allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; chest pain; confusion; dizziness; fast heartbeat; fatigue; loss of appetite; personality changes; seizures; severe muscle or joint pain; severe or persistent diarrhea; shakiness; stomach pain or cramps; sudden onset of a cold sweat; unexplained weight loss; vision changes; vomiting; yellowing of skin or eyes.
Synercid Side Effects - for the Professional
Synercid
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 STUDIESSafety 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:
| 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 |
Adverse reactions with an incidence of ≥1% and possibly or probably related to Synercid administration include:
| 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 STUDIESIn 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:
| % 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:
| % 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 STUDIESThe following table 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).
| Parameter | Critically High or Low Value |
Synercid Critically High or Low |
Comparator Critically High or Low |
|---|---|---|---|
| AST | > 10 x ULN | 9 (0.9) | 2 (0.2) |
| ALT | > 10 x ULN | 4 (0.4) | 4 (0.4) |
| Total Bilirubin | > 5 x ULN | 9 (0.9) | 2 (0.2) |
| Conjugated Bilirubin | > 5 x ULN | 29 (3.1) | 12 (1.3) |
| LDH | > 5 x ULN | 10 (2.6) | 8 (2.1) |
| Alk Phosphatase | > 5 x ULN | 3 (0.3) | 7 (0.7) |
| Gamma-GT | > 10 x ULN | 19 (1.9) | 10 (1.0) |
| CPK | > 10 x 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) | |
| CO2 | > 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/mm3 | 2 (0.2) | 2 (0.2) |
| < 50,000/mm3 | 6 (0.6) | 7 (0.7) |
NON-COMPARATIVE TRIALS
CLINICAL ADVERSE REACTIONSApproximately 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 were:
| % of patients with adverse reaction | |||
|---|---|---|---|
| Adverse Reactions | 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 EVENTSThe 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.
OTHERSerious 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.
TopSide Effects by Body System
General
In a study with 93 patients, 21.5% discontinued treatment due to side effects. The most common side effects were arthralgia, myalgia, nausea, and rash.
Patients have discontinued therapy with dalfopristin-quinupristin as compared to placebo for the following reasons: venous adverse events (9.2% to 12% vs. 2% to 4% placebo), rash (1% to 2% vs. 0.5% to 0.9% placebo), nausea (0.9% to 1.1% vs. 0% to 0.6% placebo), vomiting (0.5% to 0.9% vs. 0% to 0.5% placebo), pain (0.5% to 0.9% vs. 0% placebo), and pruritus (0.5% to 0.9% vs. 0.3% to 0.5% placebo).
Local
Local side effects have frequently included inflammation at the infusion site (42%), pain at the infusion site (40%), infusion site edema (17.3%), and infusion site reaction (13.4%).
The manufacturer recommends flushing of the vein with dextrose in water solution following each infusion of dalfopristin-quinupristin to minimize venous irritation. Consideration should be given to changing the infusion site in patients with moderate to severe venous irritation. Dalfopristin-quinupristin infusion (standard diluent volume of 250 mL) may also be further diluted (500 to 750 mL) in these patients. Venous adverse events occurred predominately in patients who had peripheral infusions, therefore, a peripherally inserted central catheter or a central venous catheter may be utilized in selected patients.
Musculoskeletal
Musculoskeletal side effects have included elevated CPK (>10 times upper limit of normal: 1.6%), and arthralgia, myalgia (some severe), and myasthenia in less than 1% of patients. Bone pain and neck rigidity have been reported in less than 0.1% of patients.
Some cases noted improvement of symptoms with a reduction in dose frequency to every 12 hours. Resolution of symptoms has been reported following discontinuation of dalfopristin-quinupristin.
One trial with 93 patients reported an incidence of 10.8% and 8.6%, respectively, for arthralgia and myalgia.
Intravenous dalfopristin-quinupristin plus minocycline were associated with myalgia and arthralgia in 36% of neutropenic cancer patients (n=56).
Hepatic
Hepatic side effects have included hyperbilirubinemia (>5 times upper limit of normal) in up to 25% of patients and ALT and AST elevations. Isolated hyperbilirubinemia (primarily conjugated bilirubin) can occur and is thought to be due to dalfopristin-quinupristin competing with bilirubin for excretion. Hepatitis and jaundice have also been reported in less than 0.1% of patients. Elevated alkaline phosphatase (0.3%), GGT (>10 times upper limit of normal: 1.9%), and LDH (>5 times upper limit of normal: 2.6%) have also been reported.
Cardiovascular
Cardiovascular side effects have included palpitations, peripheral edema, and phlebitis in less than 1% of patients. Hypotension has occurred in less than 0.2% of patients. Arrhythmia, cerebral hemorrhage, cerebral vascular accident, heart arrest, pericardial effusion, pericarditis, shock, supraventricular tachycardia, syncope, ventricular extrasystoles, and ventricular fibrillation have been reported in less than 0.1% of patients.
Nervous system
Nervous system side effects have included headache (1.6%). Anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesia, and vasodilation have been reported in less than 1% of patients. Convulsion, dysautonomia, encephalopathy, grand mal convulsion, neuropathy, paraplegia, and tremor have been reported in less than 0.1% of patients.
Gastrointestinal
Gastrointestinal side effects have included nausea (4.6%), diarrhea (2.7%), and vomiting (2.7%). Abdominal pain, constipation, dyspepsia, oral moniliasis, pancreatitis, pseudomembranous enterocolitis, and stomatitis have been reported in less than 1% of patients. Gastrointestinal hemorrhage (less than 0.2%) and mesenteric arterial occlusion (less than 0.1%) have also been reported.
Mild cases of pseudomembranous enterocolitis may respond to discontinuation of dalfopristin-quinupristin alone. Moderate to severe cases may require fluid replacement, electrolytes, protein supplementation, and antibiotics for treating C. difficile.
Dermatologic
Dermatologic side effects have included rash (2.5%) and pruritus (1.5%), and skin ulcer (less than 0.1%). Maculopapular rash, sweating, and urticaria have been reported in less than 1% of patients.
Endocrine
Endocrine side effects have included hypoglycemia in less than 0.1% of patients.
Genitourinary
Genitourinary side effects have included hematuria and vaginitis in less than 1% of patients.
Hematologic
Hematologic side effects have included thrombophlebitis (2.4%), and coagulation disorder, hemolysis, hemolytic anemia, hypoplastic anemia, and pancytopenia in less than 0.1% of patients. Decreased hemoglobin (2.6%), increased hematocrit (0.2%), increased platelets (0.2%), and decreased platelets (0.6%), and reversible reticulocytopenia have also been reported.
Hypersensitivity
Hypersensitivity reactions have been reported in less than 1% of patients. Anaphylactoid reaction has been rarely reported (less than 0.1%).
Metabolic
Metabolic side effects have included gout and peripheral edema in less than 1% of patients. Acidosis, alkalosis, hypoglycemia, hyponatremia,hypovolemia, hyperkalemia, and hyperglycemia have also been reported.
Respiratory
Respiratory side effects have included dyspnea and pleural effusion in less than 1% of patients. Apnea, hypoventilation, hypoxia, and respiratory distress syndrome have been reported in less than 0.1%.
Other
Other side effects have included pain (1.5%), and abdominal pain, worsening of underlying illness, chest pain, fever, and infection in less than 1% of patients.
Renal
Renal side effects have included elevations in creatinine (0.1%) and BUN (0.3%).
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