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.

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:

Joint pain; mild diarrhea; muscle pain; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Synercid:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody or dark urine; bloody or watery stools; chest pain; confusion; dizziness; fainting; fast or irregular heartbeat; fatigue; fever, chills, or persistent sore throat; leg or calf pain, redness, swelling, or tenderness; one-sided weakness; pain, swelling, itching, or burning at the injection site; seizures; severe muscle or joint pain; severe or persistent diarrhea or vomiting; slurred speech; stomach or back pain or cramps; tremor; unusual tiredness or weakness; vision problems; white patches in the mouth; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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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 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:

% 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:

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:

	% 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 STUDIES

The 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 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 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 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.

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Side Effects by Body System - for Healthcare Professionals

General

In all 5 comparative studies, patients discontinued therapy with dalfopristin-quinupristin as compared to comparator for the following reasons: venous adverse events (9.2% versus 2% comparator), rash (1% versus 0.5% comparator), nausea (0.9% versus 0.6% comparator), vomiting (0.5% versus 0.5% comparator), pain (0.5% versus 0% comparator), and pruritus (0.5% versus 0.3% comparator).

In the 2 comparative studies for complicated skin and skin structure infections (cSSSI), the side effect profile observed differed significantly from the profile observed in the other comparative studies. In these 2 comparative cSSSI studies, patients discontinued therapy with dalfopristin-quinupristin as compared to comparator for the following reasons: venous adverse events (12% versus 2% comparator), rash (2% versus 0.9% comparator), nausea (1.1% versus 0% comparator), vomiting (0.9% versus 0% comparator), pain (0.9% versus 0% comparator), and pruritus (0.9% versus 0.5% comparator). Venous adverse events were mainly observed in patients with peripheral infusions.

In noncomparative studies, approximately one-third of patients discontinued therapy due to side effects; however, the discontinuation rate due to side effects possibly or probably related to dalfopristin-quinupristin was about 5%. The side effects leading to therapy discontinuation included increased total bilirubin (2.7%), increased conjugated bilirubin (2.3%), treatment-related arthralgia (2.3%), and treatment-related myalgia (1.8%). High baseline total and conjugated bilirubin levels were recorded in 46.5% and 59% of patients, respectively, prior to study entry.

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.

Local

Local side effects have frequently included inflammation at the infusion site (all comparative studies: 42%; comparative cSSSI studies: 44.7%), pain at the infusion site (all comparative studies: 40%; comparative cSSSI studies: 38.2%), infusion site edema (all comparative studies: 17.3%; comparative cSSSI studies: 18%), and infusion site reaction (all comparative studies: 13.4%; comparative cSSSI studies: 11.6%).

The manufacturer recommends flushing of the vein with 5% 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

Some cases of arthralgia and myalgia 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).

Musculoskeletal side effects have included arthralgia (up to 7.8%; severe: 3.3%), arthralgia and myalgia (up to 7.4%), myalgia (up to 5.1%; severe: 3.1%), elevated creatine phosphokinase (greater than 10 times ULN; 1.6%), and myasthenia (less than 1%). Bone pain and neck rigidity have been reported in less than 0.1% of patients.

Gastrointestinal

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.

Gastrointestinal side effects have included nausea (all comparative studies: 4.6%; comparative cSSSI studies: 4%; noncomparative studies: up to 4.9%), vomiting (all comparative studies: 2.7%; comparative cSSSI studies: 3.7%), and diarrhea (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%), mesenteric arterial occlusion (less than 0.1%), and Clostridium difficile associated diarrhea have been reported.

Hepatic

Hepatic side effects have included increased conjugated bilirubin (greater than 5 times ULN; 3.1%), gamma-glutamyltransferase (greater than 10 times ULN; 1.9%), total bilirubin (greater than 5 times ULN; 0.9%), AST (greater than 10 times ULN; 0.9%), and ALT (greater than 10 times ULN; 0.4%). Irrespective of relationship to dalfopristin-quinupristin, increased total bilirubin (greater than 5 times ULN; 25%) and conjugated bilirubin (greater than 5 times ULN; 34.6%) were reported during noncomparative studies. 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 been reported in less than 0.1% of patients.

High baseline total and conjugated bilirubin levels were recorded in 46.5% and 59% of patients, respectively, prior to noncomparative study entry.

Cardiovascular

Cardiovascular side effects have included thrombophlebitis (all comparative studies: 2.4%), thrombus or thrombophlebitis (comparative cSSSI studies: 1.7%), and hypotension (less than 0.2%). Palpitations, vasodilation, and phlebitis have been reported in less than 1% of patients. Arrhythmia, cerebral hemorrhage, cerebrovascular accident, heart arrest, pericardial effusion, pericarditis, supraventricular tachycardia, ventricular extrasystoles, and ventricular fibrillation have been reported in less than 0.1% of patients.

Dermatologic

Dermatologic side effects have included rash (all comparative studies: 2.5%; comparative cSSSI studies: 3.1%), pruritus (1.5%), and skin ulcer (less than 0.1%). Maculopapular rash, sweating, and urticaria have been reported in less than 1% of patients.

Hematologic

Hematologic side effects have included decreased hemoglobin (less than 8 g/dL; 2.6%), decreased platelets (less than 50,000/mm3; 0.6%), increased hematocrit (greater than 60%; 0.2%), increased platelets (greater than 1,000,000/mm3; 0.2%), and reversible reticulocytopenia. Coagulation disorder, hemolysis, hemolytic anemia, hypoplastic anemia, and pancytopenia have been reported in less than 0.1% of patients.

Metabolic

Metabolic side effects have included increased lactate dehydrogenase (greater than 5 times ULN; 2.6%), blood glucose (greater than 22.2 mmol/L; 1.3%), alkaline phosphatase (greater than 5 times ULN; 0.3%), bicarbonates (greater than 40 mmol/L; 0.3%), and potassium (greater than 6 mmol/L; 0.3%), and decreased bicarbonates (less than 10 mmol/L; 0.5%), sodium (less than 120 mmol/L; 0.5%), carbon dioxide (less than 15 mmol/L; 0.2%), and blood glucose (less than 2.2 mmol/L; 0.1%). Gout has been reported in less than 1% of patients. Acidosis, hypoglycemia, hyponatremia, and hypovolemia have been reported in less than 0.1% of patients. Alkalosis, hyperkalemia, and hyperglycemia have also been reported.

Nervous system

Nervous system side effects have included headache (1.6%). Confusion, dizziness, hypertonia, insomnia, leg cramps, and paresthesia have been reported in less than 1% of patients. Convulsion, dysautonomia, encephalopathy, grand mal convulsion, neuropathy, paraplegia, syncope, and tremor have been reported in less than 0.1% of patients.

Other

Other side effects have included pain (all comparative studies: 1.5%; comparative cSSSI studies: 3.1%) and shock (less than 0.1%). Abdominal pain, worsening of underlying illness, chest pain, fever, peripheral edema, and infection have been reported in less than 1% of patients.

Hypersensitivity

Hypersensitivity side effects have included allergic reaction (less than 1%) and anaphylactoid reaction (less than 0.1%). Angioedema and anaphylactic shock have been reported during postmarketing experience.

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%.

Genitourinary

Genitourinary side effects have included hematuria and vaginitis in less than 1% of patients.

Psychiatric

Psychiatric side effects have included anxiety in less than 1% of patients.

Renal

Renal side effects have included elevated BUN (35.5 mmol/L or greater; 0.3%) and creatinine (440 mcmol/L or greater; 0.1%).

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