Quinupristin and Dalfopristin

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

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 5: Percent (%) of Patients Discontinuing Therapy by Reaction Type

Adverse reactions with an incidence of ≥1% and possibly or probably related to Synercid administration include:

Table 6: Adverse Reactions with an Incidence of ≥1% and Possibly or Probably Related to Synercid Administration

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

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 7: Drug Related Events Most Frequently Leading to Discontinuation of Therapy

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 8: The Most Frequently Reported Venous and Non-Venous Adverse Reactions Possibly or Probably Related to Study Drug

There were eight (1.7%) episodes of thrombus or thrombophlebitis in the Synercid arms and none in the comparator arms.

Table 9 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 9: Laboratory Events

Non- Comparative Trials

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 10:

Table 10: The Most Common Events Probably or Possibly Related to Therapy

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.

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.

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.

Read the entire FDA prescribing information for Synercid (Quinupristin and Dalfopristin)

Skin and Skin Structure Infections

Treatment of complicated skin and skin structure infections caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains) or Streptococcus pyogenes (group A β-hemolytic streptococci, GAS).1 2 8

For information on diagnosis and management of skin and skin structure infections, consult current IDSA clinical practice guidelines available at .43

Methicillin-resistant Staphylococcus aureus Infections

Has been used as salvage therapy in critically ill patients for treatment of severe infections (e.g., bacteremia, infective endocarditis) caused by methicillin-resistant S. aureus† (MRSA; also known as oxacillin-resistant S. aureus or ORSA) when vancomycin was ineffective.3 21 26 32 127

Some clinicians state quinupristin/dalfopristin is one of several options for treatment of persistent MRSA bacteremia in adults who fail to respond to vancomycin or when the infection is known to be caused by MRSA with reduced susceptibility to vancomycin and daptomycin.32

For information on treatment of infections caused by MRSA, consult current IDSA clinical practice guidelines available at .32 For information on diagnosis and management of infective endocarditis caused by MRSA, consult current AHA guidelines available at .127

Vancomycin-resistant Enterococcus faecium Infections

Has been used for treatment of serious or life-threatening infections caused by susceptible vancomycin-resistant Enterococcus faecium†, including bacteremia, infective endocarditis, intra-abdominal infections, skin and skin structure infections, and urinary tract infections.2 3 6 7 9 24 28 29 33 34

Treatment of vancomycin-resistant E. faecium infections no longer included in FDA-approved labeling;30 some clinicians suggest reserving quinupristin/dalfopristin for refractory vancomycin-resistant E. faecium infections that fail to respond to other anti-infectives.29 33

Storage

Parenteral

2–8°C.1

Following reconstitution with 5% dextrose injection or sterile water for injection, further dilute in 5% dextrose injection within 30 minutes.1 Use diluted solution as soon as possible to minimize risk of microbial contamination;1 stable for up to 5 hours at room temperature or up to 54 hours when refrigerated at 2–8°C.1 Do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Antibiotic, Streptogramin

Hypersensitivity to quinupristin, dalfopristin, other streptogramins (eg, pristinamycin, virginiamycin), or any component of the formulation

Refer to adult dosing.

Skin and skin structure infection, complicated: Children ≥12 years and Adolescents: Refer to adult dosing.

No dosage adjustment necessary.

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

CycloSPORINE (Systemic): Quinupristin may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

>10%:

Hepatic: Hyperbilirubinemia (3% to 35%)

Local: Local pain (40% to 44%), local inflammation (at infusion site: 38% to 42%), localized edema (17% to 18%), infusion site reaction (12% to 13%)

Neuromuscular & skeletal: Arthralgia (≤47%), myalgia (≤47%)

1% to 10%:

Cardiovascular: Thrombophlebitis (2%)

Central nervous system: Pain (2% to 3%), headache (2%)

Dermatologic: Skin rash (3%), pruritus (2%)

Endocrine & metabolic: Increased lactate dehydrogenase (3%), increased gamma-glutamyl transferase (2%), hyperglycemia (1%)

Gastrointestinal: Nausea (3% to 5%), vomiting (3% to 4%), diarrhea (3%)

Hematologic & oncologic: Anemia (3%)

Neuromuscular & skeletal: Increased creatine phosphokinase (2%)

<1% (Limited to important or life-threatening): Anaphylactoid reaction, apnea, brain disease, cardiac arrhythmia, dysautonomia, dyspnea, gout, hematuria, hemolytic anemia, hepatitis, hyperkalemia, hypersensitivity reaction, hypotension, maculopapular rash, mesenteric artery occlusion, myasthenia, neuropathy, pancreatitis, pancytopenia, paraplegia, paresthesia, pericarditis, pleural effusion, pseudomembranous colitis, respiratory distress, seizure, shock, stomatitis, syncope, thrombocytopenia, urticaria