ype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

ynercid with drugs which are cytochrome p450 3a4 substrates and possess a narrow therapeutic window requires caution and monitoring of these drugs ( e.g. , cyclosporine), whenever possible. concomitant medications metabolized by the cytochrome p450 3a4 enzyme system that may prolong the qtc interval should be avoided. concomitant administration of synercid and nifedipine (repeated oral doses) and midazolam (intravenous bolus dose) in healthy volunteers led to elevated plasma concentrations of these drugs. the c max increased by 18% and 14% (median values) and the auc increased by 44% and 33% for nifedipine and midazolam, respectively. table 2: selected drugs that are predicted to have plasma concentrations increased by synercid this list of drugs is not all inclusive. antihistamines: astemizole, terfenadine anti-hiv (nnrtis and protease inhibitors): delavirdine, nevirapine, indinavir, ritonavir antineoplastic agents: vinca alkaloids ( e.g. , vinblastine), docetaxel, paclitaxel benzodiazepines: midazolam, diazepam calcium channel blockers: dihydropyridines ( e.g. , nifedipine), verapamil, diltiazem cholesterol-lowering agents: hmg-coa reductase inhibitors ( e.g. , lovastatin) gi motility agents: cisapride immunosuppressive agents: cyclosporine, tacrolimus steroids: methylprednisolone other: carbamazepine, quinidine, lidocaine, disopyramide clostridium difficile associated diarrhea (cdad) has been reported with use of nearly all antibacterial agents, including synercid , and may range in severity from mild diarrhea to fatal colitis. treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of c. difficile . c. difficile produces toxins a and b which contribute to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibiotic use. careful medical history is necessary since cdad has been reported to occur over two months after the administration of antibacterial agents. if cdad is suspected or confirmed, ongoing antibiotic use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of c. difficile , and surgical evaluation should be instituted as clinically indicated.

on in animal studies toxicity was higher when synercid was administered as a bolus compared to slow infusion. however, the safety of an intravenous bolus of synercid has not been studied in humans. clinical trial experience has been exclusively with an intravenous duration of 60 minutes and, thus, other infusion rates cannot be recommended. arthralgias/myalgias episodes of arthralgia and myalgia, some severe, have been reported in patients treated with synercid . in some patients, improvement has been noted with a reduction in dose frequency to q12h. in those patients available for follow-up, treatment discontinuation has been followed by resolution of symptoms. the etiology of these myalgias and arthralgias is under investigation. superinfections the use of antibiotics may promote the overgrowth of nonsusceptible organisms. should superinfection occur during therapy, appropriate measures should be taken. hyperbilirubinemia elevations of total bilirubin greater than 5 times the upper limit of normal were noted in approximately 25% of patients in the non-comparative studies. (see adverse reactions: non-comparative trials . ) in some patients, isolated hyperbilirubinemia (primarily conjugated) can occur during treatment, possibly resulting from competition between synercid and bilirubin for excretion. of note, in the comparative trials, elevations in alt and ast occurred at a similar frequency in both the synercid and comparator groups.

trials of synercid suggest that the incidence of adverse effects in patients with chronic liver insufficiency or cirrhosis was comparable to that in patients with normal hepatic function. pharmacokinetic data in patients with hepatic cirrhosis (child pugh a or b) suggest that dosage reduction may be necessary but exact recommendations cannot be made at this time. (see clinical pharmacology: special populations and precautions: general: hepatic insufficiency sections .) pediatric patients the recommended dose of synercid for pediatric patients (12 to < 18 years of age) is 7.5 mg/kg q12h. no dosing recommendations are available in pediatric patients less than 12 years of age. (see precautions: pediatric use . )

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 .

ype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

ndard deviation ) (dose = 7.5 mg/kg q8h; n=10) c max c max = maximum drug plasma concentration (mcg/ml) auc auc = area under the drug plasma concentration-time curve (mcg.h/ml) t 1/2 t 1/2 = half-life (hr) quinupristin and metabolites 3.20 ± 0.67 7.20 ± 1.24 3.07 ± 0.51 dalfopristin and metabolite 7.96 ± 1.30 10.57 ± 2.24 1.04 ± 0.20 the clearances of unchanged quinupristin and dalfopristin are similar (0.72 l/h/kg), and the steady-state volume of distribution for quinupristin is 0.45 l/kg and for dalfopristin is 0.24 l/kg. the elimination half-life of quinupristin and dalfopristin is approximately 0.85 and 0.70 hours, respectively. the total protein binding of quinupristin is higher than that of dalfopristin. synercid does not alter the in vitro binding of warfarin to proteins in human serum. penetration of unchanged quinupristin and dalfopristin in noninflammatory blister fluid corresponds to about 19% and 11% of that estimated in plasma, respectively. the penetration into blister fluid of quinupristin and dalfopristin in combination with their major metabolites was in total approximately 40% compared to that in plasma. in vitro , the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome-p450 or glutathione-transferase enzyme activities. synercid has been shown to be a major inhibitor ( in vitro inhibits 70% cyclosporin a biotransformation at 10 mcg/ml of synercid ) of the activity of cytochrome p450 3a4 isoenzyme. (see warnings . ) synercid can interfere with the metabolism of other drug products that are associated with qtc prolongation. however, electrophysiologic studies confirm that synercid does not itself induce qtc prolongation. (see warnings . ) fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination. special populations elderly the pharmacokinetics of quinupristin and dalfopristin were studied in a population of elderly individuals (range 69 to 74 years). the pharmacokinetics of the drug products were not modified in these subjects. gender the pharmacokinetics of quinupristin and dalfopristin are not modified by gender. renal insufficiency in patients with creatinine clearance 6 to 28 ml/min, the auc of quinupristin and dalfopristin in combination with their major metabolites increased about 40% and 30%, respectively. in patients undergoing continuous ambulatory peritoneal dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. the plasma auc of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively. the high molecular weight of both components of synercid suggests that it is unlikely to be removed by hemodialysis. hepatic insufficiency in patients with hepatic dysfunction (child-pugh scores a and b), the terminal half-life of quinupristin and dalfopristin was not modified. however, the auc of quinupristin and dalfopristin in combination with their major metabolites increased about 180% and 50%, respectively. (see dosage and administration and precautions .) obesity (body mass index ≥30): in obese patients the c max and auc of quinupristin increased about 30% and those of dalfopristin about 40%. pediatric patients the pharmacokinetics of synercid in patients less than 16 years of age have not been studied. microbiology the streptogramin components of synercid , quinupristin and dalfopristin, are present in a ratio of 30 parts quinupristin to 70 parts dalfopristin. these two components act synergistically so that synercid's microbiologic in vitro activity is greater than that of the components individually. quinupristin's and dalfopristin's metabolites also contribute to the antimicrobial activity of synercid . in vitro synergism of the major metabolites with the complementary parent compound has been demonstrated. mechanism of action the site of action of quinupristin and dalfopristin is the bacterial ribosome. dalfopristin has been shown to inhibit the early phase of protein synthesis while quinupristin inhibits the late phase of protein synthesis. synercid is bactericidal against isolates of methicillin- susceptible and methicillin- resistant staphylococci. the mode of action of synercid differs from that of other classes of antibacterial agents such as ß-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. therefore, there is no cross resistance between synercid and these agents when tested by the minimum inhibitory concentration (mic) method. resistance resistance to synercid is associated with resistance to both components ( i.e. , quinupristin and dalfopristin). in non-comparative studies, emerging resistance to synercid has occurred. interaction with other antibacterials in vitro combination testing of synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin against enterobacteriaceae and pseudomonas aeruginosa did not show antagonism. in vitro combination testing of synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism. antimicrobial activity synercid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in the indications and usage section. gram-positive bacteria staphylococcus aureus (methicillin- susceptible isolates only) streptococcus pyogenes the following in vitro data are available, but their clinical significance is unknown. at least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (mic) less than or equal to the susceptible breakpoint for quinupristin and dalfopristin ( synercid ) against isolates of similar genus or organism group. however, the efficacy of synercid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. gram-positive bacteria corynebacterium jeikeium staphylococcus aureus (methicillin- resistant isolates) staphylococcus epidermidis (including methicillin- resistant isolates) streptococcus agalactiae susceptibility testing for specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by fda for this drug, please see: https://www.fda.gov/stic.

e = 7.5 mg/kg q8h; n=10) c max c max = maximum drug plasma concentration (mcg/ml) auc auc = area under the drug plasma concentration-time curve (mcg.h/ml) t 1/2 t 1/2 = half-life (hr) quinupristin and metabolites 3.20 ± 0.67 7.20 ± 1.24 3.07 ± 0.51 dalfopristin and metabolite 7.96 ± 1.30 10.57 ± 2.24 1.04 ± 0.20 the clearances of unchanged quinupristin and dalfopristin are similar (0.72 l/h/kg), and the steady-state volume of distribution for quinupristin is 0.45 l/kg and for dalfopristin is 0.24 l/kg. the elimination half-life of quinupristin and dalfopristin is approximately 0.85 and 0.70 hours, respectively. the total protein binding of quinupristin is higher than that of dalfopristin. synercid does not alter the in vitro binding of warfarin to proteins in human serum. penetration of unchanged quinupristin and dalfopristin in noninflammatory blister fluid corresponds to about 19% and 11% of that estimated in plasma, respectively. the penetration into blister fluid of quinupristin and dalfopristin in combination with their major metabolites was in total approximately 40% compared to that in plasma. in vitro , the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome-p450 or glutathione-transferase enzyme activities. synercid has been shown to be a major inhibitor ( in vitro inhibits 70% cyclosporin a biotransformation at 10 mcg/ml of synercid ) of the activity of cytochrome p450 3a4 isoenzyme. (see warnings . ) synercid can interfere with the metabolism of other drug products that are associated with qtc prolongation. however, electrophysiologic studies confirm that synercid does not itself induce qtc prolongation. (see warnings . ) fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination. special populations elderly the pharmacokinetics of quinupristin and dalfopristin were studied in a population of elderly individuals (range 69 to 74 years). the pharmacokinetics of the drug products were not modified in these subjects. gender the pharmacokinetics of quinupristin and dalfopristin are not modified by gender. renal insufficiency in patients with creatinine clearance 6 to 28 ml/min, the auc of quinupristin and dalfopristin in combination with their major metabolites increased about 40% and 30%, respectively. in patients undergoing continuous ambulatory peritoneal dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. the plasma auc of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively. the high molecular weight of both components of synercid suggests that it is unlikely to be removed by hemodialysis. hepatic insufficiency in patients with hepatic dysfunction (child-pugh scores a and b), the terminal half-life of quinupristin and dalfopristin was not modified. however, the auc of quinupristin and dalfopristin in combination with their major metabolites increased about 180% and 50%, respectively. (see dosage and administration and precautions .) obesity (body mass index ≥30): in obese patients the c max and auc of quinupristin increased about 30% and those of dalfopristin about 40%. pediatric patients the pharmacokinetics of synercid in patients less than 16 years of age have not been studied.

area).

y, these values were 113 (51.1%) and 120 (54.1%) patients in the synercid and comparator arms, respectively. patients were found not to be clinically evaluable for reasons such as: wrong diagnosis, lower extremity infection in patients with diabetes or peripheral vascular disease since these infections were assumed to include aerobic gram-negative and anaerobic organisms, no specimen for culture obtained, insufficient therapy, no test of cure assessment, etc. for the patients found to be clinically evaluable, in study jrv 304 the success rate was 49.5% in the synercid arm and 51.9% in the comparator arm. in study jrv 305, the success rates were 66.4% and 64.2% in the synercid and comparator arms, respectively. table 10 shows the clinical success rate (combined results from two clinical trials) in the clinically evaluable population. due to the small numbers of patients in the subsets, statistical conclusions could not be reached. table 10: the clinical success rate in the clinically evaluable population cured or improved infection type synercid comparator (n/n) (%) (n/n) (%) erysipelas (cellulitis) 52/82 (63.4) 43/77 (55.8) post-operative infections 14/38 (36.8) 24/42 (57.1) traumatic wound infection 33/55 (60.0) 33/55 (60.0) safety discontinuations of therapy because of adverse reactions which were probably or possibly due to drug therapy occurred more than four times as often in the synercid group than in the comparator group. approximately half of the discontinuations in the synercid arm were due to venous adverse events. (see adverse reactions: clinical reactions: skin and skin structure studies . ) keep out of the reach of children.

will develop resistance and will not be treatable by synercid or other antibacterial drugs in the future.