Source: FDA, National Drug Code (US) Revision Year: 2019
Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin (formed by drug hydrolysis).
Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using a bioassay following multiple 60-minute infusions of Synercid in two groups of healthy young adult male volunteers. Each group received 7.5 mg/kg of Synercid intravenously q12h or q8h for a total of 9 or 10 doses, respectively. The pharmacokinetic parameters were proportional with q12h and q8h dosing; those of the q8h regimen are shown in Table 1:
Table 1. Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD*) (dose = 7.5 mg/kg q8h; n=10):
| Cmax† (mcg/mL) | AUC‡ (mcg.h/mL) | t1/2§(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 |
* SD= Standard Deviation
† Cmax = Maximum drug plasma concentration
‡ AUC = Area under the drug plasma concentration-time curve
§ t1/2 = Half-life
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.
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.
The pharmacokinetics of quinupristin and dalfopristin are not modified by gender.
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.
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 Cmax and AUC of quinupristin increased about 30% and those of dalfopristin about 40%.
The pharmacokinetics of Synercid in patients less than 16 years of age have not been studied.
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.
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 to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin). In non-comparative studies, emerging resistance to Synercid has occurred.
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.
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
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.
Long-term carcinogenicity studies in animals have not been conducted with Synercid. Five genetic toxicity tests were performed. Synercid, dalfopristin, and quinupristin were tested in the bacterial reverse mutation assay, the Chinese hamster ovary cell HGPRT gene mutation assay, the unscheduled DNA synthesis assay in rat hepatocytes, the Chinese hamster ovary cell chromosome aberration assay, and the mouse micronucleus assay in bone marrow. Dalfopristin was associated with the production of structural chromosome aberrations when tested in the Chinese hamster ovary cell chromosome aberration assay. Synercid and quinupristin were negative in this assay. Synercid, dalfopristin, and quinupristin were all negative in the other four genetic toxicity assays.
No impairment of fertility or perinatal/postnatal development was observed in rats at doses up to 12 to 18 mg/kg (approximately 0.3 to 0.4 times the human dose based on body-surface area).
Two randomized, open-label, controlled clinical trials of Synercid (7.5 mg/kg q12h intravenously [iv]) in the treatment of complicated skin and skin structure infections were performed. The comparator drug was oxacillin (2g q6h iv) in the first study (JRV 304) and cefazolin (1g q8h iv) in the second study (JRV 305); however, in both studies vancomycin (1g q12h iv) could be substituted for the specified comparator if the causative pathogen was suspected or confirmed methicillin-resistant staphylococcus or if the patient was allergic to penicillins, cephalosporins or carbapenems. Study JRV 304 enrolled 450 patients (n=229 Synercid; n=221 Comparator) and Study JRV 305 enrolled 443 patients (n=221 Synercid; n=222 Comparator).
In the first study, 105 patients (45.9%) and 106 patients (48.0%) in the Synercid and Comparator arms, respectively, were found to be clinically evaluable. For the second study, 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) |
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.)
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