INFORMATION FOR HEALTH PROFESSIONALS
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SYNERCID® IV is a sterile freeze-dried formulation of mesylated quinupristin and dalfopristin (two semisynthetic pristinamycin derivatives) in the ratio 30:70 (%w/w). Each vial contains 150 mg quinupristin (derived from pristinamycin I) and 350 mg dalfopristin (derived from pristinamycin IIA).
Also included in Synercid IV as excipients are methanesulfonic acid and sodium hydroxide.
Quinupristin is a hygroscopic, white to very slightly yellow powder. The main component of quinupristin has a chemical formula of C53H67N9O10S and molecular weight of 1022.24.
Dalfopristin is a hygroscopic, white to slightly yellow powder. It has a chemical formula of C34H50N4O9S and a molecular weight of 690.85.
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| Quinupristin CAS number 120138-50-3 |
Dalfopristin CAS number 112362-50-2 |
Microbiology
The streptogramins quinupristin and dalfopristin individually possess bacteriostatic activity against Gram-positive bacteria as do the principal components, PI and PIIA, of the naturally occurring streptogramin pristinamycin. The main target of quinupristin and dalfopristin is the bacterial ribosome. When combined, quinupristin and dalfopristin as Synercid IV, exert bactericidal activity by inhibiting early and late phases of bacterial protein synthesis and interact synergistically at the ribosomal site so that Synercid IV's activity is much greater than that of the components individually. Therefore, the mode of action of streptogramins, e.g., Synercid IV, differs somewhat from that of the macrolides and lincosamides.
The high affinity of Synercid IV to bind to the ribosome contributes to its bactericidal activity which is uncharacteristic of the non-streptogramin members of the Macrolide-Lincosamide-Streptogramin (MLS) antibiotics. Consequently, Synercid IV has improved activity against pathogens resistant to macrolides and lincosamides. Synercid IV is also frequently active against pathogens resistant to β-lactam, glycopeptide, and quinolone antibiotics due to differences in chemical structure and mode of action.
A prolonged post-antibiotic effect (PAE) of Synercid IV was observed with Staphylococcus aureus (10 hours) and Streptococcus pneumoniae (9.1 hours) in the neutropenic mouse thigh abscess model, confirming in vitro data.
In non-comparative studies, emerging resistance to Synercid IV during treatment of VREF infections occurred in 1.8% (6/338) of bacteriologically evaluable patients. Resistance to Synercid IV is associated with resistance to both components (ie. quinupristin and dalfopristin).
In vitro tests with S. aureus, including methicillin- and erythromycin-resistant strains, often show Synercid IV to act synergistically with some β-lactam agents, especially the cephalosporins. In vitro tests with some strains of vancomycin-resistant E. faecium show Synercid IV to act synergistically with glycopeptides. A post-antibiotic effect (PAE) of Synercid IV was observed for S. aureus strains (n=20) when tested in vitro by several methods. This PAE ranged from 0.5 to 8 hours. A PAE in the range of 0.9 to >5.5 hours was shown for vancomycin resistant E. faecium strains (n=3) tested in vitro.
Antagonism was not generally reported for any Gram-positive pathogens. In vitro tests with antibiotics active against Pseudomonas aeruginosa or Enterobacteriaceae, eg., cefotaxime, ciprofloxacin, aztreonam, or gentamicin, did not show antagonism with Synercid IV.
Quinupristin and dalfopristin's metabolites also contribute to the antimicrobial activity of Synercid IV because their MICs range from comparable to several-fold lower than those of either quinupristin or dalfopristin. In addition, in vitro synergism of the major metabolites with the complementary parent compound has been demonstrated (See Pharmacokinetics).
Breakpoints
The following MIC breakpoints separating susceptible from resistant organisms are recommended:
In vitro antibacterial spectrum
Susceptible; the pathogen is likely to be inhibited if blood concentrations reach normally achievable levels (MIC90 ≤ 1 mcg/mL):
Aerobic Gram-positive micro-organisms: Corynebacterium jeikeium, Enterococcus faecium* (including Van A {Vancomycin-resistant and Teicoplanin-resistant} or Van B {Vancomycin-resistant and Teicoplanin-susceptible} strains), Listeria monocytogenes, Staphylococcus aureus * (methicillin-susceptible and -resistant) , Staphylococcus capitis, Staphylococcus epidermidis* (methicillin-susceptible and -resistant) , Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Staphylococcus warneri, Streptococcus agalactiae*, Streptococcus pneumoniae (penicillin-susceptible* and -resistant) , Streptococcus pyogenes*, and viridans group streptococci.
Aerobic Gram-negative micro-organisms: Legionella pneumophila, Legionella spp., Moraxella catarrhalis, Neisseria meningitidis and Neisseria gonorrhoeae.
Anaerobic micro-organism: Porphyromonas asaccharolytica.
Atypical micro-organism: Mycoplasma pneumoniae.
Using tissue culture methods, Chlamydiae pneumoniae are considered susceptible.
Moderately susceptible; the result should be considered equivocal and, if the infection cannot be treated with alternative, clinically feasible drugs, the test should be repeated (MIC90 = 2 mcg/mL):
Aerobic Gram-positive micro-organisms: Enterococcus hirae, Lactobacillus spp., Leuconostoc spp., Group C streptococci, and Group G streptococci.
Anaerobic micro-organisms: Clostridium perfringens and Peptostreptococcus spp.
Resistant (Non-susceptible); the pathogen is unlikely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable (MIC90 ≥ 4 mcg/mL):
Aerobic Gram-positive micro-organisms: Enterococcus avium, Enterococcus casseliflavus, Enterococcus durans, Enterococcus faecalis, Enterococcus gallinarum, Pediococcus spp ., and Streptococcus bovis.
Aerobic Gram-negative micro-organisms: Acinetobacter spp ., Enterobacteriaceae, Haemophilus influenzae* , Haemophilus parainfluenzae, and Pseudomonas spp.
Anaerobic micro-organisms: Bacteroides spp. , Clostridium difficile, Fusobacterium spp., Prevotella bivia, Prevotella melaninogenica, and Veillonella spp .
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
** Haemophilus influenzae strains with MICs ≤ 2 mcg/mL may be considered susceptible and MIC of 4 mcg/mL considered moderately susceptible
Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are, however, rapidly converted to several major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated for dalfopristin (formed by drug hydrolysis). In vitro synergism of quinupristin's metabolites with dalfopristin, and of dalfopristin's metabolite with quinupristin, has been demonstrated. (See Microbiology).
Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using bioassay following multiple 60-minute infusions of Synercid IV in two groups of healthy young male volunteers. Each group received 7.5 mg/kg intravenously 12 hourly or 8 hourly for a total of 9 and 10 doses, respectively. The pharmacokinetic parameters were comparable with both dosage regimens; those of the 8 hourly regimen are shown in the following table:
Mean (±SD) steady-state pharmacokinetic parameters of quinupristin,
dalfopristin and metabolites
(n = 10)
| Dose Regimen | Cmax1 (mcg/mL) | AUC2 (mcg.h/mL) | t ½3 (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 |
1Cmax = Maximum drug plasma concentration
2 AUC = Area under the drug plasma concentration-time curve
3t ½ = Half-life
The clearances of unchanged quinupristin and dalfopristin are similar (0.7 L/h/kg), and the apparent volume of distribution for both products is approximately 1.0 L/kg. The elimination half-lives of quinupristin and dalfopristin are approximately 0.9 and 0.75 hours, respectively.
The protein binding ranges from 55 to 78% for quinupristin and from 11 to 26% for dalfopristin.
Penetration of unchanged quinupristin and dalfopristin in non-inflammatory 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.
Radiolabeled quinupristin and dalfopristin were shown to penetrate into ex vivo human macrophages with ratios of intracellular to extracellular concentrations of 60:1 for quinupristin and 30:1 for dalfopristin after 1 hour. A slow release from macrophages was complete at 5 hours for both quinupristin and dalfopristin.
In a mouse model of Streptococcus pneumoniae, Synercid IV penetration into the lung was demonstrated.
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. However, Synercid IV has been shown to be an inhibitor of the CYP 3A4 isoenzyme. (See Interactions with other drugs).
Faecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75-77% 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 faecal elimination.
Elderly : Pharmacokinetics of quinupristin and dalfopristin are not modified in the elderly.
Gender : Pharmacokinetics of quinupristin and dalfopristin are not modified with gender.
Renal insufficiency (Creatinine clearance between 6-28mL/min): The AUC of quinupristin and dalfopristin in combination with their major metabolites increased by about 1.4 and 1.3 fold, respectively. (See Dosage and Administration).
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 increases about 1.2 and 1.3 fold (See Dosage and Administration). The high molecular weight of both components of Synercid IV suggests that it is unlikely to be removed by haemodialysis.
Hepatic insufficiency: In patients with hepatic cirrhosis, 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 by about 2.8 and 1.5 fold, respectively. (See Dosage and Administration and Precautions).
Obese: In obese patients, the Cmax and AUC of quinupristin increases about 1.3 fold and the AUC of dalfopristin about 1.4 fold (See Dosage and Administration and Precautions).
Children: Pharmacokinetics of Synercid IV in paediatric subjects have not been studied.
Preclinical safety data
In animal toxicity studies, Synercid IV caused severe vascular lesions which increased in severity according to the dose, the solution concentration, the duration of the infusion and the total duration of repeated administrations. The vascular lesions were only partly reversible once treatment ceased.
Histamine release was observed in dogs, monkeys and mice at Synercid IV doses of 5, 20 and 103 mg/kg, respectively. However, this has not been observed in human healthy volunteers at single doses up to 29.4 mg/kg and multiple doses up to 7.5 mg/kg 8 hourly. Synercid IV caused histamine-induced hypotension in anaesthetised dogs at 10 mg/kg IV and was shown to have moderate potential for causing anaphylaxis or anaphylactic-type reactions in guinea-pigs.
In the non-comparative trials, patients often presented with multiple co-morbidities and/or physiologic impairments, and may have been intolerant to or failed other antibacterial therapies.
Results are available from four non-comparative studies of Synercid IV (7.5 mg/kg every 8 hours) for the treatment of vancomycin-resistant Enterococcus faecium (VREF) (N=1222). Three of these studies were prospective, the fourth consisted of a collection of individual emergency-use requests.
Of the 1222 patients, 27% did not have a specific site of infection identified, but presented with pure growth of VREF in two or more blood cultures. Ninety percent (90%) of these patients had clearance of their VREF bacteremia within the first 48-72 hours of therapy.
Because of the emergency use nature of the VREF trials and the variability in data collection in these severely ill patients, the percentage of patients found to be evaluable was 24.4%. The overall efficacy rate (defined as clinical success and eradication of the initial pathogen) in the evaluable patients (n=298) was 52.3%. The most common sites of infection included intra-abdominal, skin and skin structure, and the urinary tract. In these subgroups, the efficacy rates for evaluable patients having the most complete documentation were 46.3% (n=67), 66.7% (n=15), and 73.9% (n=23), respectively.
Results are available from five comparative and four non-comparative phase III studies of Synercid IV (7.5 mg/kg every 8 or every 12 hours) for the treatment of methicillin-resistant Staphylococcus aureus infections. The By-pathogen Bacteriological Success rate (Eradicated and Presumed Eradicated) in Bacteriologically Evaluable patients was 61.8% (34/55). Comparator (Vancomycin) results are available for both Hospital-Acquired Pneumonia and complicated Skin and Skin Structure Infections with a By-pathogen Bacteriological Success rate similar to Synercid IV (61.5% - 16/26).
Synercid IV is indicated for the treatment of suspected or proven Methicillin Resistant Staphylococcus aureus or Vancomycin-Resistant Enterococcus Faecium infections requiring intravenous therapy where other antibiotics are inappropriate.
Synercid IV can be used for treatment of the above indications in β-lactam-, quinolone- or glycopeptide-allergic or intolerant patients.
Synercid IV is contraindicated in patients with known hypersensitivity to Synercid IV or to any of its components or other streptogramins (e.g. pristinamycin, virginiamycin).
Synercid IV should not be diluted with saline solutions as it is not compatible with sodium chloride.
Synercid IV should not be mixed with, or physically added to other drugs since compatibility has not been studied.
With intermittent infusion of Synercid IV and other drugs through a common intravenous line, the line should be flushed before and after Synercid IV administration with 5% glucose.
As Synercid IV contains no antibacterial preservative, it should be reconstituted under strict aseptic conditions. The reconstituted solution should be diluted within 30 minutes.
Following completion of the infusion, the vein should be flushed with 5% glucose solution to minimise venous irritation. Flushing with saline or heparin immediately after Synercid IV administration is not recommended.
Synercid IV should be administered as an intravenous infusion over 60 minutes. Safety and efficacy of an intravenous infusion duration of other than 60 minutes has not been studied.
If moderate to severe venous irritation occurs following peripheral administration of Synercid IV, consideration should be given to increasing the infusion volume to 500 or 750 mL, changing the infusion site, or infusion through a peripherally inserted central catheter (PICC) or central venous catheter.
Clinical trial data suggests that the incidence of adverse effects in patients with chronic liver insufficiency or cirrhosis is comparable to that in patients with normal hepatic function. However, based on the pharmacokinetic parameters in patients with hepatic cirrhosis, (using bioassays measuring each parent drug plus their in vitro active metabolites, a dosage reduction may be warranted but precise recommendations cannot be made at present. (See Dosage and Administration).
Long-term carcinogenicity studies in animals have not been conducted with Synercid IV.
Genetic toxicity studies were performed with Synercid IV, in bacterial and mammalian tests in vivo and in vitro. The tests used included the bacterial reverse mutation (Ames test), the CHO/HGPRT gene mutation test, the in vitro unscheduled DNA synthesis test in rat hepatocytes, the chromosome aberration test in CHO-K1 cells and the in vivo mouse micronucleus test in bone marrow.
No evidence for in vitro mutagenic activity and no induction of DNA repair or in vivo clastogenic effect of Synercid IV, dalfopristin or quinupristin were detected with these tests.
Dalfopristin was associated with the production of structural chromosome aberrations when tested in the Chinese hamster ovary cell chromosome aberration assay. Synercid IV and quinupristin were negative in this assay.
Category B3
Reproductive studies have been performed in mice at doses up to 40 mg/kg/day (approximately half the human dose based on body-surface area), in rats at doses up to 120 mg/kg/day (approximately 2.5 times the human dose based on body-surface area), and have revealed no evidence of harm to the fetus due to Synercid IV. Synercid IV was associated with decreased fetal weights and increased post-implantation losses and abortions when administered IV at doses ≥ 6 mg/kg/day. This may be secondary to maternal toxicity, however a no observed effect dose was not established There were no effects on the peri-natal and post-natal development of rat pups when given to pregnant rats at doses up to 8mg/kg/day (approximately 0.4 times the human dose based on body surface area ).
There are no adequate and well-controlled studies with Synercid IV in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.
Use in Lactation
In lactating rats, quinupristin was excreted in milk. It is not known whether
Synercid IV is excreted in human breast milk. Consequently, lactating women
should be advised not to breast feed during Synercid IV treatment.
A limited number of paediatric patients (32 under 12 years) in non-comparative "emergency use" studies have been successfully treated with Synercid IV according to the adult dosage schedule. (See Dosage and Administration).
No impairment of fertility was observed in rats at IV doses up to 12 mg/kg/day ( although it was likely that these doses were associated with blood drug levels lower than those expected in humans during a course of treatment).
Synercid IV is unlikely to affect the ability to drive or operate machines.
In vitro drug interaction studies have demonstrated that the cytochrome P450 3A4 isoenzyme is significantly inhibited by Synercid IV and that the CYP 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine are inhibited by Synercid IV. Thus it is reasonable to expect that the concomitant administration of Synercid IV and other drugs primarily metabolised by the CYP450 3A4 enzyme system may result in plasma levels of the drugs that could increase or prolong both therapeutic and adverse reactions. Therefore, dosage adjustment of these drugs may be necessary.
A drug interaction between Synercid IV and digoxin cannot be excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Synercid IV has shown in vitro activity (MICs of 0.25 mg/mL when tested on two strains) against Eubacterium lentum. Digoxin is metabolized in part by bacteria in the gut and as such, a drug interaction based on Synercid IV's inhibition of digoxin's gut metabolism (by Eubacterium lentum ) may be possible.
In vitro combination testing of Synercid IV with aztreonam, cefotaxime, ciprofloxacin, and gentamicin, against Enterobacteriaceae and Pseudomonas aeruginosa did not show antagonism.
In vitro combination testing of Synercid IV 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.
Coadministration of Synercid IV with drugs which are metabolised by cytochrome P450 3A4 enzyme system and which may prolong the QTc interval (e.g. terfenadine, astemizole, cisapride, disopyramide, quinidine and lignocaine) should be avoided.
Concomitant administration of a single dose of cyclosporin A and Synercid IV in healthy volunteers led to elevated plasma levels of cyclosporin A. Therefore, a dosage reduction of cyclosporin A based on monitoring of cyclosporin A levels may be necessary.
In vitro studies have not shown significant inhibition of human CYP 1A2, 2A6, 2C9, 2C19, 2D6, or 2E1 by Synercid IV and thus clinical interaction with drugs metabolised by these cytochrome P450 isoenzymes is not expected.
In comparative clinical studies, increases in total and conjugated bilirubin greater than 5 times the Upper Limit of Normal (ULN) were reported in 0.9% and 3.1% of patients, respectively.
Other laboratory changes reported as clinically significant, irrespective of relationship to Synercid IV administration:
| Incidence greater than 1% | increases in eosinophils, blood urea nitrogen, gammaglutamyl
transferase, lactose dehydrogenase, creatinine phosphokinase, AST, ALT,
blood glucose, alkaline phosphatase, creatinine. decreases in haemoglobin, haematocrit. increases and decreases in potassium, platelets. |
|---|
In addition in non-comparative studies, the discontinuation rate due to adverse
laboratory reactions possibly or probably related to Synercid IV was 2.0%. Most
patients discontinued because of liver function test abnormalities.
Decrease in white blood cells, carbon dioxide, neutrophils and bicarbonate were also reported with an incidence greater than 1%.
One case of pancytopenia was reported.
Other
Episodes of arthralgia and myalgia have been reported, particularly in patients treated with an 8 hourly regimen. Should severe or protracted arthralgia or myalgia occur, a switch to a 12 hourly regimen may be considered. The occurrence of arthralgia and myalgia may be related to the duration of Synercid IV treatment.
As with other antimicrobials, use of Synercid IV may result in overgrowth of non-susceptible micro-organisms (e.g. Enterococcus faecalis, enteric Gram-negative bacilli). Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.
The safety of Synercid IV has been evaluated in 1099 patients enrolled in 5 comparative clinical trials and in 1199 patients in four non-comparative studies. This latter group of patients received Synercid IV for Gram-positive infections for which no other treatment option was appropriate. The patients in this population were severely ill, with multiple background diseases, physiological impairments and intolerance to other antibacterial therapies.
In comparative clinical studies, the discontinuation rate due to adverse reactions possibly or probably related to Synercid IV was 6.1% for systemic reactions and 10.7% for local venous reactions. For systemic reactions, most patients discontinued due to rash (1%), nausea (0.8%), vomiting (0.5%), pruritus (0.5%), and pain (0.5%).
| Incidence equal to or greater than 1% | Local venous reactions (peripheral administration):
inflammation (42.0%), pain (40.0%), oedema (17.3%), injection site
reaction (13.4%), thrombophlebitis (2.4%). Systemic adverse reactions : nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%), rash (2.5%), headache (1.6%), pruritus (1.5%), pain (1.5%). |
|---|---|
| Incidence less than 1% but greater than 0.1% | abdominal pain, infection, fever, allergic reaction, cellulitis, chest pain, aggravated reaction, phlebitis, palpitation, oral moniliasis, stomatitis, constipation, dyspepsia, pseudomembraneous enterocolitis, pancreatitis, peripheral oedema, gout, arthralgia, myalgia, myasthenia, vasodilation, paraesthesia, confusion, dizziness, hypertonia, insomnia, anxiety, leg cramps, pneumonia, dyspnoea, pleural effusion, sweating, maculopapular rash, urticaria, vaginitis, urinary tract infection, haematuria. |
In addition, in non-comparative studies, the discontinuation rate due to
systemic and local adverse reactions was 5.4% and 0.7% respectively. Most
patients discontinued because of arthralgia (2.3%) and myalgia (1.8%).
Systemic adverse reactions reported were arthralgia (9.5%), myalgia (7.3%) and asthenia (1.1%). In the Emergency-use studies, arthralgia and/or myalgia were reported in 13.0% (156/1199) of patients, possibly associated with the duration of Synercid IV treatment, and these adverse reactions led to discontinuation of treatment in 2.9% (35/1199) of patients. Adverse reactions reported with an incidence of less than 1%, but greater than 0.1%: hyponatremia, anorexia, hypotension, back pain, cyclosporin level increased, tachycardia, jaundice, hepatitis, and pharyngitis.
No cases of ototoxicity have been reported during Synercid IV clinical trials. The clinical profile of Synercid IV suggests that there is no nephrotoxic effect.
Deaths in 0.3% (7/2298) of patients was reported during clinical studies as possibly related to Synercid IV.
Synercid IV should not be administered as an intravenous bolus.. Synercid IV should be administered by intravenous infusion in 5% glucose solution (normally 250 mL) over a 60-minute period (See Precautions).
The recommended dose of Synercid IV is 7.5mg/kg every 8 hours.
In patients with severe underlying conditions, administration of Synercid IV through central venous access (e.g., PICC) can be considered to decrease the incidence of venous irritation.
Elderly: No dosage adjustment is required for use in the elderly. (See Pharmacokinetics).
Renal Insufficiency: No dosage adjustment is required for use in renally impaired patients and patients undergoing peritoneal dialysis.(See Pharmacokinetics).
Hepatic Insufficiency: Clinical trial data suggests that the incidence of adverse effects in patients with chronic liver insufficiency or cirrhosis is comparable to that in patients with normal hepatic function. However, based on the pharmacokinetic parameters in patients with hepatic cirrhosis, a dosage reduction to 5 mg/kg of Synercid IV is recommended if tolerability at 7.5 mg/kg is unacceptable. (See Pharmacokinetics and Precautions).
Data from clinical trials of Synercid IV 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.
Obese Patients: No dosage adjustment is required for use in obese patients. (See Pharmacokinetics).
Paediatric Patients: A limited number of paediatric patients (32 under 12 years) in non comparative ("emergency use") studies have been successfully treated with Synercid IV according to the adult dosage schedule (See Precautions).
Synercid IV should not be mixed with, or physically added to other drugs since compatibility has not been studied . Flushing with saline or heparin immediately after Synercid IV administration is not recommended.
With intermittent infusion of Synercid IV and other drugs through a common intravenous line, the line should be flushed before and after Synercid IV administration with 5% glucose.
Vials are for single use in one patient on one occasion only. Any unused solution should be discarded.
As Synercid IV contains no antibacterial preservative, it should be reconstituted under strict aseptic conditions.
NOTE: As for other parenteral drug products inspect visually for particulate matter prior to administration.
No symptomatic cases of overdose with Synercid IV have been reported. Patients who receive an overdose should be carefully observed and given supportive treatment. Synercid IV is not removed by peritoneal dialysis (See Pharmacokinetics). The high molecular weight of both components of Synercid IV suggests that it is unlikely to be removed by haemodialysis.
The unopened vials should be stored under refrigeration at 2 to 8°C.
Reconstituted vials should be further diluted immediately. Chemical and physical stability of the diluted solution prior to the infusion is established at 3 hours at room temperature or 48 hours if stored at 4°C. The storage of the diluted infusion solution should be as short as possible to minimise the risk of microbial contamination. The diluted infusion solution should not be stored for more than 24 hours under refrigeration 2 to 8°C. The solution should not be frozen.
Synercid IV is available in 500 mg sterile single-dose vials.
Synercid IV is supplied as a sterile freeze-dried pyrogen-free preparation in single-dose 10 mL type I glass vials with a chlorobutyl rubber stopper and an aluminium cap with dark blue flip-off cover.
Cartons containing one single-dose Synercid IV vial containing sufficient quinupristin/ dalfopristin as the mesylate salts to deliver 500 mg for intravenous administration.
Synercid IV is a prescription Medicine.
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May 2005