Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/610
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Synercid (Injection)
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Synercid should be administered by intravenous infusion in 5% Dextrose in Water solution over a 60-minute period. The recommended dosage for the treatment of infections is described in the table below. An infusion pump or device may be used to control the rate of infusion. If necessary, central venous access (e.g., PICC) can be used to administer Synercid to decrease the incidence of venous irritation. The minimum recommended treatment duration for Complicated
Skin and Skin Structure Infections is seven days. For Vancomycin-Resistant Enterococcus faecium infection, the treatment
duration should be determined based on the site and severity of the infection. Special Populations: Elderly: No dosage adjustment of Synercid is required for use in the elderly. Renal Insufficiency: No
dosage adjustment of Synercid is required
for use in patients with renal impairment or patients undergoing peritoneal
dialysis. (See CLINICAL PHARMACOLOGY:
Pharmacokinetics.) Hepatic Insufficiency: Data from clinical 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. Pediatric Patients (less than
16 years of age): Based on a limited number of pediatric patients
treated under emergency-use conditions, no dosage adjustment of Synercid is required. (See PRECAUTIONS:
Pediatric Use.)<br/>Preparation and administration of solution:: NOTE: As for other parenteral drug products, Synercid should be inspected visually for particulate matter prior to administration.
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Synercid (quinupristin
and dalfopristin powder for injection) I.V., a streptogramin antibacterial
agent for intravenous administration, is a sterile lyophilized formulation
of two semisynthetic pristinamycin derivatives, quinupristin (derived from
pristinamycin I) and dalfopristin (derived from pristinamycin IIA) in the
ratio of 30:70 (w/w). Quinupristin is a white to very slightly yellow, hygroscopic powder. It is a combination of three peptide macrolactones. The main component of quinupristin (>88.0%) has the following chemical name: N-[(6R,9S,10R,13S,15aS,18R,22S,24aS)-22-[p-(dimethylamino)benzyl]-6-ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(3S)-3-quinuclidinylthio] methyl]-12H-pyrido[2,1-f]pyrrolo-[2,1-l][1,4,7,10,13,16] oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide. The
main component of quinupristin has an empirical formula of CHNOS,
a molecular weight of 1022.24 and the following structural formula: Dalfopristin is a slightly yellow to yellow, hygroscopic, powder. The chemical name for dalfopristin is: (3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone. Dalfopristin
has an empirical formula of CHNOS,
a molecular weight of 690.85 and the following structural formula:
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Pharmacokinetics: 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 the following table: 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 protein binding of Synercid is moderate. 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��g/mL of Synercid) of the activity of cytochrome P450 3A4 isoenzyme. 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. 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.<br/>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. Obesity (body mass
index���30): In obese patients the Cand 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. Synercid is bacteriostatic against Enterococcus
faecium and bactericidal against strains of methicillin-susceptible
and methicillin-resistant staphylococci. 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. 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),��-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism. The mode of action differs from that of other classes of antibacterial agents such as��-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. There is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method. In non-comparative
studies, emerging resistance to Synercid during
treatment of VREF infections occurred. Resistance to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin). Synercid has been shown to be active against most
strains of the following microorganisms, both in
vitro and in clinical infections, as described in the INDICATIONS AND USAGE section. Aerobic gram-positive microorganismsEnterococcus faecium (Vancomycin-resistant
and multi-drug resistant strains only)Staphylococcus
aureus (methicillin-susceptible strains only)Streptococcus
pyogenes NOTE: Synercid is not active against Enterococcus faecalis. Differentiation of enterococcal
species is important to avoid misidentification of Enterococcus
faecalis as Enterococcus faecium. The
following in vitro data are available, but their clinical significance is unknown. The
combination of quinupristin and dalfopristin (Synercid) exhibits in vitro minimum
inhibitory concentrations (MIC's) of���1.0��g/mL against
most (���90%) isolates of the following microorganisms; however, the
safety and effectiveness of Synercid in
treating clinical infections due to these microorganisms have not been established
in adequate and well-controlled clinical trials. Aerobic gram-positive microorganismsCorynebacterium jeikeiumStaphylococcus
aureus (methicillin-resistant strains)Staphylococcus
epidermidis (including methicillin-resistant strains)Streptococcus agalactiae
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Synercid is contraindicated
in patients with known hypersensitivity to Synercid, or with prior hypersensitivity to other streptogramins (e.g., pristinamycin or virginiamycin).
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Synercid is supplied
as a sterile lyophilized pyrogen-free preparation in single-dose 10 mL type
I glass vials with gray elastomeric closure, and aluminum seal with a dark
blue flip-off cap for the 500 mg vial and a red flip-off cap for the 600 mg
vial.
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One of Synercid's
approved indications is for the treatment of patients with serious or life-threatening
infections associated with vancomycin-resistant Enterococcus
faecium (VREF) bacteremia. Synercid has
been approved for marketing in the United States for this indication under
FDA's accelerated approval regulations that allow marketing of products
for use in life-threatening conditions when other therapies are not available.
Approval of drugs for marketing under these regulations is based upon a demonstrated
effect on a surrogate endpoint that is likely to predict clinical benefit. Approval
of this indication is based upon Synercid's
ability to clear VREF from the bloodstream, with clearance of bacteremia considered
to be a surrogate endpoint. There are no results from well-controlled clinical
studies that confirm the validity of this surrogate marker. However, a study
to verify the clinical benefit of therapy with Synercid on traditional clinical endpoints (such as cure of the underlying
infection) is presently underway.
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General: Venous
Irritation: Following completion of a peripheral infusion, the vein
should be flushed with 5% Dextrose in Water solution to minimize venous irritation. DO NOT FLUSH with saline or heparin after
Synercid administration because of incompatibility concerns. If
moderate to severe venous irritation occurs following peripheral administration
of Synercid diluted in 250 mL of Dextrose
5% in water, consideration should be given to increasing the infusion volume
to 500 or 750 mL, changing the infusion site, or infusing by a peripherally
inserted central catheter (PICC) or a central venous catheter. In clinical
trials, concomitant administration of hydrocortisone or diphenhydramine did
not appear to alleviate venous pain or inflammation. Rate of Infusion: 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. 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. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Drug Interactions: In vitro drug interaction studies have shown
that Synercid significantly inhibits cytochrome
P450 3A4. Synercid does
not significantly inhibit human cytochrome P450 1A2, 2A6, 2C9, 2C19, 2D6,
or 2E1. Therefore, clinical interactions with drugs metabolized by these cytochrome
P450 isoenzymes are not expected. A drug interaction
between Synercid and digoxin cannot be
excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Synercid has shown in vitro activity
(MICs of 0.25 mcg/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's
inhibition of digoxin's gut metabolism (by Eubacterium
lentum) may be possible. 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),��-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism. Carcinogenesis, Mutagenesis, Impairment
of Fertility: 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). Pregnancy: Teratogenic Effects: Pregnancy Category B: 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 in rabbits at doses up to 12 mg/kg/day (approximately half the human dose
based on body-surface area) and have revealed no evidence of impaired fertility
or harm to the fetus due to Synercid. There
are, however, no adequate and well-controlled studies with Synercid 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. Nursing Mothers: In lactating
rats, Synercid was excreted in milk. It
is not known whether Synercid is excreted
in human breast milk. Because many drugs are excreted in human milk, caution
should be exercised when Synercid is administered
to a nursing woman. Hepatic Insufficiency: Following
a single 1-hour infusion of Synercid (7.5
mg/kg) to patients with hepatic insufficiency, plasma concentrations were
significantly increased. (See CLINICAL
PHARMACOLOGY: Special Populations.) However, the effect
of dose reduction or increase in dosing interval on the pharmacokinetics of Synercid in these patients has not been studied.
Therefore, no recommendations can be made at this time regarding the appropriate
dose modification. Pediatric Use: Synercid has
been used in a limited number of pediatric patients under emergency-use conditions
at a dose of 7.5 mg/kg q8h or q12h. However, the safety and effectiveness
of Synercid in patients under 16 years
of age have not been established. Geriatric Use: In phase
3 comparative trials of Synercid, 37%
of patients (n=404) were���65 years of age, of which 145 were���75
years of age. In the phase 3 non-comparative trials, 29% of patients (n=346)
were���65 years of age, of which 112 were���75 years of age. There
were no apparent differences in the frequency, type, or severity of related
adverse reactions including cardiovascular events between elderly and younger
individuals.
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There are four reports of patients receiving Synercid doses at up to three times that recommended (7.5 mg/kg). No adverse
events were considered possibly or probably related to Synercid overdose. Signs of acute overdosage may include dyspnea, emesis,
tremors, and ataxia as seen in animals given extremely high doses (50 mg/kg)
of Synercid. Patients who receive an overdose
should be carefully observed and given supportive treatment. Synercid is not removed by peritoneal dialysis or by hemodialysis.
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quinupristin and dalfopristin
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Synercid (Injection)
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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.<br/>COMPARATIVE TRIALS:<br/>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:<br/>CLINICAL REACTIONS���ALL COMPARATIVE STUDIES: Adverse reactions with an incidence of���1% and possibly
or probably related to Synercid administration
include: 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<br/>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: 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: There were eight (1.7%) episodes of thrombus or thrombophlebitis
in the Synercid arms and none in the comparator
arms.<br/>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).<br/>NON-COMPARATIVE TRIALS:<br/>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: 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.<br/>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.<br/>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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Drug Interactions: In vitro drug interaction studies have demonstrated
that Synercid significantly inhibits cytochrome
P450 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine.
In addition, 24 subjects given Synercid 7.5
mg/kg q8h for 2 days and 300 mg of cyclosporine on day 3 showed an increase
of 63% in the AUC of cyclosporine, an increase of 30% in the Cof
cyclosporine, a 77% increase in the tof cyclosporine, and,
a decrease of 34% in the clearance of cyclosporine. Therapeutic
level monitoring of cyclosporine should be performed when cyclosporine must
be used concomitantly with Synercid. It is reasonable to expect that the concomitant administration
of Synercid and other drugs primarily metabolized by the cytochrome P450 3A4
enzyme system may likely result in increased plasma concentrations of these
drugs that could increase or prolong their therapeutic effect and/or increase
adverse reactions. (See Table below.) Therefore, coadministration of Synercid
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 Cincreased
by 18% and 14% (median values) and the AUC increased by 44% and 33% for nifedipine
and midazolam, respectively. Table of Selected Drugs
That Are Predicted to Have Plasma Concentrations Increased by Synercid + 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 + This list of drugs is not all inclusive. 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. difficle 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.
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Synercid is indicated
in adults for the treatment of the following infections when caused by susceptible
strains of the designated microorganisms.<br/>Vancomycin-resistant Enterococcus faecium (VREF): Synercid is indicated
for the treatment of patients with serious or life-threatening infections
associated with vancomycin-resistant Enterococcus
faecium (VREF) bacteremia. One
of Synercid's approved indications
is for the treatment of patients with serious or life-threatening infections
associated with vancomycin-resistant Enterococcus
faecium (VREF) bacteremia. Synercid has
been approved for marketing in the United States for this indication under
FDA's accelerated approval regulations that allow marketing of products
for use in life-threatening conditions when other therapies are not available.
Approval of drugs for marketing under these regulations is based upon a demonstrated
effect on a surrogate endpoint that is likely to predict clinical benefit. Approval
of this indication is based upon Synercid's
ability to clear VREF from the bloodstream, with clearance of bacteremia considered
to be a surrogate endpoint. There are no results from well-controlled clinical
studies that confirm the validity of this surrogate marker. However, a study
to verify the clinical benefit of therapy with Synercid on traditional clinical endpoints (such as cure of the underlying
infection) is presently underway. Complicated
skin and skin structure infections caused by Staphylococcus
aureus (methicillin susceptible) or Streptococcus
pyogenes. (See CLINICAL
STUDIES.)
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Synercid
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