Quinupristin and Dalfopristin (Systemic)
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VA CLASSIFICATION
Primary: AM900
Commonly used brand name(s): Synercid.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antibacterial (systemic) —
Indications
Note: Quinupristin and dalfopristin for injection is approved for marketing in the U.S. for the treatment of vancomycin-resistant Enterococcus faecium (VREF) bacteremia under FDA's accelerated approval process, using clearance of VREF from the blood stream as a surrogate end point. A well-controlled clinical study using traditional clinical end points is presently being conducted{01}.
General considerations
Quinupristin and dalfopristin are bacteriostatic against Enterococcus faecium and bacteriocidal against strains of methicillin-susceptible and methicillin-resistant staphylococci. They are not active against Enterococcus faecalis. Enterococcal species therefore must be differentiated to avoid misidentification of Enterococcus faecalis as Enterococcus faecium{01}.
The mode of action of quinupristin and dalfopristin combination is different from that of other classes of antibacterial agent. When tested with the minimum inhibitory concentration method, there is no cross-resistance between the combination and β-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides or tetracyclines{01}. Resistance to the combination is associated with the resistance to both quinupristin and dalfopristin{01}.
Accepted
Septicemia, bacterial (treatment)—Quinupristin and dalfopristin for injection is indicated for the treatment of serious or life-threatening bacteremia caused by vancomycin-resistant Enterococcus faecium{01}.
Skin and skin structure infections, complicated (treatment)—Quinupristin and dalfopristin for injection is indicated for the treatment of complicated skin and skin structure infection by Staphylococcus aureus (methicillin susceptible) or Streptococcus pyogenes {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Quinupristin and dalfopristin combination, a streptogamin antibacterial agent for intravenous administration, is a sterile lyophilized formulation of two semisynthetic pristinamycin derivatives. Quinupristin is derived from pristinamycin I, while dalfopristin is derived from pristinamycin IIA. Quinupristin and dalfopristin are present in a ratio of 30 parts quinupristin to 70 parts of dalfopristin.
Chemical group—
Pristinamycin{01}
Molecular weight—
Quinupristin: 1022.24{01}
Dalfopristin: 690.85{01}
Mechanism of action/Effect:
Quinupristin and dalfopristin combination is bacteriostatic against Enterococcus faecium and bactericidal against strains of methicillin-susceptible and methicillin-resistant staphylococci. The site of action of quinupristin and dalfopristin combination is the bacterial ribosome. Dalfopristin inhibits the early phase of protein synthesis in the bacterial ribosome and quinupristin inhibits the late phase of protein synthesis. The combination of the two components acts synergistically and is more effective in vitro than each component alone{01}. In vitro synergism of the major metabolites with the complimentary parent compound has been demonstrated.
Distribution:
Distribution of unchanged quinupristin and dalfopristin in noninflamed blister fluid is approximately 19% and 11% of estimated plasma level, respectively. When combining with their major metabolites, the amount penetrated into the blister fluid is approximately 40% of plasma level{01}.
VolD (steady–state)—
Quinupristin: 0.45 L/kg{01}.
Dalfopristin: 0.24 L/kg{01}.
Protein binding:
Moderate{01}
Biotransformation:
Quinupristin and dalfopristin are biotransformed in the liver into several active metabolites. Quinupristin is converted into glutathione and cysteine conjugated metabolites, and dalfopristin is hydrolyzed into nonconjugated metabolite{01}.
The in vitrotransformation of the parent drugs is not dependent on cytochrome P450 or glutathione transferase enzyme{01}. However, they are major inhibitors of cytochrome P450 3A4 isoenzyme{01}.
Elimination
Quinupristin 0.85 hour{01}
Dalfopristin 0.70 hour{01}
Peak serum concentration:
Quinupristin and metabolites: 3.2 mcg/mL at a dose of 7.5 mg/kg every 8 hours{01}
Dalfopristin and metabolite: 7.96 mcg/mL at a dose of 7.5 mg/kg every 8 hours{01}
In obese patients (body mass index ³30): Quinupristin level increased by about 30% and dalfopristin level by about 40%{01}
Elimination:
Primary elimination is probably by biliary excretion{01}
Fecal—Approximately 75 to 77% of dose of both parent drugs and their metabolites{01}
Renal—Approximately 15% of quinupristin and 19% of dalfopristin dose{01}
In dialysis—Not removed by peritoneal dialysis or hemodialysis{01}
Precautions to Consider
Cross-sensitivity and/or related problems
Patients allergic to other streptogramins (e.g. pristinamycin or virginiamycin) may be allergic to quinupristin or dalfopristin also{01}.
Carcinogenicity/Mutagenicity
Long-term carcinogenicity in animals has not been studied. Quinupristin and quinupristin-dalfopristin combination were negative 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 in the Chinese hamster ovary cell chromosome aberration assay and was negative in the other four genetic toxicity tests{01}.
Pregnancy/Reproduction
Fertility—
There was no impairment of fertility 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){01}
Pregnancy—
Adequate and well-controlled studies in humans have not been done.
Reproductive studies in mice at doses up to 40 mg/kg per day (approximately half the human dose based on body-surface area), in rats at doses up to 120 mg/kg per day (approximately 2.5 times the human dose based on body-surface area), and in rabbits at doses up to 12 mg/kg per day (approximately half the human dose based on body-surface area) showed no evidence of teratogenic effects or impairment of fertility{01}.
FDA Pregnancy Category B
Breast-feeding
It is not known whether quinupristin and dalfopristin are distributed into breast milk. However, problems in humans have not been documented{01}.
Quinupristin and dalfopristin have been detected in the milk of lactating rats.
Pediatrics
Although quinupristin and dalfopristin have been used in a limited number of pediatric patients at a dose of 7.5 mg/kg every 8 or 12 hours, their safety and efficacy in patients younger than 16 years of age have not been established{01}.
Geriatrics
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of quinupristin and dalfopristin in the elderly.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Note: In vitro drug interaction studies have demonstrated that quinupristin and dalfopristin combination significantly inhibits cytochrome P450 3A4 metabolism of some drugs primarily metabolized by the cytochrome P450 3A4 enzyme system. Therefore, concurrent administration of quinupristin and dalfopristin combination with drugs that are cytochrome P450 3A4 subtrates and possess a narrow therapeutic index requires caution and monitoring of these drugs. Concurrent medications metabolized by the cytochrome P450 3A4 enzyme system that may prolong the QTc interval should be avoided{01}.
Quinupristin and dalfopristin combination 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{01}.
A drug interaction between quinupristin and dalfopristin combination and digoxin cannot be excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Quinupristin and dalfopristin combination has shown in vitro activity against Eubacterium lentium. Digoxin is metabolized in part by bacteria in the gut and therefore, a drug interaction based on quinupristin and dalfopristin combination inhibition or digoxin's gut metabolism by E. lentium is possible{01}.
Astemizole or
» Terfenadine (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these antihistamines by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma antihistamine concentrations should be monitored and dosage adjustment may be necessary{01})
Carbamazepine or
Disopyramide or
Lidocaine or
Quinidine (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of carbamazepine, disopyramide, lidocaine, or quinidine by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma carbamazepine, disopyramide, lidocaine, and quinidine concentrations should be monitored and dosage adjustment may be necessary{01})
Cisapride (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of cisapride by inhibiting the cytochrome P450 3A4 metabolism of cisapride, resulting in prolongation of its effect and/or increased adverse reactions; plasma cisapride concentrations should be monitored and dosage adjustment may be necessary{01})
» Cyclosporine or
Tacrolimus (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these immunosuppressives by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their effect and/or increased adverse reactions; plasma concentrations of these immunosuppressive agents should be monitored and dosage adjustment may be necessary{01})
Delavirdine or
Indinavir or
Nevirapine or
Ritonavir (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these non-nucleoside reverse transcriptase inhibitors [NNRTIs] and protease inhibitors by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma NNRTI and protease inhibitor concentrations should be monitored and dosage adjustment may be necessary{01})
Diazepam or
» Midazolam (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these benzodiazepines by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma benzodiazepine concentrations should be monitored and dosage adjustment may be necessary{01})
Diltiazem or
» Nifedipine or
Verapamil (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these calcium channel blocking agents by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma calcium channel blocking agent concentrations should be monitored and dosage adjustment may be necessary{01})
Docetaxel or
Paclitaxel or
Vinblastine (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of these antineoplastic agents by inhibiting the cytochrome P450 3A4 metabolism of these agents, resulting in prolongation of their therapeutic effect and/or increased adverse reactions; plasma antineoplastic concentrations should be monitored and dosage adjustment may be necessary{01})
HMG-CoA reductase inhibitors, such as
Lovastatin (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of lovastatin by inhibiting the cytochrome P450 3A4 metabolism of lovastatin, resulting in prolongation of its effect and/or increased adverse reactions; plasma lovastatin concentrations should be monitored and dosage adjustment may be necessary{01})
Methylprednisolone (concurrent use with quinupristin and dalfopristin may result in increased plasma concentrations of methylprednisolone by inhibiting the cytochrome P450 3A4 metabolism of methylprednisolone, resulting in prolongation of its effect and/or increased adverse reactions; plasma methylprednisolone concentrations should be monitored and dosage adjustment may be necessary{01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH) (values may be increased{01})
» Bilirubin, serum and
Blood urea nitrogen (BUN) and
Creatinine, serum and
Glucose, blood (concentrations may be increased{01})
Hematocrit and
Hemoglobin (concentrations may be decreased{01})
Platelet count (may be increased or decreased{01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist:
» Hypersensitivity to quinupristin, dalfopristin, or to other streptogramins{01}
Hepatic function impairment (plasma concentrations of quinupristin and dalfopristin may be significantly increased; however, the effect of dose reduction or increase in dosing interval on the pharmacokinetics of quinupristin and dalfopristin in patients with hepatic function impairment has not been studied; dosage adjustment may be necessary; however, there are no recommendations regarding the appropriate dose modification{01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Culture and sensitivity test
Liver function test
» Total and conjugated bilirubin
Side/Adverse Effects
Note: The safety of quinupristin and dalfopristin combination was evaluated in 1099 patients enrolled in five comparative clinical trials. In addition, four noncomparative clinical trials (3 prospective and 1 retrospective in design) were conducted in which 1199 patients received quinupristin and dalfopristin combination for infections due to gram-positive pathogens for which no other treatment option was available. In noncomparative trials, the patients were severely ill, and often with multiple clinical conditions, and may have been intolerant or failed other antibacterial therapies.
Approximately one-third of patients discontinued therapy in noncomparative trials due to adverse reactions. However, the discontinuation rate due to adverse reactions assessed by the investigator as possibly or probably related to quinupristin and dalfopristin combination therapy was approximately 5%.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Infusion site reaction (pain, redness, and/or swelling at the place of injection)
{01}
Incidence less frequent
Arthralgia (joint pain)— incidence 3.3%
myalgia (muscle pain)—incidence 3.1%
thrombophlebitis{01} (pain at the injection site)— incidence 2.4%
{01}
Note: Episodes of arthralgia and myalgia, some severe, have been reported in patients treated with quinupristin and dalfopristin (systemic). In some patients improvement has been noted with a reduction in dose frequency to every 12 hours. In those patients available for follow-up, discontinuation of treatment has been followed by resolution of symptoms. The etiology of these myalgias and arthralgias is under investigation.
Incidence rare
Chest pain
palpitation (pounding or racing of the heart)
hematuria (blood in urine)
vaginitis (redness, burning sensation, or pain in vagina)
pseudomembranous enterocolitis (abdominal or stomach cramps and pain, severe; abdominal tenderness; diarrhea, watery and severe, which may also be bloody; fever)
maculopapular rash (skin rash with red patches ), urticaria (hives)
{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Diarrhea — incidence 2.7%
headache{01}
nausea{01}
pain{01}
pruritus{01} (itching)
rash{01}
vomiting
{01}
Incidence rare
confusion
dizziness
hypertonia (unusual muscle tone), leg cramps
myasthenia ( muscle weakness), paresthesia (numbness or tingling sensation )
constipation
dyspepsia (stomach discomfort or bloating), oral moniliasis (oral yeast infection)
{01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Note: In clinical trials, four patients received quinupristin and dalfopristin combination at doses three times the recommended dose. No adverse effect was considered possibly or probably related to quinupristin and dalfopristin combination overdosage. In animals given extremely high doses of quinupristin and dalfopristin combination dyspnea, emesis, tremors, and ataxia were observed. Therefore, patients who receive higher doses than the recommended dose should be carefully observed and given supportive treatment. Quinupristin and dalfopristin combination is not removed by peritoneal dialysis or hemodialysis.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Quinupristin and Dalfopristin (Systemic).
Consider advising the patient on the following (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to quinupristin, dalfopristin, or other streptogramins (e.g. pristinamycin or virginiamycin)
Breast-feeding—Quinupristin and dalfopristin are distributed into the milk of lactating rats; use with caution in mothers who are breast-feeding
Other medications, especially cyclosporine, midazolam, nifedipine, or terfenadine
Proper use of this medication
» Importance of receiving medication for full course of therapy and on regular schedule
» Proper dosing
Side/adverse effects
Signs of potential side effects, especially infusion site reaction, arthralgia, myalgia, thrombophlebitis, chest pain, palpitation, hematuria, vaginitis, pseudomembranous enterocolitis, maculopapular rash, or urticaria.
General Dosing Information
If quinupristin and dalfopristin combination is to be given concurrently with another medication, each medication should be given separately in accordance with the recommended dosage and route of administration for each drug. With intermittent infusion of quinupristin and dalfopristin combination and other agents through a common intravenous line, the line should be flushed before and after administration with 5% dextrose in water solution.
If moderate to severe venous irritation occurs following peripheral administration of quinupristin and dalfopristin combination 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. In clinical trials, concurrent administration of hydrocortisone or diphenhydramine did not appear to alleviate venous pain or inflammation.
Parenteral Dosage Forms
QUINUPRISTIN AND DALFOPRISTIN FOR INJECTION
Note: Dosage is expressed in terms of the combination of quinupristin and dalfopristin in a ratio of 30:70 (w/w). For example, a 500 milligram (mg) dose contains quinupristin 150 mg and dalfopristin 350 mg.{01}
Usual adult dose
Bacterial septicemia
Intravenous infusion, 7.5 mg per kg of body weight every 8 hours{01}.
Note: The duration of treatment for vancomycin-resistant Enterococcus faecium infection should be determined based on the site and the severity of the infection.
Complicated skin and skin structure infection
Intravenous infustion, 7.5 mg per kg of body weight every 12 hours for a minimum of 7 days{01}.
Usual pediatric dose
Children up to 16 years of age—Safety and efficacy have not been established{01}.
Usual geriatric dose
See Usual adult dose {01}.
Size(s) usually available:”
U.S.—
500 mg (quinupristin 150 mg and dalfopristin 350 mg) (Rx) [Synercid]
Canada—
Not commercially available.
Packaging and storage:
Prior to reconstitution, store between 2 and 8 °C (36 and 46 °F).
Preparation of dosage form:
Quinupristin and Dalfopristin for Injection is reconstituted for use by slowly adding 5 mL of 5% dextrose for injection or sterile water for injection to the single-dose vial to produce a solution containing 100 mg quinupristin and dalfopristin per mL. The vial should be gently swirled by manual rotation without shaking to ensure dissolution of contents while limiting foam formation. After the solution is allowed to sit for a few minutes until all the foam has disappeared, the resulting solution is clear.
Note: Quinupristin and Dalfopristin for Injection does not contain an antibacterial preservative. Therefore, it should be reconstituted under strict aseptic conditions. The reconstituted solution should be diluted within 30 minutes. The storage time of the diluted solution should be as short as possible to minimize the risk of microbial contamination.
Stability:
Diluted solution is stable for 5 hours at room temperature or 54 hours if stored between 2 and 8 °C (36 and 46 °F). Do not freeze the solution{01}.
Incompatibilities:
Quinupristin and dalfopristin injection is not compatible with normal saline and should not be mixed with other drugs. However, it is compatible with aztreonam 20 mg/mL, ciprofloxacin 1 mg/mL, fluconazole 2 mg/mL, haloperidol 0.2 mg/mL, metoclopramide 5 mg/mL, and potassium chloride 40 mEq/L{01}.
Developed: 12/20/1999
References
- Product Information: Synercid® I.V., quinupristin and dalfopristin. Rhone-Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA, USA, Rev 7/1999.
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