SYNERCID Powder for solution for injection Ref.[10268] Active ingredients: Dalfopristin Quinupristin

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 C_max of cyclosporine, a 77% increase in the t_1/2 of 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 C_max increased by 18% and 14% (median values) and the AUC increased by 44% and 33% for nifedipine and midazolam, respectively.

Table 2. Selected Drugs That Are Predicted to Have Plasma Concentrations Increased by Synercid*:

* This list of drugs is not all inclusive.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Synercid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Comparative Trials

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:

Table 3. Percent (%) of Patients Discontinuing Therapy by Reaction Type:

Clinical Reactions – All Comparative Studies

Adverse reactions with an incidence of ≥1% and possibly or probably related to Synercid administration include:

Table 4. Adverse Reactions with an Incidence of ≥1% and Possibly or Probably Related to Synercid Administration:

Additional adverse reactions that were possibly or probably related to Synercid with an incidence less than 1% within each body system are listed below:

Body as a Whole: abdominal pain, worsening of underlying illness, allergic reaction, chest pain, fever, infection;

Cardiovascular: palpitation, phlebitis;

Digestive: constipation, dyspepsia, oral moniliasis, pancreatitis, pseudomembranous enterocolitis, stomatitis;

Metabolic: gout, peripheral edema;

Musculoskeletal: arthralgia, myalgia, myasthenia;

Nervous: anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesia, vasodilation;

Respiratory: dyspnea, pleural effusion;

Skin and Appendages: maculopapular rash, sweating, urticaria;

Urogenital: hematuria, vaginitis

Clinical Reactions – Skin and Skin Structure Studies

In two of the five comparative clinical trials Synercid (n=450) and comparator regimens (e.g., oxacillin/vancomycin or cefazolin/vancomycin; n=443) were studied for safety and efficacy in the treatment of complicated skin and skin structure infections. The adverse event profile seen in the Synercid patients in these two studies differed significantly from that seen in the other comparative studies. What follows is safety data from these two studies.

Discontinuation of therapy was most frequently due to the following drug related events:

Table 5. Drug Related Events Most Frequently Leading to Discontinuation of Therapy:

Venous adverse events were seen predominately in patients who had peripheral infusions. The most frequently reported venous and non-venous adverse reactions possibly or probably related to study drug were:

Table 6. The Most Frequently Reported Venous and Non-Venous Adverse Reactions Possibly or Probably Related to Study Drug:

There were eight (1.7%) episodes of thrombus or thrombophlebitis in the Synercid arms and none in the comparator arms.

Laboratory Events – All Comparative Studies

Table 7 shows the number () of patients exhibiting laboratory values above or below the clinically relevant “critical” values during treatment phase (with an incidence of 0.1 or greater in either treatment group).

Table 7. Laboratory Events:

Non-comparative Trials

Clinical Adverse Reactions

Approximately one-third of patients discontinued therapy in these trials due to adverse events. However, the discontinuation rate due to adverse reactions assessed by the investigator as possibly or probably related to Synercid therapy was approximately 5.0%.

There were three prospectively designed non-comparative clinical trials in patients (n=972) treated with Synercid. One of these studies (301), had more complete documentation than the other two (398A and 398B). The most common events probably or possibly related to therapy are presented in Table 8:

Table 8. The Most Common Events Probably or Possibly Related to Therapy:

The percentage of patients who experienced severe related arthralgia and myalgia was 3.3% and 3.1%, respectively. The percentage of patients who discontinued treatment due to related arthralgia and myalgia was 2.3% and 1.8%, respectively.

Laboratory Events

The most frequently observed abnormalities in laboratory studies were in total and conjugated bilirubin, with increases greater than 5 times upper limit of normal, irrespective of relationship to Synercid, reported in 25.0% and 34.6% of patients, respectively. The percentage of patients who discontinued treatment due to increased total and conjugated bilirubin was 2.7% and 2.3%, respectively. Of note, 46.5% and 59.0% of patients had high baseline total and conjugated bilirubin levels before study entry.

Other

Serious adverse reactions in clinical trials, including non-comparative studies, considered possibly or probably related to Synercid administration with an incidence <0.1% include: acidosis, anaphylactoid reaction, apnea, arrhythmia, bone pain, cerebral hemorrhage, cerebrovascular accident, coagulation disorder, convulsion, dysautonomia, encephalopathy, grand mal convulsion, hemolysis, hemolytic anemia, heart arrest, hepatitis, hypoglycemia, hyponatremia, hypoplastic anemia, hypoventilation, hypovolemia, hypoxia, jaundice, mesenteric arterial occlusion, neck rigidity, neuropathy, pancytopenia, paraplegia, pericardial effusion, pericarditis, respiratory distress syndrome, shock, skin ulcer, supraventricular tachycardia, syncope, tremor, ventricular extrasystoles and ventricular fibrillation. Cases of hypotension and gastrointestinal hemorrhage were reported in less than 0.2% of patients.

Post-marketing Experiences

In addition to adverse events reported from clinical trials, reports of angioedema and anaphylactic shock have been identified during post approval use of Synercid.

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. (See ADVERSE REACTIONS: Non-Comparative Trials) In some patients, isolated hyperbilirubinemia (primarily conjugated) can occur during treatment, possibly resulting from competition between Synercid and bilirubin for excretion. Of note, in the comparative trials, elevations in ALT and AST occurred at a similar frequency in both the Synercid and comparator groups.

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.

Prescribing Synercid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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.

Patients should be counseled that antibacterial drugs including Synercid should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Synercid is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Synercid or other antibacterial drugs in the future.

In vitro drug interaction studies have shown that Synercid significantly inhibits cytochrome P450 3A4. (See WARNINGS.)

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), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

Teratogenic Effects

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.

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.

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.

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.