SYNERCID Powder for intravenous injection Ref.[108275] Active ingredients:

Warnings

SYNERCID (quinupristin and dalfopristin in the ratio of 30:70) infusion should not be administered as an intravenous bolus.

Hypersensitivity

If signs of hypersensitivity develop, SYNERCID therapy should be discontinued and appropriate therapy should be provided. Hypersensitivity reactions have been seen with SYNERCID including rash, bullous lesions, itching, toxic epidermal necrolysis, anaphylactoid reactions and bronchospasm leading to respiratory arrest. Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving all antibiotics. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis, interstitial nephritis; acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other haemotologic abnormalities (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Pseudomembranous colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including SYNERCID, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficle is one primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficle colitis.

Drug interactions

In vitro drug interaction studies have demonstrated that cytochrome P450 3A4 (CYP 3A4) is significantly inhibited by SYNERCID. In in vitro studies, SYNERCID inhibited the CYP 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine. Thus, it is reasonable to expect that the concomitant administration of SYNERCID and other drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentration levels of these drugs that could increase or prolong their therapeutic effect and/or increase adverse reactions (see partial list below). Therefore, coadministration of SYNERCID with drugs which are metabolized by the CYP 3A4 isoenzyme system and that possess a narrow therapeutic window requires caution, and monitoring (clinical and/or drug concentrations) of these drugs (e.g. cyclosporine) should be performed, whenever possible (also see PRECAUTIONS: Drug interactions).

A list of drugs (not all-inclusive) for which metabolism is largely dependent upon the CYP 3A4 isoenzyme and for which concomitant administration with SYNERCID is predicted to cause an increase in plasma concentration follows:

• Antihistamines: terfenadine*, astemizole*
• Anti-HIV (NNRTls and protease inhibitors): delavirdine, nevirapine, indinavir
• Antineoplastic agents: vinca alkaloids (e.g. vinblastine), docetaxel, paclitaxel
• Benzodiazepines: midazolam, diazepam
• Calcium channels blockers: dihydropyrines (e.g. nifedipine), verapamil, diltiazem
• Cholesterol-lowering agents: HMG-CoA reductase inhibitors (e.g. lovastatin)
• GI mobility agents: cisapride*
• Immunosuppressive agents: cyclosporine, tacrolimus
• Other: carbamazepine, lidocaine*, quinidine*, disopyramide*

Note: Those drugs which cause prolongation of the QTc interval are marked with an asterisk (*).

Potential for QTc prolongation (secondary effect)

Concomitant administration of SYNERCID may accentuate the effect of drugs which prolong the electrocardiographic QTc interval because SYNERCID inhibits CYP 3A4 and therefore potentially increases the plasma level of these drugs (see *above). Concomitant use of medication metabolized by the cytochrome P450 3A4 enzyme system that may prolong the QTc interval should be avoided (also see CLINICAL PHARMACOLOGY: Metabolism).

Precautions

General

Venous infusion

In clinical studies, when infused by a peripheral catheter, SYNERCID (quinupristin and dalfopristin in the ratio of 30:70) caused local adverse venous events in a significant number of patients, leading to premature treatment discontinuation in approximately 11% of patients. In preclinical and human volunteer studies, there was a direct relationship between the infusion concentration and the incidence of venous reactions. In human volunteer studies, the incidence of severe venous reactions was substantially higher in subjects treated with the q8h regimen than with the q12h regimen.

Following completion of the infusion, the vein should be flushed with 5% dextrose injection to minimize venous irritation. It is recommended not to flush with saline or heparin immediately after SYNERCID administration (SYNERCID is not compatible with saline solutions).

If moderate to severe venous irritation occurs following peripheral administration of SYNERClD, consideration should be given to increasing the infusion volume to 500 or 750 mL of 5% dextrose injection, changing the infusion site, or infusing by a peripherally inserted central catheter (PICC) or a central venous catheter.

The safety and efficacy of an intravenous infusion duration other than 60 minutes have not been studied, and therefore SYNERCID should be administered by IV infusion over a period of 60 minutes.

Arthralgias and myalgias

Episodes of arthralgia and myalgia, some severe, have been reported primarily in patients treated with a q8h regimen. In some patients improvement in these episodes has been noted with a reduction in dose frequency to q12h. Patients who are switched to a q12h regimen should be closely monitored to ensure that they achieve an ongoing satisfactory response to therapy since efficacy against VREF infections at this lower dose has not been demonstrated. The aetiology of these arthralgias and myalgias is unknown.

Superinfections

As with other antimicrobials, use of SYNERCID may result in overgrowth of non-susceptible microorganisms. Repeated evaluation of the patient’s condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.

Hyperbilirubinemia

Elevations of conjugated bilirubin greater than 5 times the upper limit of normal were noted in 8.6% of the patients with normal baseline values in the non-comparative studies. Elevations of conjugated bilirubin greater than 5 times the upper limit of normal were noted in 0.8% of the patients with normal baseline values in the comparative studies. In some patients, hyperbilirubinemia alone (primarily conjugated) can occur during treatment with SYNERClD, possibly resulting from competition between SYNERCID and bilirubin for excretion.

Note that plasma concentrations of quinupristin metabolites are increased by more than five-fold when total bilirubin exceeds three times the upper limit of normal. It is not known what effect, if any, these increases in exposure to metabolites have on the safety and efficacy of SYNERCID.

Special populations

Patients with hepatic insufficiency

Following a single 1-hour infusion of SYNERCID (7.5 mg/kg) to patients with hepatic insufficiency (Child-Pugh scores A and B), plasma concentrations were significantly increased (See ACTION AND CLINICAL PHARMACOLOGY; Special populations: Patients with hepatic insufficiency). The effect of dose reduction or increase in dosing interval on the pharmacokinetics of SYNERCID in these patients has not been studied. The pharmacokinetics of SYNERCID in patients with severe hepatic impairment has not been studied. The effect of dose reduction or increase in dosing interval on efficacy in patients with hepatic impairment is not known. Therefore, no recommendations can be made regarding an appropriate dose modification. Use SYNERCID with caution in this population since hepatic adverse events were seen in clinical trials (see ADVERSE REACTIONS).

Pregnant women

There are no adequate and well-controlled studies with SYNERCID in pregnant women. Because animal reproduction studies are not always predictive of the human response, SYNERCID should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

No teratogenic effect was evidenced in embryofetal toxicity studies performed in rats and mice with intravenous doses of SYNERCID up to 120 mg/kg/day (corresponding to approximately 5 times in rats and 2 times in mice the human daily recommended dose). Slight fetal immaturity was observed at 120 mg/kg/day and at 40 mg/kg/day in rats and mice, respectively. In rabbits, as expected from its antibacterial activity, the administration of SYNERCID from 2 to 120 mg/kg/day (corresponding to approximately 10 times lower to 5 times higher than the human daily recommended dose) produced gastrointestinal disturbances resulting in high maternal toxicity. This did not allow for the meaningful assessment of the relationship between SYNERCID and embryofetal development. However, no increased incidence of fetal malformations was noted.

Nursing mothers

In lactating rats, quinupristin was excreted in milk. It is not known whether SYNERCID is excreted in human breast milk. Consequently, SYNERCID should not be administered to a breast-feeding woman.

Pediatric patients

The safety and efficacy of SYNERCID in patients under 16 years of age has not been established. However, 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.

Drug interactions

Cytochrome P450 3A4 mediated interactions

In vitro drug interaction studies have shown that SYNERCID significantly inhibits cytochrome P450 3A4 (also see WARNINGS: Drug interactions).

Cyclosporine A: Concomitant administration of SYNERCID and cyclosporine A (300 mg dose) in healthy volunteers led to elevated plasma concentrations of cyclosporine A. The AUC of cyclosporine A increased by a median 63% (range from a 5% decrease to 222% increase), and C_max by a median of 33% (range was from an 8% decrease to 109% increase). Therefore a dosage reduction of cyclosporine A based on monitoring of cyclosporine A levels may be necessary.

Nifedipine and midazolam: 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.

Other:

In vitro drug interaction studies have shown that SYNERCID does not significantly inhibit human CYP 1A2, 2A6, 2C9, 2C19, 2D6, or 2E1. Therefore clinical interactions with drugs metabolized by these P450 isoenzymes are not expected.

Digoxin: A drug interaction between SYNERCID and digoxin cannot be excluded but is unlikely to occur via CYP 3A4 enzyme inhibition. SYNERCID has shown in vitro activity (MIC’s of 0.25 mcglmL 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.

The safety of SYNERCID (quinupristin and dalfopristin in the ratio of 30:70) was evaluated in 1099 patients enrolled in comparative clinical trials. Additionally, non-comparative clinical trials were conducted in 1199 patients who received SYNERCID for infections due to Gram-positive pathogens for which no other treatment option was appropriate; in this population, the patients were severely ill, with multiple background diseases, physiological impairments, and intolerant to other antibacterial therapies.

In the comparative clinical trials, the discontinuation rate due to adverse reactions possibly or probably related to SYNERCID was 6.1% for systemic reactions and 10.7% for local reactions, respectively. For the systemic adverse reactions, most patients discontinued due to rash (1%), nausea (0.8%), vomiting (0.5%), pruritus (0.5%), and pain (0.5%).

In the non-comparative trials, the discontinuation rate due to systemic and local adverse reactions was 5.4% and 0.7%, respectively. Local reactions were seen less frequently in the noncomparative studies than in comparative trials because there was less peripheral administration of the SYNERCID in the non-comparative studies. Most patients discontinued SYNERCID because of arthralgia (2.3%) and myalgia (1.8%). The percentage of patients who experienced severe related arthralgia and myalgia was 3.3% and 3.1% respectively. Adverse reactions seen in clinical trials with an incidence equal to or greater than 1% which were possibly or probably related to SYNERCID administration are listed below:

Adverse reactions seen in clinical trials with an incidence equal to or greater than 1% which were possibly or probably related to SYNERCID administration:

^* Includes patients who had at least one infusion via a peripheral line.

Less frequent adverse reactions related to SYNERCID (comparative and non-comparative clinical studies):

Adverse reactions that were possibly or probably related to SYNERCID with an incidence less than 1% but greater than 0.1% within each body system:

Body as a whole: abdominal pain, aggravation reaction, back pain, cellulitis, chest pain, fever, infection

Cardiovascular: hypotension, palpitation, phlebitis, tachycardia

Digestive: anorexia, constipation, dyspepsia, jaundice, oral moniliasis, pancreatitis, pharyngitis, pseudomembranous enterocolitis, stomatitis

Hypersensitivity: allergic reaction, urticaria

Hepatobiliary: hepatitis, cholestatic jaundice

Metabolic: gout, hyponatremia, peripheral edema

Musculoskeletal: arthralgia, myalgia, myasthenia

Nervous: anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesia, vasodilatation

Respiratory: dyspnea, pleural effusion, pneumonia

Skin and appendages: maculopapular rash, sweating

Urogenital: hematuria, urinary tract infection, vaginitis

Other: cyclosporin level increased

Cases of hypotension and gastrointestinal hemorrhage were reported in less than 0.2% of patients.

Serious adverse reactions in clinical trials, including non-comparative studies considered possibly or probably related to SYNERCID administration with an incidence less than 0.1% include: acidosis, agranulocytosis, anaphylactoid reaction, apnea, arrhythmia, atrial flutter, atrioventricular third degree block, bilateral hearing loss, bone pain, bronchospasm, cardiac arrest, cerebral hemorrhage, cerebrovascular accident, coagulation disorder, convulsion, dysautonomia, encephalopathy, grand mal convulsion, hemolysis, hemolytic anemia, hepatitis, hypoglycemia, hyponatremia, hypoplastic anemia, hypoventilation, hypovolemia, hypoxia, jaundice, leukocytosis, mesenteric arterial occlusion, mesenteric embolism, neck rigidity, neuropathy, pancytopenia, paraplegia, pericardial effusion, pericarditis, pseudogout, pulmonary embolism, respiratory arrest, respiratory distress syndrome, shock, shortness of breath, skin ulcer, supraventricular tachycardia, syncope, tremor, thrombocytosis, toxic epidermal necrolysis, ventricular extrasystoles and ventricular fibrillation.

In these clinical trials, death was reported as possibly related to SYNERCID in 0.3% of patients. One of these patients experienced a drug-induced acute cholestatic hepatitis, was discontinued from SYNERCID therapy, and died two weeks later with multiple organ failure.

Laboratorv changes

Comparative trials

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 administration and with an incidence greater than 1%:

Increases in eosinophils, platelets, blood urea nitrogen, gamma glutamyl transferase, creatinine phosphokinase, lactate dehydrogenase, ALT, AST.

Decreases in hemoglobin, hematocrit, platelets and potassium.

Hemoglobin values below 8 g/dL were observed in 2.6% of SYNERCID patients.

One case of severe thrombocytopenia was reported as related to SYNERCID therapy. The discontinuation rate due to adverse laboratory reactions possibly or probably related to SYNERCID was 0.5%. Most discontinuations were due to elevated AST (0.4%), ALT (0.3%), gamma glutamyl transferase (0.3%), total bilirubin (0.3%), conjugated bilirubin (0.2%) or alkaline phosphatase (0.2%).

Non-comparative trials

In the non-comparative clinical studies, the following changes were reported as clinically significant, irrespective of relationship to SYNERCID administration, and with an incidence greater than 1 %:

Increases in blood urea nitrogen, creatinine, eosinophils, platelets, gamma glutamyl transferase, alkaline phosphatase, conjugated bilirubin, total bilirubin, ALT, AST, lactate dehydrogenase, potassium

Decreases in hematocrit, hemoglobin, platelets, white blood cells, neutrophils, potassium

One case of pancytopenia was considered related to SYNERCID therapy.

The discontinuation rate due to adverse laboratory reactions possibly or probably related to SYNERCID was 2.0%. Most of these patients discontinued because of elevated total bilirubin (0.9%), elevated alkaline phosphatase (0.9%), AST (0.8%), ALT (0.7%), gamma glutamyl transferase (0.6%), conjugated bilirubin (0.5%) or lactate dehydrogenase (0.4%).

Liver function test abnormalities

Patients who started SYNERCID therapy with normal baseline values of selected liver function tests (N) and developed significant abnormalities (n) while on SYNERCID treatment:

3% of patients in the Emergency-Use studies who had normal baseline bilirubin and AST and ALT developed >3X ULN AST or ALT and Total Bilirubin while on-treatment. No patients in the comparative studies who had normal baseline liver function tests developed >3X ULN AST or ALT and Total Bilirubin while on-treatment with SYNERCID.

In the non-comparative clinical trials in patients with normal baseline liver function tests, 32.7% of patients reported elevated AST on treatment, 22.7% reported elevated ALT on treatment, 41.7% reported elevated total bilirubin on treatment, 54.3% reported elevated conjugated bilirubin on treatment, and 40.8% reported elevated ALP on treatment. These figures are irrespective of relationship to SYNERCID.

Not all patients who had elevated liver function tests post-treatment were followed until their tests returned to pre-treatment levels. Prolonged elevations of liver function tests occurred in a minority of patients.