ERYTHROMYCIN LACTOBIONATE

Erythromycin is produced by a strain of Streptomyces erythraeus and belongs to the macrolide group of antibiotics. It is basic and readily forms salts with acids. Erythromycin lactobionate for injection, USP is a soluble salt of erythromycin suitable for intravenous administration. The lactobionic acid content is 244 mg per vial. Lactobionic acid and/or erythromycin are used to adjust the pH during the manufacture of the product. When reconstituted as directed, each mL contains 50 mg of erythromycin activity. The pH of the reconstituted solution is 6.5 -7.5. Erythromycin lactobionate is chemically known as erythromycin mono (4-0-β-Dgalactopyranosyl-D-gluconate) (salt). The structural formula is: Structural Formula

Erythromycin lactobionate for injection, USP is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the diseases listed below when oral administration is not possible or when the severity of the infection requires immediate high serum levels of erythromycin. Intravenous therapy should be replaced by oral administration at the appropriate time. Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci); Streptococcus pneumoniae (Diplococcus pneumoniae); Haemophilus influenzae (when used concomitantly with adequate doses of sulfonamides, since many strains of H. influenzae are not susceptible to the erythromycin concentrations ordinarily achieved). (See appropriate sulfonamide labeling for prescribing information). Lower respiratory tract infections of mild to moderate severity caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci); Streptococcus pneumoniae (Diplococcus pneumoniae). Respiratory tract infections due to Mycoplasma pneumoniae. Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes and Staphylococcus aureus (resistant staphylococci may emerge during treatment). Diphtheria: As an adjunct to antitoxin infections due to Corynebacterium diphtheriae to prevent establishment of carriers and to eradicate the organism in carriers. Erythrasma: In the treatment of infections due to Corynebacterium minutissimum . Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae : Erythromycin lactobionate for injection, USP, followed by erythromycin stearate or erythromycin base orally, as an alternative drug in treatment of acute pelvic inflammatory disease caused by N. gonorrhoeae in female patients with a history of sensitivity to penicillin. Before treatment of gonorrhea, patients who are suspected of also having syphilis should have a microscopic examination for T. pallidum (by immunofluorescence or darkfield) before receiving erythromycin and monthly serologic tests for a minimum of 4 months thereafter. Legionnaires' Disease caused by Legionella pneumophila . Although no controlled clinical efficacy studies have been conducted, in vitro and limited preliminary clinical data suggest that erythromycin may be effective in treating Legionnaires' Disease. Prevention of Initial Attacks of Rheumatic Fever Penicillin is considered by the American Heart Association to be the drug of choice in the prevention of initial attacks of rheumatic fever (treatment of Group A betahemolytic streptococcal infections of the upper respiratory tract e.g., tonsillitis, or pharyngitis). 1 Erythromycin is indicated for the treatment of penicillin-allergic patients. The therapeutic dose should be administered for ten days. Prevention of Recurrent Attacks of Rheumatic Fever Penicillin or sulfonamides are considered by the American Heart Association to be the drugs of choice in the prevention of recurrent attacks of rheumatic fever. In patients who are allergic to penicillin and sulfonamides, oral erythromycin is recommended by the American Heart Association in the long-term prophylaxis of streptococcal pharyngitis (for the prevention of recurrent attacks of rheumatic fever). 1 Prevention of Bacterial Endocarditis Although no controlled clinical efficacy trials have been conducted, oral erythromycin has been recommended by the American Heart Association for prevention of bacterial endocarditis in penicillin-allergic patients with prosthetic cardiac valves, most congenital cardiac malformations, surgically constructed systemic pulmonary shunts, rheumatic or other acquired valvular dysfunction, idiopathic hypertrophic subaortic stenosis (IHSS), previous history of bacterial endocarditis and mitral valve prolapse with insufficiency when they undergo dental procedures and surgical procedures of the upper respiratory tract. 2 To reduce the development of drug-resistant bacteria and maintain the effectiveness of erythromycin and other antibacterial drugs, erythromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

For the treatment of severe infections in adults and pediatric patients, the recommended intravenous dose of erythromycin lactobionate is 15 to 20 mg/kg/day. Higher doses, up to 4 g/day, may be given for severe infections. Administration of doses of ≥4 g/day may increase the risk for the development of erythromycin-induced hearing loss in elderly patients, particularly those with reduced renal or hepatic function. Erythromycin Lactobionate for Injection, USP, must be administered by continuous or intermittent intravenous infusion only. Due to the irritative properties of erythromycin, IV push is an unacceptable route of administration. Continuous infusion of erythromycin lactobionate is preferable due to the slower infusion rate and lower concentration of erythromycin; however, intermittent infusion at six hour intervals is also effective. Intravenous erythromycin should be replaced by oral erythromycin as soon as possible. For slow continuous infusion: The final diluted solution of erythromycin lactobionate is prepared to give a concentration of 1 g per liter (1 mg/mL). For intermittent infusion: Administer one-fourth the total daily dose of erythromycin lactobionate by intravenous infusion in 20 to 60 minutes at intervals not greater than every six hours. The final diluted solution of erythromycin lactobionate is prepared to give a concentration of 1 to 5 mg/mL. No less than 100 mL of IV diluent should be used. Infusion should be sufficiently slow to minimize pain along the vein. For treatment of acute pelvic inflammatory disease caused by N. Gonorrhoeae , in female patients hypersensitive to penicillins, administer 500 mg erythromycin lactobionate every six hours for three days, followed by oral administration of 250 mg erythromycin stearate or base every six hours for seven days. For treatment of Legionnaires' Disease: Although optimal doses have not been established, doses utilized in reported clinical data were 1 to 4 grams daily in divided doses. Administration of doses of ≥ 4 g/day may increase the risk for the development of erythromycin-induced hearing loss in elderly patients, particularly those with reduced renal or hepatic function. In the treatment of Group A beta-hemolytic streptococcal infections of the upper respiratory tract (e.g., tonsillitis or pharyngitis), the therapeutic dosage of erythromycin should be administered for ten days. The American Heart Association suggests a dosage of 250 mg of erythromycin orally, twice a day in long-term prophylaxis of streptococcal upper respiratory tract infections for the prevention of recurring attacks of rheumatic fever in patients allergic to penicillin and sulfonamides. 1 In prophylaxis against bacterial endocarditis (See INDICATIONS AND USAGE ) the oral regimen for penicillin allergic patients is erythromycin 1 gram, 1 hour before the procedure followed by 500 mg six hours later. 2 Preparation of Solution: Erythromycin lactobionate for Injection, USP is a lyophilized powder, which requires reconstitution and further dilution before administration according to the steps below: Reconstitute Erythromycin lactobionate for Injection, USP by adding 10 mL of Sterile Water for Injection, USP to the 500 mg single-dose vial to give a concentration of 50 mg of erythromycin activity per milliliter (50 mg/mL). Do not use other diluents in this step because other diluents may cause precipitation during reconstitution. Do not use diluents containing preservatives or inorganic salts. The reconstituted solution is stable at refrigerator temperature for 2 weeks, or for 24 hours at room temperature. Add the reconstituted solution to one of the following diluents before administration to give a concentration of 1 g of erythromycin activity per liter (1 mg/mL) for continuous infusion or 1 to 5 mg/mL for intermittent infusion: Do not use other diluents in this step 2. Acidic solutions of Erythromycin lactobionate for Injection, USP (solutions with a pH < 5.5) are unstable and lose their potency rapidly. Do not add any drug or chemical agent to an erythromycin lactobionate for injection solution unless its effect on the chemical and physical stability of the solution has first been determined. Stability The final diluted solution of erythromycin lactobionate should be completely administered within 8 hours, since it is not suitable for storage. Discard unused portion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic. Erythromycin is contraindicated in patients taking terfenadine or astemizole, cisapride, pimozide, ergotamine, or dihydroergotamine (See WARNINGS and PRECAUTIONS – Drug Interactions ). Do not use erythromycin concomitantly with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins) that are extensively metabolized by cytochrome P450 isoform 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (See WARNINGS and PRECAUTIONS – Drug Interactions ).

Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes (See WARNINGS ). Side effects following the use of intravenous erythromycin are rare. Occasional venous irritation has been encountered, but if the infusion is given slowly, in dilute solution, preferably by continuous intravenous infusion or intermittent infusion in no less than 20 to 60 minutes, pain and vessel trauma are minimized. Allergic reactions ranging from urticaria to anaphylaxis have occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely. There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency and in patients receiving high doses of erythromycin. Elderly patients, particularly those with reduced renal or hepatic function, may also be at increased risk for developing this effect when erythromycin doses of 4 grams/day or higher are given (See DOSAGE AND ADMINISTRATION ). To report SUSPECTED ADVERSE REACTIONS, contact [email protected] or 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Serious adverse reactions have been reported in patients taking erythromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem, vasospasm and ischemia with ergotamine/dihydroergotamine) (See PRECAUTIONS – Drug Interactions ). Drug Interactions Erythromycin administration in patients receiving 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase inhibitors (statins) that are extensively metabolized by cytochrome P450 isoform 3A4 (e.g., lovastatin or simvastatin) has been reported to cause increased risk of myopathy, including rhabdomyolysis. Do not administer erythromycin with lovastatin or simvastatin (See CONTRAINDICATIONS ). Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase of serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy. There have been published reports suggesting that when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations. This decrease could result in subtherapeutic concentrations of erythromycin. Erythromycin administration in patients receiving carbamazepine has been reported to cause increased serum levels of carbamazepine with subsequent development of signs of carbamazepine toxicity. Concomitant administration of erythromycin and digoxin has been reported to result in elevated serum digoxin levels. There have been reports of increased anticoagulant effects, which may be more pronounced in elderly when erythromycin and oral anticoagulants (e.g., warfarin) are used concomitantly. Colchicine is a substrate for both CYP3A4 and the efflux transporter P-glycoprotein (P-gp). Erythromycin is considered a moderate inhibitor of CYP3A4. A significant increase in colchicine plasma concentration is anticipated when co-administered with moderate CYP3A4 inhibitors such as erythromycin. If co-administration of colchicine and erythromycin is necessary, the starting dose of colchicine may need to be reduced, and the maximum colchicine dose should be lowered. Patients should be monitored for clinical symptoms of colchicine toxicity (See WARNINGS ). Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered (See sildenafil prescribing information). Erythromycin has been reported to decrease the clearance of triazolam, midazolam and related benzodiazepines, and thus may increase the pharmacological effect of these benzodiazepines. Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the central nervous system, extremities and other tissues (See CONTRAINDICATIONS ). Erythromycin has been reported to significantly alter the metabolism of the nonsedating antihistamines, terfenadine and astemizole, when taken concomitantly. Rare cases of serious cardiovascular adverse events, including electrocardiographic QT/QTc interval prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias, have been observed (See CONTRAINDICATIONS ). In addition, deaths have been reported rarely with concomitant administration of terfenadine and erythromycin. The use of erythromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these other drugs. There have been reports of interactions of erythromycin with carbamazepine, cyclosporine, hexobarbital, phenytoin, alfentanil, disopyramide, bromocriptine, valproate, terfenadine, and astemizole. Serum concentrations of drugs metabolized by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent verapamil, a calcium-channel blocker. Cimetidine may inhibit the metabolism of erythromycin, which may lead to an increased plasma concentration. Erythromycin has been reported to decrease the clearance of racemic zopiclone and, thus, may also decrease the clearance of eszopiclone, the S-enantiomer of racemic zopiclone. Accordingly, erythromycin may increase the pharmacodynamic effects of eszopiclone. Dose reduction of eszopiclone may be necessary (See eszopiclone prescribing information).