E.E.S 400

Erythromycin is produced by a strain of Saccharopolyspora erythraea (formerly Streptomyces erythraeus ) and belongs to the macrolide group of antibiotics. It is basic and readily forms salts with acids. The base, the stearate salt, and the esters are poorly soluble in water. Erythromycin ethylsuccinate is an ester of erythromycin suitable for oral administration. Erythromycin ethylsuccinate is known chemically as erythromycin 2'-(ethylsuccinate). The molecular formula is C 43 H 75 NO 16 and the molecular weight is 862.06. The structural formula is: E.E.S. Granules are intended for reconstitution with water. Each 5-mL teaspoonful of reconstituted cherry-flavored suspension contains erythromycin ethylsuccinate equivalent to 200 mg of erythromycin. The pleasant tasting, fruit-flavored liquids are supplied ready for oral administration. E.E.S. 200 Liquid: Each 5-mL teaspoonful of fruit-flavored suspension contains erythromycin ethylsuccinate equivalent to 200 mg of erythromycin. E.E.S. 400 Liquid: Each 5-mL teaspoonful of orange-flavored suspension contains erythromycin ethylsuccinate equivalent to 400 mg of erythromycin. Granules and ready-made suspensions are intended primarily for pediatric use but can also be used in adults. E.E.S. 400 film-coated tablets: Each tablet contains erythromycin ethylsuccinate equivalent to 400 mg of erythromycin. The film-coated tablets are intended primarily for adults or older children. Chemical Structure Inactive Ingredients E.E.S. Granules: Citric acid, FD&C Red No. 3, magnesium aluminum silicate, sodium carboxymethylcellulose, sodium citrate, sucrose and artificial flavor. E.E.S. 400 film-coated tablets: confectioner's sugar (contains corn starch), corn starch, FD&C Red No. 40, magnesium stearate, polacrilin potassium, sodium citrate and Opadry ® Pink 321A140035 (consists of the following ingredients: D&C Red #30, D&C Yellow #10, glycerol monocaprylocaprate, Macrogol (PEG) Polyvinyl Alcohol Graft Copolymer, polyvinyl alcohol partially hydrolyzed, talc and titanium dioxide. E.E.S. 200 Liquid: FD&C Red No. 40, methylparaben, polysorbate 60, propylparaben, sodium citrate, sucrose, water, xanthan gum and natural and artificial flavors. E.E.S. 400 Liquid: D&C Yellow No. 10, FD&C Yellow No. 6, methylparaben, polysorbate 60, propylparaben, sodium citrate, sucrose, water, xanthan gum and natural and artificial flavors.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of E.E.S. and other antibacterial drugs, E.E.S. 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. E.E.S. is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the diseases listed below: Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes, Streptococcus pneumoniae, or 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 pneumoniae or Streptococcus pyogenes . Listeriosis caused by Listeria monocytogenes . Pertussis (whooping cough) caused by Bordetella pertussis . Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals rendering them noninfectious. Some clinical studies suggest that erythromycin may be helpful in the prophylaxis of pertussis in exposed susceptible individuals. Respiratory tract infections due to Mycoplasma pneumoniae . Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes or Staphylococcus aureus (resistant staphylococci may emerge during treatment). Diphtheria: Infections due to Corynebacterium diphtheriae , as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers. Erythrasma: In the treatment of infections due to Corynebacterium minutissimum . Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). Extraenteric amebiasis requires treatment with other agents. Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae : 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. Patients should have a serologic test for syphilis before receiving erythromycin as treatment of gonorrhea and a follow-up serologic test for syphilis after 3 months. Syphilis caused by Treponema pallidum : Erythromycin is an alternate choice of treatment for primary syphilis in patients allergic to the penicillins. In treatment of primary syphilis, spinal fluid examinations should be done before treatment and as part of follow-up after therapy. Erythromycins are indicated for the treatment of the following infections caused by Chlamydia trachomatis : conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections during pregnancy. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of uncomplicated urethral, endocervical, or rectal infections in adults due to Chlamydia trachomatis . When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of nongonococcal urethritis caused by Ureaplasma urealyticum . 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. Prophylaxis 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 Streptococcus pyogenes infections of the upper respiratory tract, e.g., tonsillitis or pharyngitis). Erythromycin is indicated for the treatment of penicillin-allergic patients. 1 The therapeutic dose should be administered for 10 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

Erythromycin ethylsuccinate suspensions and film-coated tablets may be administered without regard to meals. Children Age, weight, and severity of the infection are important factors in determining the proper dosage. In mild to moderate infections, the usual dosage of erythromycin ethylsuccinate for children is 30 to 50 mg/kg/day in equally divided doses every 6 hours. For more severe infections, this dosage may be doubled. If twice-a-day dosage is desired, one-half of the total daily dose may be given every 12 hours. Doses may also be given three times daily by administering one-third of the total daily dose every 8 hours. The following dosage schedule is suggested for mild to moderate infections: Body Weight Total Daily Dose Under 10 lbs 30 to 50 mg/kg/day 15 to 25 mg/lb/day 10 to 15 lbs 200 mg 16 to 25 lbs 400 mg 26 to 50 lbs 800 mg 51 to 100 lbs 1200 mg over 100 lbs 1600 mg Adults 400 mg erythromycin ethylsuccinate every 6 hours is the usual dose. Dosage may be increased up to 4 g per day according to the severity of the infection. If twice-a-day dosage is desired, one-half of the total daily dose may be given every 12 hours. Doses may also be given three times daily by administering one-third of the total daily dose every 8 hours. For adult dosage calculation, use a ratio of 400 mg of erythromycin activity as the ethylsuccinate to 250 mg of erythromycin activity as the stearate, base or estolate. In the treatment of streptococcal infections, a therapeutic dosage of erythromycin ethylsuccinate should be administered for at least 10 days. In continuous prophylaxis against recurrences of streptococcal infections in persons with a history of rheumatic heart disease, the usual dosage is 400 mg twice a day. For Treatment of Urethritis Due to C. trachomatis or U. urealyticum 800 mg three times a day for 7 days. For Treatment of Primary Syphilis Adults 48 to 64 g given in divided doses over a period of 10 to 15 days. For Intestinal Amebiasis Adults 400 mg four times daily for 10 to 14 days. Children 30 to 50 mg/kg/day in divided doses for 10 to 14 days. For Use in Pertussis Although optimal dosage and duration have not been established, doses of erythromycin utilized in reported clinical studies were 40 to 50 mg/kg/day, given in divided doses for 5 to 14 days. For Treatment of Legionnaires' Disease Although optimal doses have not been established, doses utilized in reported clinical data were those recommended above (1.6 to 4 g daily in divided doses). Directions for Mixing E.E.S. Granules 100 mL Add 77 mL water and shake vigorously. This makes 100 mL of suspension. 200 mL Add 154 mL water and shake vigorously. This makes 200 mL of suspension.

Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic. Erythromycin is contraindicated in patients taking terfenadine, astemizole, pimozide, or cisapride (see PRECAUTIONS – Drug Interactions ). Do not use erythromycin concomitantly with HMG CoA reductase inhibitors (statins) that are extensively metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhea and anorexia. Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur (see WARNINGS section). Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS section). Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes (see WARNINGS ). 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 reports of interstitial nephritis coincident with erythromycin use. There have been rare reports of pancreatitis and convulsions. There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency and in patients receiving high doses of erythromycin.

Theophylline Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in 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 decrease in erythromycin serum concentrations of approximately 35%. The mechanism by which this interaction occurs is unknown. The decrease in erythromycin concentrations due to co-administration of theophylline could result in subtherapeutic concentrations of erythromycin. Verapamil Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. Digoxin Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels. Anticoagulants There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to interactions of erythromycin with various oral anticoagulants may be more pronounced in the elderly. Erythromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome p450 enzyme system (CYP3A). Coadministration of erythromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving erythromycin. The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. The following CYP3A based drug interactions have been observed with erythromycin products in post-marketing experience: Ergotamine/dihydroergotamine Post-marketing reports indicate that coadministration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of erythromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS ). Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. HMG-CoA Reductase Inhibitors Erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Sildenafil (Viagra) Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered. (See Viagra package insert.) There have been spontaneous or published reports of CYP3A based interactions of erythromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, vinblastine, and bromocriptine. Concomitant administration of erythromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS ). In addition, there have been reports of interactions of erythromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. 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/QT c 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. There have been post-marketing reports of drug interactions when erythromycin is co-administered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, most likely due to inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported (see CONTRAINDICATIONS ). Colchicine 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 ).

Recommended storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Store granules, prior to mixing, at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. After mixing, refrigerate and use within 10 days.