Professional Information — ERYTHROMYCIN ETHYLSUCCINATE

Indications and Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of erythromycin ethylsuccinate tablets, USP and other antibacterial drugs, erythromycin ethylsuccinate tablets, USP 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.

Erythromycin ethylsuccinate tablets, USP are 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. influenzaeare 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 S treptococcus pneumoniaeor 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 pyogenesor 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. gonorrhoeaein 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 vitroand 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 pyogenesinfections of the upper respiratory tract, e.g., tonsillitis or pharyngitis). Erythromycin is indicated for the treatment of penicillin-allergic patients. ¹The 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

Dosage and Administration

Erythromycin ethylsuccinate tablets may be administered without regard to meals. To avoid unpleasant taste, the 400 mg tablets should not be chewed.

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:

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. trachomatisor 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).

Contraindications

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.

Adverse Reactions

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.

Drug Interactions

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 _cinterval 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 ).

Overdosage

In case of overdosage, erythromycin should be discontinued. Overdosage should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures should be instituted.

Erythromycin is not removed by peritoneal dialysis or hemodialysis.

Description

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).

Erythromycin ethylsuccinate tablets, USP for oral administration are intended primarily for adults or older children. Each tablet contains erythromycin ethylsuccinate equivalent to 400 mg of erythromycin activity. The molecular formula is C ₄₃H ₇₅NO ₁₆and the molecular weight is 862.06. The structural formula is:

Inactive Ingredients

Confectioner's sugar (contains corn starch), corn starch, FD&C Red No. 40, magnesium stearate, polacrilin potassium and sodium citrate.

Clinical Pharmacology

Orally administered erythromycin ethylsuccinate tablets are readily and reliably absorbed. Comparable serum levels of erythromycin are achieved in the fasting state and nonfasting states.

Erythromycin diffuses readily into most body fluids. Only low concentrations are normally achieved in the spinal fluid, but passage of the drug across the blood-brain barrier increases in meningitis. In the presence of normal hepatic function, erythromycin is concentrated in the liver and excreted in the bile; the effect of hepatic dysfunction on excretion of erythromycin by the liver into the bile is not known. Less than 5 percent of the orally administered dose of erythromycin is excreted in active form in the urine.

Erythromycin crosses the placental barrier, but fetal plasma levels are low. The drug is excreted in human milk.

Microbiology

Mechanism of Action

Erythromycin acts by inhibition of protein synthesis by binding 50S ribosomal subunits of susceptible organisms. It does not affect nucleic acid synthesis.

Resistance

The major route of resistance is modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity while efflux can also be significant.

Interactions With Other Antimicrobials

Antagonism exists in vitrobetween erythromycin and clindamycin, lincomycin, and chloramphenicol.

Antimicrobial Activity

Erythromycin has been shown to be active against most isolates of the following microorganisms both in vitroand in clinical infections (see INDICATIONS AND USAGE ).

Aerobic bacteria

Gram-positive bacteria:
Corynebacterium diphtheriae
Corynebacterium minutissimum
Listeria monocytogenes
Staphylococcus aureus (resistant organisms may emerge during treatment)
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative bacteria:
Bordetella pertussis
Haemophilus influenzae
Legionella pneumophila
Neisseria gonorrhoeae

Other microorganisms

Chlamydia trachomatis
Entamoeba histolytica
Mycoplasma pneumoniae
Treponema pallidum
Ureaplasma urealyticum

The following in vitrodata are available, but their clinical significance is unknown .

At least 90 percent of the following bacteria exhibit in vitrominimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for erythromycin against isolates of similar genus or organism group. However, the efficacy of erythromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria

Gram-positive bacteria:
Viridans group streptococci

Gram-negative bacteria:
Moraxella catarrhalis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

How Supplied / Storage and Handling

Erythromycin ethylsuccinate Tablets, USP, 400 mg are supplied as mottled pink, oval tablets bearing the Code 74 ZE in:

Bottles of 30 ( ND C24338 -110-03)

Recommended storage

Protect tablets from exposure to light and moisture. Store below 86°F (30°C).

Patient Counseling Information

Patients should be counseled that antibacterial drugs, including erythromycin ethylsuccinate tablets, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When erythromycin ethylsuccinate tablets 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 erythromycin ethylsuccinate tablets or other antibacterial drugs in the future.

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.