Erythromycin delayed-release capsules, usp

Orally administered erythromycin base and its salts are readily absorbed in the microbiologically active form. Interindividual variations in the absorption of erythromycin are, however, observed, and some patients do not achieve acceptable serum levels. Erythromycin is largely bound to plasma proteins, and the freely dissociating bound fraction after administration of erythromycin base represents 90% of the total erythromycin absorbed. After absorption, erythromycin diffuses readily into most body fluids. In the absence of meningeal inflammation, low concentrations are normally achieved in the spinal fluid, but the passage of the drug across the blood-brain barrier increases in meningitis.

The drug is excreted in human milk. The drug crosses the placental barrier, but plasma levels are low. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

In the presence of normal hepatic function erythromycin is concentrated in the liver and is excreted in the bile; the effect of hepatic dysfunction on biliary excretion of erythromycin is not known. After oral administration, less than 5% of the administered dose can be recovered in the active form in the urine.

The enteric coating of pellets in Erythromycin Delayed-release Capsules protects the erythromycin base from inactivation by gastric acidity. Because of their small size and enteric coating, the pellets readily pass intact from the stomach to the small intestine and dissolve efficiently to allow absorption of erythromycin in a uniform manner. After administration of a single dose of a 250 mg Erythromycin Delayed-release Capsule, peak serum levels in the range of 1.13 to 1.68 mcg/mL are attained in approximately 3 hours and decline to 0.30-0.42 mcg/mL in 6 hours. Optimal conditions for stability in the presence of gastric secretion and for complete absorption are attained when erythromycin is taken on an empty stomach.

Microbiology:

Erythromycin acts by inhibition of protein synthesis by binding 50 S ribosomal subunits of susceptible organisms. It does not affect nucleic acid synthesis. Antagonism has been demonstrated in vitro between erythromycin and clindamycin, lincomycin, and chloramphenicol.

Many strains of Haemophilus influenzae are resistant to erythromycin alone but are susceptible to erythromycin and sulfonamides used concomitantly.

Staphylococci resistant to erythromycin may emerge during a course of therapy.

Erythromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive Organisms:

Corynebacterium diphtheriae

Corynebacterium minutissimum

Listeria monocytogenes

Staphylococcus aureus (resistant organisms may emerge during treatment)

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Organisms:

Bordetella pertussis

Legionella pneumophila

Neisseria gonorrhoeae

Other Microorganisms:

Chlamydia trachomatis

Entamoeba histolytica

Mycoplasma pneumoniae

Treponema pallidum

Ureaplasma urealyticum

Susceptibility Tests:

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of erythromycin powder. The MIC values should be interpreted according to the following criteria:

MIC (ug/mL) Interpretation </=0.5 Susceptible (S) 1-4 Intermediate (I) >/=8 Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard erythromycin powder should provide the following MIC values:

Microorganism MIC (ug/mL) S. aureus ATCC 29213 0.12-0.5

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-ug erythromycin to test the susceptibility of microorganisms to erythromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-ug erythromycin disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation >/=23 Susceptible (S) 14-22 Intermediate (I) </=13 Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for erythromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-ug erythromycin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism Zone Diameter (mm) S. aureus ATCC 25923 22-30

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Erythromycin Delayed-release Capsules and other antibacterial drugs, Erythromycin Delayed-release Capsules 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 is indicated in the treatment of infections caused by susceptible strains of the designated microorganisms 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 diphtheria , 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 .

Syphilis caused by Treponema pallidum : Erythromycin is an alternate choice of treatment for primary syphilis in penicillin-allergic patients. In treatment of primary syphilis, spinal fluid examinations should be done before treatment and as part of follow-up after therapy.

Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). Extraenteric amebiasis requires treatment with other agents.

Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae : Erythromycin lactobionate for injection, USP followed by 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. 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.

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. 3 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). 3

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.

Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels.

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: Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

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/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.

There have been post-marketing reports of drug interactions when erythromycin was coadministered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes most likely due to the inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported. (See CONTRAINDICATIONS .)

Drug/Laboratory Test interactions:   Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term (2-year) oral studies conducted in rats with erythromycin ethylsuccinate and erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies have not been conducted. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25 percent of diet.

Pregnancy:    Teratogenic effects. Pregnancy Category B: There is no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25 percent of diet) prior to and during mating, during gestation, and through weaning of two successive litters. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery:   The effect of erythromycin on labor and delivery is unknown.

Nursing Mothers:   Erythromycin is excreted in human milk. Caution should be exercised when erythromycin is administered to a nursing woman.

Pediatric Use:   See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections.

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

Erythromycin is not removed by peritoneal dialysis or hemodialysis.

Erythromycin is well absorbed and may be given without regard to meals. Optimum blood levels are obtained in a fasting state (administration at least one half hour and preferably two hours before or after a meal); however, blood levels obtained upon administration of enteric-coated erythromycin products in the presence of food are still above minimal inhibitory concentrations (MICs) of most organisms for which erythromycin is indicated.

ADULTS: The usual dose is 250 mg every 6 hours taken one hour before meals. If twice-a-day dosage is desired, the recommended dose is 500 mg every 12 hours. Dosage may be increased up to 4 grams per day, according to the severity of infection. Twice-a-day dosing is not recommended when doses larger than 1 gram daily are administered.

CHILDREN: Age, weight, and severity of the infection are important factors in determining the proper dosage. The usual dosage is 30 to 50 mg/kg/day, in divided doses. For the treatment of more severe infections, this dose may be doubled.

Streptococcal infections: A therapeutic dosage of oral erythromycin should be administered for at least 10 days. For continuous prophylaxis against recurrences of streptococcal infections in persons with a history of rheumatic heart disease, the dose is 250 mg twice a day.

Primary syphilis:   30 to 40 grams given in divided doses over a period of 10-15 days.

Intestinal amebiasis:   250 mg four times daily for 10 to 14 days for adults; 30 to 50 mg/kg/day in divided doses for 10 to 14 days for children.

Legionnaires' Disease:   Although optimal doses have not been established, doses utilized in reported clinical data were those recommended above (1 to 4 grams daily in divided doses).

Urogenital infections during pregnancy due to Chlamydia trachomatis:   Although the optimal dose and duration of therapy have not been established, the suggested treatment is erythromycin 500 mg, by mouth, 4 times a day on an empty stomach for at least 7 days. For women who cannot tolerate this regimen, a decreased dose of 250 mg, by mouth, 4 times a day should be used for at least 14 days.

For adults with uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis in whom tetracyclines are contraindicated or not tolerated: 500 mg, by mouth, 4 times a day for at least 7 days.

Pertussis:   Although optimum dosage and duration of therapy have not been established, doses of erythromycin utilized in reported clinical studies were 40-50 mg/kg/day, given in divided doses for 5 to 14 days.

Nongonococcal urethritis due to Ureaplasma urealyticum: When tetracycline is contraindicated or not tolerated: 500 mg of erythromycin, orally, four times daily for at least 7 days.

Acute pelvic inflammatory disease due to N. gonorrhoeae:   500 mg IV of erythromycin lactobionate for injection, USP every 6 hours for 3 days followed by 250 mg of erythromycin, orally every 6 hours for 7 days.

HOW SUPPLIED

Erythromycin Delayed-release Capsules, USP, are clear and opaque maroon capsules bearing the corporate logo

and Abbo-Code ER with pink and yellow particles containing 250 mg of erythromycin supplied in bottles of 100 ( NDC 0074-6301-13) and 500 ( NDC 0074-6301-53).

Recommended Storage: Store below 86°F (30°C). Protect from moisture and excessive heat.

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.