WARNINGS
There have been reports of hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, occurring in patients receiving oral erythromycin products.
There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including E.E.S., and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.
Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)
PRECAUTIONS
General
Prescribing E.E.S. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Since erythromycin is principally excreted by the liver, caution should be exercised when erythromycin is administered to patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY and WARNINGS sections.)
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome have been reported in patients receiving erythromycin therapy.
There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. A possible dose-response effect was described with an absolute risk of IHPS of 5.1% for infants who took erythromycin for 8-14 days and 10% for infants who took erythromycin for 15-21 days.5 Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or neonatal Chlamydia trachomatis infections), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.
Prolonged or repeated use of erythromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, erythromycin should be discontinued and appropriate therapy instituted.
When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.
Information for Patients
Patients should be counseled that antibacterial drugs including E.E.S.
should only be used to treat bacterial infections. They do not treat
viral infections (e.g., the common cold). When E.E.S. 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 E.E.S. 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.
Drug Interactions
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.
Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class.
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 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.)
Drug/Laboratory Test Interactions
Erythromycin interferes with the fluorometric determination
of urinary catecholamines.
Carcinogenesis, Mutagenesis,Impairment of Fertility
Long-term (2-year) oral studies 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% 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% 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.
Geriatric Use
Elderly patients, particularly those with reduced renal or hepatic function, may be at increased risk for developing erythromycin-induced hearing loss. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
Elderly patients may be more susceptible to the development of torsades de pointes arrhythmias than younger patients. (See ADVERSE REACTIONS).
Elderly patients may experience increased effects of oral anticoagulant therapy while undergoing treatment with erythromycin. (See PRECAUTIONS - Drug Interactions).
E.E.S.® Granules contains 25.9 mg (1.1 mEq) of sodium per individual dose.
E.E.S.® 200 Liquid and E.E.S.® 400 Liquid contain 23.7 mg/mL or 1.0 mEq/mL of sodium.
The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.
E.E.S. 400 Filmtab contains 47 mg (2 mEq) of sodium per tablet and 10.0 mg (0.3 mEq) of potassium per tablet.
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