ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL FOR ORAL SUSPENSION, USP

Revised MARCH 2007
11001190

Rx only

Erythromycin ethylsuccinate and sulfisoxazole acetyl, when reconstituted with water as directed on the label, the granules form a white, cherry flavored suspension that provides the equivalent of 200 mg erythromycin activity and the equivalent of 600 mg of sulfisoxazole activity per teaspoonful (5 mL).

Erythromycin is produced by a strain of Saccaropolyspora erythraea and belongs to the macrolide group of antibiotics. It is basic and readily forms salts and esters. Erythromycin ethylsuccinate is the 2’-ethylsuccinyl ester of erythromycin. It is essentially a tasteless form of the antibiotic suitable for oral administration, particularly in suspension dosage forms. The chemical name is erythromycin 2’-(ethylsuccinate). Erythromycin ethylsuccinate has the following structural formula:

Sulfisoxazole acetyl or N¹ -acetyl sulfisoxazole is an ester of sulfisoxazole. Chemically, sulfisoxazole is N¹ -(3,4-dimethyl-5-isoxazotyl) sulfanilamide. Sulfisoxazole acetyl has the following structural formula:

Orally administered erythromycin ethylsuccinate suspensions are readily and reliably absorbed. Erythromycin ethylsuccinate products have demonstrated rapid and consistent absorption in both fasting and nonfasting conditions. However, higher serum concentrations are obtained when these products are given with food. Erythromycin is largely bound to plasma proteins. 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. Erythromycin crosses the placental barrier and is excreted in human milk. 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.

Wide variation in blood levels may result following identical doses of a sulfonamide. Blood levels should be measured in patients receiving these drugs for serious infections. Free sulfonamide blood levels of 50 to 150 mcg/mL may be considered therapeutically effective for most infections, with blood levels of 120 to 150 mcg/mL being optimal for serious infections. The maximum sulfonamide level should be 200 mcg/mL, because adverse reactions occur more frequently above this concentration.

Following oral administration, sulfisoxazole is rapidly and completely absorbed; the small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Sulfonamides are present in the blood as free, conjugated (acetylated and possibly other forms), and protein-bound forms. The amount present as “free” drug is considered to be the therapeutically active form. Approximately 85% of a dose of sulfisoxazole is bound to plasma proteins, primarily to albumin; 65% to 72% of the unbound portion is in the nonacetylated form.

Maximum plasma concentrations of intact sulfisoxazole following a single 2 g oral dose of sulfisoxazole to healthy adult volunteers ranged from 127 to 211 mcg/mL (mean 169 mcg/mL), and the time of peak plasma concentration ranged from 1 to 4 hours (mean, 2.5 hours). The elimination half-life of sulfisoxazole ranged from 4.6 to 7.8 hours after oral administration. The elimination of sulfisoxazole has been shown to be slower in elderly subjects (63 to 75 years) with diminished renal function (creatine clearance 37 to 68 mL/min).¹ After multiple-dose oral administration of 500 mg q.i.d. to healthy volunteers, the average steady-state plasma concentrations of intact sulfisoxazole ranged from 49.9 to 88.8 mcg/mL (mean 63.4 mcg/mL).²

Sulfisoxazole and its acetylated metabolites are excreted primarily by the kidneys through glomerular filtration. Concentrations of sulfisoxazole are considerably higher in the urine than in the blood. The mean urinary recovery following oral administration of sulfisoxazole is 97% within 48 hours; 52% of this is intact drug, and the remainder is the N⁴-acetylated metabolite.

Sulfisoxazole is distributed only in extracellular body fluids. It is excreted in human milk. It readily crosses the placental barrier. In healthy subjects, cerebrospinal fluid concentrations of sulfisoxazole vary; in patients with meningitis, however, concentrations of free drug in cerebrospinal fluid as high as 94 mcg/mL have been reported.

For treatment of ACUTE OTITIS MEDIA in children that is caused by susceptible strains of Haemophilus influenzae.

Erythromycin ethylsuccinate and sulfisoxazole acetyl for oral suspension is contraindicated in the following patient populations:

• Patients with a known hypersensitivity to either of its components, children younger than 2 months, pregnant women at term, and mothers nursing infants less than 2 months of age.

Use in pregnant women at term, in children less than 2 months of age, and in mothers nursing infants less than 2 months of age is contraindicated because sulfonamides may promote kernicterus in the newborn by displacing bilirubin from plasma proteins.

Erythromycin is contraindicated in patients taking terfenadine. (See PRECAUTIONS, Drug Interactions:.)

FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, AND OTHER BLOOD DYSCRASIAS.

SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL FOR ORAL SUSPENSION, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders. (See PRECAUTIONS.)

Clinical signs such as sore throat, fever, pallor, rash, purpura, or jaundice may be early indications of serious reactions.

There have been reports of hepatic dysfunction, with or without jaundice, occurring in patients receiving oral erythromycin products.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin ethylsuccinate and sulfisoxazole acetyl for oral suspension, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis”.

After diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

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 erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

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.)

No information is available on a specific result of overdose with erythromycin ethylsuccinate and sulfisoxazole acetyl for oral suspension. Overdosage of erythromycin should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

The amount of a single dose of sulfisoxazole that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage.

General principles of treatment include the immediate discontinuation of the drug, instituting gastric lavage or emesis, forcing oral fluids, and administering intravenous fluids if urine output is low and renal function is normal. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If the patient becomes cyanotic, the possibility of methemoglobinemia should be considered and, if present, the condition should be treated appropriately with intravenous 1% methylene blue. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective, and hemodialysis is only moderately effective in removing sulfonamides.

The acute toxicity of sulfisoxazole in animals is as follows:

ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL FOR ORAL SUSPENSION SHOULD NOT BE ADMINISTERED TO INFANTS UNDER 2 MONTHS OF AGE BECAUSE OF CONTRAINDICATIONS OF SYSTEMIC SULFONAMIDES IN THIS AGE GROUP.

Erythromycin Ethylsuccinate and Sulfisoxazole Acetyl for Oral Suspension is available for teaspoon dosage in 100 mL (NDC 21695-690-00) bottles, in the form of granules to be reconstituted with water. The suspension provides erythromycin ethylsuccinate equivalent to 200 mg erythromycin activity and sulfisoxazole acetyl equivalent to 600 mg sulfisoxazole per teaspoonful (5 mL).

1. Biovert A, Barbeau G. Belanger PM: Pharmacokinetics of sulfisoxazole in young and elderly subjects. Gerontology 1984; 30: 125-131.
2. Oie S. Gambertoglio JG, Fleckenstein L: Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing. J Pharmacokinet Biopharm 1982; 10: 157 - 172.
3. National Committee for Clinical Laboratory Standards: Performance Standards for Antimicrobial Disk Susceptibility Tests, ed 4. Approved Standard NCCLS Document M2-A4, Vol 10, No. 7. Villanova, Pa: NCCLS, 1990.

Manufactured by Duramed Pharmaceuticals, Inc.
Packaged by Pharmaceutics International, Inc.
Hunt Valley, Maryland 21031
for Duramed Pharmaceuticals, Inc.
Subsidiary of Barr Pharmaceuticals, Inc.
Pomona, NY 10970

Revised MARCH 2007
BR-0445

Repackaged by:

Rebel Distributors Corp

Thousand Oaks, CA 91320

Erythromycin ES 200mg/ 600mg/5ml