ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL

ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL — erythromycin ethylsuccinate and sulfisoxazole acetyl granule, for suspension
Physicians Total Care, Inc.

Revised MARCH 2007
11001190

Rx only

DESCRIPTION:

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:

structural formula
(click image for full-size original)

C45 H75 NO16 Molecular Weight: 862.06

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:

structural formula
(click image for full-size original)

C13 H15 N3 O4 S Molecular Weight: 309.34

Inactive Ingredients:

Artificial flavor, lactose anhydrous, methylparaben, polysorbate 80, povidone, simethicone, sodium citrate anhydrous and sucrose.

CLINICAL PHARMACOLOGY:

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.

Microbiology:

This product has been formulated to contain sulfisoxazole for concomitant use with erythromycin.

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

The sulfonamides are bacteriostatic agents, and the spectrum of activity is similar for all. Sulfonamides inhibit bacterial synthesis of dihydrofolic acid by preventing the condensation of the pteridine with para -aminobenzoic acid through competitive inhibition of the enzyme dihydropteroate synthetase. Resistant strains have altered dihydropteroate synthetase with reduced affinity for sulfonamides or produce increased quantities of para -aminobenzoic acid.

Susceptibility Testing:

Quantitative methods that require measurement of zone diameter give the most precise estimates of the susceptibility of bacteria to antimicrobial agents. One such standardized single-disc procedure3 has been recommended for use with discs to test susceptibility to erythromycin and sulfisoxazole. Interpretation involves correlation of the zone diameters obtained in the disc test with minimal inhibitory concentration (MIC) values for erythromycin and sulfisoxazole.

If the standardized procedure of disc susceptibility is used, a 15 mcg erythromycin disc should give a zone diameter of at least 18 mm when tested against an erythromycin-susceptible bacterial strain, and a 250-300 mcg sulfisoxazole disc should give a zone diameter of at least 17 mm when tested against a sulfisoxazole-susceptible bacterial strain.

In vitro sulfonamides susceptibility tests are not always reliable because media containing excessive amounts of thymidine are capable of reversing the inhibitory effect of sulfonamides, which may result in false resistant reports. The tests must be carefully coordinated with bacteriological and clinical responses. When the patient is already taking sulfonamides, follow-up cultures should have aminobenzoic acid added to the isolation media but not to subsequent susceptibility test media.

INDICATIONS AND USAGE:

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

CONTRAINDICATIONS:

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:.)

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