SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP

DESCRIPTION

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displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

Sulfamethoxazole and trimethoprim oral suspension USP is a synthetic antibacterial combination product. Sulfamethoxazole is N
¹-(5-methyl-3-isoxazolyl) sulfanilamide. It is an almost white odorless, tasteless compound. It has the following structural formula:

C₁₀H₁₁N₃O₃S                   M.W. 253.28

Trimethoprim is a 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to light yellow, odorless, bitter compound. It has the following structural formula:

C₁₄H₁₈N₄O₃                     M.W. 290.32

Each teaspoonful (5 mL) of the oral suspension contains 200 mg sulfamethoxazole and 40 mg trimethoprim as well as the following inactive ingredients: alcohol 0.04% (v/v), carboxymethylcellulose sodium, cherry flavoring, citric acid, color red FD&C No. 40, glycerin, methylparaben, microcrystalline cellulose, polysorbate 80, purified water, saccharin sodium, sodium benzoate, and sorbitol solution.

CLINICAL PHARMACOLOGY

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displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Sulfamethoxazole and trimethoprim oral suspension is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound, and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N₄-acetylation although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3′- and 4′-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION ). Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL, respectively. These steady-state levels were achieved after 3 days of drug administration.¹ Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N₄-acetylated metabolite². When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid, and middle ear fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in human milk.

INDICATIONS AND USAGE

id: da111133-f138-4eeb-adda-66685bb13d4a
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim oral suspension and other antibacterial drugs, sulfamethoxazole and trimethoprim oral suspension 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.

CONTRAINDICATIONS

id: 86c4beae-1e5f-44ef-a813-2c639ea92897
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Sulfamethoxazole and trimethoprim oral suspension is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and trimethoprim oral suspension is also contraindicated in pregnant patients at term and in nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and trimethoprim oral suspension is contraindicated in pediatric patients less than 2 months of age.

WARNINGS

id: a373ac30-f83d-49e2-b525-c56cd4168122
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

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 SULFAMETHOXAZOLE/TRIMETHOPRIM 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 disorder (see PRECAUTIONS ). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions. 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. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim oral suspension, USP, 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 antiobiotic 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.

ADVERSE REACTIONS

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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). 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, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY OF THE RESPIRATORY TRACT (SEE WARNINGS). Hematologic Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Allergic Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schönlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported. Gastrointestinal Hepatitis, including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. Genitourinary Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria. Metabolic Hyperkalemia, hyponatremia. Neurologic Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric Hallucinations, depression, apathy, nervousness. Endocrine The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal Arthralgia and myalgia. Respiratory System Cough, shortness of breath, and pulmonary infiltrates (see WARNINGS ). Miscellaneous Weakness, fatigue, insomnia.

DOSAGE AND ADMINISTRATION

id: 4c96db7e-09a2-4fa5-b854-827b7c48abdb
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

Contraindicated in pediatric patients less than 2 months of age.

HOW SUPPLIED

id: 54bb7cf9-bc29-46c4-8ebd-16f401d1acdc
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Sulfamethoxazole and trimethoprim oral suspension USP contains 200 mg sulfamethoxazole and 40 mg trimethoprim in each teaspoonful (5 mL) and is available as a pink, cherry-flavored syrup suspension supplied in the following oral dosage form: NDC 0121-4793-20, unit dose cups of 20 mL, 10 cups per tray.

REFERENCES

id: 158cc6ec-92b9-4e4c-9bec-1c330ff042bf
displayName: REFERENCES SECTION
FDA Article Code: 34093-5

Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. 1974; 14:112-117.
Kaplan SA, Weinfeld RE, Abruzzo CW, McFaden K, Jack ML, Weissman L. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. 1973; 128 (Suppl): S547-S555.
Varoquaux, O, et al. Antibiotic Susceptibility Discs; Certification Procedure. Federal Register. 1972; 37:20527-20529.
Brumfitt W, Pursell R. Trimethoprim-Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. 1973; 128 (Suppl):S657-S663.
Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Seventh Edition; Document M7-A7, Vol. 26, No. 2, CLSI, Wayne, PA, January, 2006.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard-Ninth Edition; Document M2-A9, Vol. 26, No. 1, CLSI, Wayne, PA, January, 2006.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing — Eighteenth Informational Supplement. Document M100-S18, Vol. 28, No. 1, CLSI, Wayne, PA, January, 2008.

PRINCIPAL DISPLAY PANEL – 20 mL Cup Label

id: f47b3fd6-bf83-46c0-b45f-194cbc74e4bb
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4

Delivers 20 mL

NDC 0121-4793-20 SULFAMETHOXAZOLE

and TRIMETHOPRIM

ORAL SUSPENSION

USP 800 mg/160 mg per 20 mL SHAKE WELL BEFORE USING Rx ONLY
FOR INSTITUTIONAL USE ONLY

Mfg. by: TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Pkg. by: PHARMACEUTICAL ASSOCIATES, INC.
Greenville, SC 29605
SEE INSERT A47932002