GANTANOL^®
brand of
Sulfamethoxazole TABLETS

Gantanol^® (sulfamethoxazole) is an intermediate-dosage antibacterial sulfonamide available in tablets. Each tablet contains 0.5 g sulfamethoxazole plus cornstarch, polyvinyl acetate, polyvinyl alcohol, magnesium stearate, FD&C Blue No. 1 Lake, FD&C Yellow No. 6 Lake and D&C Yellow No. 10 Lake.

Sulfamethoxazole is N¹-(5-methyl-3-isoxazolyl)sulfanilamide. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28.

Last updated on RxList: 12/8/2004

Acute, recurrent or chronic urinary tract infections (primarily pyelonephritis, pyelitis and cystitis) due to susceptible organisms (usually E. coli, Klebsiella-Enterobacter, staphylococcus, Proteus mirabilis and, less frequently, Proteus vulgaris) in the absence of obstructive uropathy or foreign bodies.

Meningococcal meningitis prophylaxis when sulfonamide-sensitive group A strains are known to prevail in family groups or larger closed populations. (The prophylactic usefulness of sulfonamides when group B or C infections are prevalent has not been proven and in closed population groups may be harmful.)

Acute otitis media due to Haemophilus influenzae when used concomitantly with adequate doses of penicillin.

Trachoma. Inclusion conjunctivitis. Nocardiosis. Chancroid. Toxoplasmosis as adjunctive therapy with pyrimethamine. Malaria due to chloroquine-resistant strains of Plasmodium falciparum, when used as adjunctive therapy.

Important Note: In vitro sulfonamide susceptibility tests are not always reliable. The test must be carefully coordinated with bacteriologic and clinical response. When the patient is already taking sulfonamides, follow-up cultures should have aminobenzoic acid added to the culture media.

Currently, the increasing frequency of resistant organisms is a limitation of the usefulness of antibacterial agents including the sulfonamides, especially in the treatment of chronic and recurrent urinary tract infections.

Wide variation in blood concentrations may result with identical doses. Blood concentrations should be measured in patients receiving sulfonamides for serious infections. Free sulfonamide blood concentrations of 5 to 15 mg/100 mL may be considered therapeutically effective for most infections, with blood concentrations of 12 to 15 mg/100 mL optimal for serious infections; 20 mg/100 mL should be the maximum total sulfonamide concentration, since adverse reactions occur more frequently above this concentration.

Systemic sulfonamides are contraindicated in pediatric patients under 2 months of age, except in the treatment of congenital toxoplasmosis as adjunctive therapy with pyrimethamine.

The usual dosage schedules are as follows:

Severe Infections: 4 tablets (2 g) initially, followed by 2 tablets (1 g) three times daily thereafter.

Patients with impaired renal function (creatinine clearance below 20 to 30 mL/min) require decreased dosage adjustment.

Tablets (pale green, scored), containing 0.5 g sulfamethoxazole † bottles of 100 (NDC 0004-0010-01). Imprint on tablets: GANTANOL^® ROCHE.

Last updated on RxList: 12/8/2004

Included in the listing that follows are adverse reactions that have not been reported with this specific drug; however, the pharmacologic similarities among the sulfonamides require that each of the reactions be considered with Gantanol administration.

Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, neutropenia, eosinophilia.

Allergic Reactions: Anaphylaxis, allergic myocarditis, serum sickness, conjunctival and scleral injection, generalized allergic reactions. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.

Dermatologic: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, photosensitivity, pruritus, urticaria, rash, generalized skin eruptions.

Gastrointestinal: Hepatitis, hepatocellular necrosis, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.

Genitourinary:Creatinine elevation, toxic nephrosis with oliguria and anuria. The frequency of renal complications is considerably lower in patients receiving the more soluble sulfonamides.

Neurologic: Convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.

Psychiatric: Hallucinations, depression, apathy.

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, myalgia.

Respiratory: Pulmonary infiltrates.

Miscellaneous: Edema (including periorbital), pyrexia, chills, weakness, fatigue, insomnia.

In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported.

It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations.

The presence of sulfamethoxazole may interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Last updated on RxList: 12/8/2004

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 and glomerulonephritis.

Deaths associated with the administration of sulfonamides have been reported from hypersensitivity reactions, hepatocellular necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

The presence of clinical signs such as sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions, including serious blood disorders.

General

Sulfonamides should be given with caution to patients with impaired renal or hepatic function and to those with severe allergy or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

Information for Patients

See PATIENT INFORMATION section.

Laboratory Tests

Complete blood counts should be done frequently in patients receiving sulfonamides. If a significant reduction in the count of any formed blood element is noted, Gantanol should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.

Drug Interactions

See DRUG INTERACTIONS section.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Sulfamethoxazole has not been adequately tested in animals to permit an evaluation of its carcinogenic potential.

Mutagenesis: Bacterial mutagenic studies have not been performed with sulfamethoxazole. No chromosomal damage was observed in human leukocytes cultured in vitro with sulfamethoxazole; the concentrations used exceeded blood levels of sulfamethoxazole following therapy with Gantanol.

Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given sulfamethoxazole in oral dosages as high as 350 mg/kg/day.

Pregnancy

Teratogenic Effects

Pregnancy Category C: In rats, oral doses of 533 mg/kg of sulfamethoxazole produced teratologic effects manifested mainly as cleft palates. The highest dose which did not cause cleft palates in rats was 512 mg/kg of sulfamethoxazole. In rabbits, 150 to 350 mg/kg/day increased maternal mortality but had no deleterious effects on fetal development.

There are no adequate and well-controlled studies of Gantanol in pregnant women. Gantanol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

See CONTRAINDICATIONS.

Nursing Mothers

See CONTRAINDICATIONS.

Pediatric Use

Gantanol is not recommended in pediatric patients under 2 months of age, except in the treatment of congenital toxoplasmosis as adjunctive therapy with pyrimethamine (see CONTRAINDICATIONS). At the present time there are insufficient clinical data on prolonged or recurrent therapy in chronic renal diseases of pediatric patients under 6 years of age.

Last updated on RxList: 12/8/2004

Acute

The amount of a single dose of sulfamethoxazole 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 institution of gastric lavage or emesis; forcing oral fluids; and the administration of 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 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 eliminating sulfamethoxazole.

Chronic

Use of sulfamethoxazole at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 3 mg to 6 mg intramuscularly daily for 3 days, or as required to restore normal hematopoiesis.

Animal Toxicity

The oral LD₅₀ of sulfamethoxazole is 2300 mg/kg in mice, 3000 mg/kg in rats and > 2000 mg/kg in rabbits.

Hypersensitivity to sulfonamides. Pediatric patients less than 2 months of age (except in the treatment of congenital toxoplasmosis as adjunctive therapy with pyrimethamine). Pregnancy at term and during the nursing period because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus.

Last updated on RxList: 12/8/2004

Sulfamethoxazole is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound, metabolized and conjugated forms. The metabolism of sulfamethoxazole occurs predominately by N₄-acetylation, although the glucuronide conjugate has been identified. The free form is considered to be the therapeutically active form. Approximately 70% of sulfamethoxazole is bound to plasma proteins; of the unbound portion, 80% to 90% is in the nonacetylated form.

Following a single 1-g oral dose in 12 volunteer male subjects, the mean peak plasma concentration of 38 µg/mL of intact sulfamethoxazole was achieved by 2 hours. The mean half-life of sulfamethoxazole is approximately 10 hours. However, patients with severe-ly impaired renal function, as shown by a creatinine clearance of less than 30 mL/minute, exhibit an increase in the half-life of sulfamethoxazole, requiring dosage regimen adjustment.

Sulfamethoxazole is excreted primarily by the kidneys chiefly through glomerular filtration but also through tubular secretion. Urine concentrations of sulfamethoxazole are considerably higher than are the concentrations in blood. Eighty percent to 100% of the dose is excreted in the urine as total sulfamethoxazole, of which 30% is intact drug with the remaining as the N₄-acetylated metabolite.

Sulfamethoxazole diffuses into cerebrospinal fluid, with peak concentrations occurring at 8 hours and reaching approximately 14% of simultaneous plasma concentrations. The drug has also been shown to distribute to aqueous humor, vaginal fluid and middle ear fluid; it also passes the placental barrier and is excreted in breast milk.

Microbiology

The systemic sulfonamides are bacteriostatic agents and the spectrum of activity is similar for all. Sulfonamides inhibit bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Resistant strains are capable of utilizing folic acid precursors or preformed folic acid.

Last updated on RxList: 12/8/2004

Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.

Last updated on RxList: 12/8/2004