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 bacteria.

Sulfamethoxazole and trimethoprim oral suspension, USP is a synthetic antibacterial combination product containing 200 mg sulfamethoxazole and 40 mg trimethoprim in each teaspoonful (5 mL).



Sulfamethoxazole is N1-(5-methyl-3-isoxazolyl) sulfanilamide; the molecular formula is C10H11N3O3S. It is a white to off-white, practically odorless, crystalline powder, tasteless compound with a molecular weight of 253.28 and the following structural formula:

Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine; the molecular formula is C14H18N4O3. It is a white or cream-colored crystals or crystalline powder with a molecular weight of 290.3 and the following structural formula:

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, citric acid anhydrous, colloidal silicon dioxide, FD&C Red #40, flavour cherry #557, glycerin, methyl paraben, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, purified water, saccharin sodium, sodium benzoate, and sorbitol solution.

Sulfamethoxazole and trimethoprim 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. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4-hydroxy metabolite is mediated via CYP2C9.



Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 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.



In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.



Approximately 70% of sulfamethoxazole and 44% of trimethoprim 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 section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68 mcg/mL, respectively. These steady-state levels were achieved after three 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 of sulfamethoxazole and trimethoprim 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 metabolite.2 When administered together as sulfamethoxazole and trimethoprim, 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 secretion, and both pass the placental barrier and are excreted in human milk.

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 empiric selection of therapy.

Urinary Tract Infections

For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.

Acute Otitis Media

For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim oral suspension in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim oral suspension is not indicated for prophylactic or prolonged administration in otitis media at any age.

Acute Exacerbations of Chronic Bronchitis in Adults

For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when a physician deems that sulfamethoxazole and trimethoprim oral suspension could offer some advantage over the use of a single antimicrobial agent.

Shigellosis

For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.

Pneumocystis jirovecii Pneumonia

For the treatment of documented Pneumocystis jirovecii pneumonia and for prophylaxis against P. jirovecii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jirovecii pneumonia.

Traveler’s Diarrhea in Adults

For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E. coli.

Sulfamethoxazole and trimethoprim oral suspension is contraindicated in the following situations:

• known hypersensitivity to trimethoprim or sulfonamides
• history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides
• documented megaloblastic anemia due to folate deficiency
• pediatric patients less than 2 months of age
• marked hepatic damage
• severe renal insufficiency when renal function status cannot be monitored
• concomitant administration with dofetilide (see PRECAUTIONS).

Embryofetal Toxicity 

Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole and trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus (see PRECAUTIONS).

Hypersensitivity and Other Serious or Fatal Reactions

Fatalities and serious adverse reactions including severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see ADVERSE REACTIONS).

Cough, shortness of breath and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with sulfamethoxazole and trimethoprim treatment.

Other severe pulmonary adverse reactions occurring within days to week of sulfamethoxazole and trimethoprim initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with sulfamethoxazole and trimethoprim products.

Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim.

Sulfamethoxazole and trimethoprim should be discontinued at the first appearance of skin rash or any sign of a serious adverse reaction. A skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis, or serious blood disorders (see PRECAUTIONS and ADVERSE REACTIONS). Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions.

Thrombocytopenia

Sulfamethoxazole and trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole and trimethoprim.

Streptococcal Infections and Rheumatic Fever

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

Clostridioides difficile  Associated Diarrhea

Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, 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.

Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia  

Treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with P. jirovecii pneumonia in a randomized placebo-controlled trial.4 Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia.

The following adverse reactions associated with the use of sulfamethoxazole and trimethoprim oral suspension or sulfamethoxazole and trimethoprim were identified in clinical trials, postmarketing or published reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). Fatalities and serious adverse reactions, including severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see WARNINGS).

Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura.

Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) (see WARNINGS).

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, renal insufficiency, oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine.

Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities), metabolic acidosis.

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.

Musculoskeletal: Arthralgia, myalgia, rhabdomyolysis.

Respiratory: Cough, shortness of breath and pulmonary infiltrates, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratory failure (see WARNINGS).

Cardiovascular System: QT prolongation resulting in ventricular tachycardia and torsades de pointes, circulatory shock (see WARNINGS).

Miscellaneous: Weakness, fatigue, insomnia.

Acute

The amount of a single dose of sulfamethoxazole and trimethoprim 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.

Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.

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. Acidification of the urine will increase renal elimination of trimethoprim. 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 and trimethoprim.

Chronic

Use of sulfamethoxazole and trimethoprim 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 5 to 15 mg daily until normal hematopoiesis is restored.

Sulfamethoxazole and trimethoprim oral suspension is contraindicated in pediatric patients less than 2 months of age.

Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children

Adults: The usual adult dosage in the treatment of urinary tract infections is 4 teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis.

Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage:

Children 2 months of age or older:

For Patients with Impaired Renal Function

When renal function is impaired, a reduced dosage should be employed using the following table:

Acute Exacerbations of Chronic Bronchitis in Adults

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 4 teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 14 days.

Pneumocystis jirovecii Pneumonia

Treatment

Adults and Children:

The recommended dosage for treatment of patients with documented Pneumocystis jirovecii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.12 The following table is a guideline for the upper limit of this dosage:

For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table.

Prophylaxis

Adults:

The recommended dosage for prophylaxis in adults is 4 teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension daily.13

Children:

For children, the recommended dose is 750 mg/m2/day sulfamethoxazole with 150 mg/m2/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.14 The following table is a guideline for the attainment of this dosage in children:

Traveler’s Diarrhea in Adults

For the treatment of traveler’s diarrhea, the usual adult dosage is 4 teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 5 days.

Sulfamethoxazole and Trimethoprim Oral Suspension, USP contains 200 mg sulfamethoxazole and 40 mg trimethoprim in each teaspoonful (5 mL). Available as a pink, cherry-flavored syrup suspension.



         50 mL Bottle                NDC 65862-496-50

         100 mL Bottle              NDC 65862-496-01

         473 mL Bottle              NDC 65862-496-47



Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature] and protect from light.



SHAKE WELL BEFORE USING.



Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112–117.
2. Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128 (Suppl): S547–S555.                                             
3. Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985; 20:575–581.
4. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct;170(4):  912-7.      
5. Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209–212.
6. Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis   secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410–414.
7. Moh R, et al. Haematological changes in adults receiving a zidovudine-containing   HAART regimen in combination with cotrimoxazole in Côte d’Ivoire. Antivir Ther. 2005;10(5):615-24.
8. Al-Khatib SM, LaPointe N, Kramer JM, Califf RM. What Clinicians Should Know About the QT Interval. JAMA. 2003;289(16):2120-2127.
9. Boyer EW, Stork C, Wang RY. Review: The Pharmacology and Toxicology of Dofetilide. Int J Med Toxicol. 2001;4(2):16.
10. Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition of procainamide and N-acetylprocainamide. Clin Pharmacol Ther. Oct 1988;44(4):467-77.
11. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl): S657–S663.
12. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327: 1853–1880.
13. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR–4):1–11.
14. CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR–2):1–13.

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520



Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 032, India



Revised: 10/2022

NDC 65862-496-50

Rx only 

Sulfamethoxazole and

Trimethoprim Oral

Suspension, USP

200 mg/40 mg per 5 mL

AUROBINDO             50 mL