Sulfamethoxazole And Trimethoprim - Sulfamethoxazole And Trimethoprim suspension prescribing information
INDICATIONS & USAGE
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 in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim 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 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 .
DOSAGE & ADMINISTRATION
Sulfamethoxazole and trimethoprim 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 four 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: | ||
| Weight | Dose - every 12 hours | |
| lb | kg | Teaspoonfuls |
| 22 | 10 | 1 (5 mL) |
| 44 | 20 | 2 (10 mL) |
| 66 | 30 | 3 (15 mL) |
| 88 | 40 | 4 (20 mL) |
For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table:
| Creatinine Clearance (mL/min) | Recommended Dosage Regimen |
| Above 30 | Usual standard regimen |
| 15–30 | ½ the usual regimen |
| Below 15 | Use not recommended |
Acute Exacerbations of Chronic Bronchitis in Adults:
The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is four 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:
| Weight | Dose - every 6 hours | |
| lb | kg | Teaspoonfuls |
| 18 | 8 | 1 (5 mL) |
| 35 | 16 | 2 (10 mL) |
| 53 | 24 | 3 (15 mL) |
| 70 | 32 | 4 (20 mL) |
| 88 | 40 | 5 (25 mL) |
| 108 | 48 | 6 (30 mL) |
| 141 | 64 | 8 (40 mL) |
| 176 | 80 | 10 (50 mL) |
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 four teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension daily. 13
Children: For children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /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:
| Body Surface Area | Dose – every 12 hours |
| (m 2 ) | Teaspoonfuls |
| 0.26 | ½ (2.5 mL) |
| 0.53 | 1 (5 mL) |
| 1.06 | 2 (10 mL) |
Traveler's Diarrhea in Adults:
For the treatment of traveler's diarrhea, the usual adult dosage is four teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 5 days.
CONTRAINDICATIONS
Sulfamethoxazole and trimethoprim 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 ).
ADVERSE REACTIONS
The following adverse reactions associated with the use of 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 oral suspension. (see WARNINGS) .
Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura.
Allergic/Immune 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, hemophagocytic lymphohistiocytosis (HLH), 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.
DRUG INTERACTIONS
Potential for Sulfamethoxazole and Trimethoprim to Affect Other Drugs
Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of sulfamethoxazole and trimethoprim with drugs that are substrates of CYP2C8 and 2C9 or OCT2.
Table 1: Drug Interactions with Sulfamethoxazole and Trimethoprim
| Drug(s) | Recommendation | Comments |
| Diuretics | Avoid concurrent use | In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. |
| Warfarin | Monitor prothrombin time and INR | It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. |
| Phenytoin | Monitor serum phenytoin levels | Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfamethoxazole and trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. |
| Methotrexate | Avoid concurrent use | Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. |
| Cyclosporine | Avoid concurrent use | There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients |
| Digoxin | Monitor serum digoxin levels | Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. |
| Indomethacin | Avoid concurrent use | Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. |
| Pyrimethamine | Avoid concurrent use | Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed. |
| Tricyclic Antidepressants (TCAs) | Monitor therapeutic response and adjust dose of TCA accordingly | The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim. |
| Oral Hypoglycemics | Monitor blood glucose more frequently | Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemic that are metabolized by CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide) or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be warranted. |
| Amantadine | Avoid concurrent use | In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole and trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. |
| Angiotensin Converting Enzyme Inhibitors | Avoid concurrent use | In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole and trimethoprim and an angiotensin converting enzyme inhibitor. 5,6 |
| Zidovudine | Monitor for hematologic toxicity | Zidovudine and sulfamethoxazole and trimethoprim are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when coadministered. 7 |
| Dofetilide | Concurrent administration is contraindicated | Elevated plasma concentrations of dofetilide have been reported following concurrent administration of trimethoprim and dofetilide. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes. 8,9 |
| Procainamide | Closely monitor for clinical and ECG signs of procainamide toxicity and/or procainamide plasma concentration if available | Trimethoprim increases the plasma concentrations of procainamide and its active N-acetyl metabolite (NAPA) when trimethoprim and procainamide are coadministered. The increased procainamide and NAPA plasma concentrations that resulted from the pharmacokinetic interaction with trimethoprim are associated with further prolongation of the QTc interval. 10 |
DESCRIPTION
Sulfamethoxazole and trimethoprim is a synthetic antibacterial combination product available in a suspension for oral administration, with each teaspoonful (5 mL) containing 200 mg sulfamethoxazole and 40 mg trimethoprim.
Sulfamethoxazole is N 1 -(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C 10 H 11 N 3 O 3 S. It is a white to off-white crystalline powder 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 C 14 H 18 N 4 O 3 . It is a white to cream colored crystalline powder with a molecular weight of 290.3 and the following structural formula:
Inactive ingredients: methylparaben 0.1% and sodium benzoate 0.1% (added as preservatives), carboxymethylcellulose sodium, citric acid (anhydrous), glycerin, microcrystalline cellulose, polysorbate 80, purified water, saccharin sodium, sorbitol, FD&C Red No. 40, and artificial cherry flavor (corn maltodextrin, artificial flavor and modified corn starch).
CLINICAL PHARMACOLOGY
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 N 4 -acetyl-, N 4 -hydroxy-, 5-methylhydroxy-, N 4 -acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N 4 -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 μg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 μg/mL and 68.0 μg/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.
Pharmacokinetics in Pediatric Patients: A simulation conducted with data from a pharmacokinetic study in 153 infants and children demonstrated that mean steady state AUC and maximum plasma concentration of trimethoprim and sulfamethoxazole would be comparable between pediatric patients 2 months to 18 years receiving 8/40 (trimethoprim/sulfamethoxazole) mg/kg/day divided every 12 hours and adult patients receiving 320/1600 (trimethoprim/sulfamethoxazole) mg/day.
Pharmacokinetics in Geriatric Patients: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-U.S. approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects. 3
Microbiology
Mechanism of Action
Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para- aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.
Resistance
In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.
Antimicrobial Activity
Sulfamethoxazole and trimethoprim have been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive bacteria:
Streptococcus pneumoniae
Aerobic gram-negative bacteria:
Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea)
Klebsiella species
Enterobacter species
Haemophilus influenzae
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Shigella flexneri
Shigella sonnei
Other Microorganisms:
Pneumocystis jirovecii
Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
HOW SUPPLIED
Sulfamethoxazole and Trimethoprim Oral Suspension, USP is supplied as a pink colored, cherry flavored suspension, free from extraneous particles containing 200 mg sulfamethoxazole and 40 mg trimethoprim per 5 mL (teaspoonful) packaged in 16 fl. oz. (473 mL) bottles – NDC 70954-258-10.
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from light.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
To report SUSPECTED ADVERSE REACTIONS, contact Novitium Pharma LLC at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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