Sulfamethoxazole and Trimethoprim: Package Insert and Label Information

SULFAMETHOXAZOLE AND TRIMETHOPRIM — sulfamethoxazole and trimethoprim injection, solution, concentrate
Somerset Therapeutics, LLC

1 INDICATIONS AND USAGE

1.1 Pneumocystis jirovecii Pneumonia

Limitation of Use:

Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors. (1.3)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria

1.2 Shigellosis

Sulfamethoxazole and trimethoprim injection is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in adults and pediatric patients two months of age and older.

1.3 Urinary Tract Infections

Sulfamethoxazole and trimethoprim injection is indicated in the treatment of severe or complicated urinary tract infections in adults and pediatric patients two months of age and older due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii , Proteus mirabilis and Proteus vulgaris when oral administration of sulfamethoxazole and trimethoprim injection is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract.

1.4 Usage

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

Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adults and Pediatric Patients (Two Months of Age and Older)

The maximum recommended daily dose is 60 mL (960 mg trimethoprim) per day.

Table 1: Dosage in Adults and Pediatric Patients (Two Months of Age and Older) by Indication

Dosage Guidelines
Infection Total Daily Dose (based on trimethoprim content) Frequency Duration
Pneumocystis jirovecii Pneumonia* 15-20 mg/kg (in 3 or 4 equally divided doses) Every 6 to 8 hours 14 days
Severe Urinary Tract Infections 8-10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 14 days
Shigellosis 8-10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 5 days

* A total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function in a published literature.1

2.2 Dosage Modifications in Patients with Impaired Renal Function

When renal function is impaired, a reduced dosage should be employed, as shown in Table 2.

Table 2: Impaired Renal Function Dosage Guidelines

Creatinine Clearance (mL/min) Recommended Dosage Regimen
Above 30 Usual standard dosage regimen
15 – 30 ½ the usual dosage regimen
Below 15 Use not recommended

2.3 Important Administration Instructions

Administer the solution by intravenous infusion over a period of 60 to 90 minutes. Avoid administration by rapid infusion or bolus injection. Do NOT administer Sulfamethoxazole and trimethoprim injection intramuscularly.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit.

2.4 Method of Preparation

Dilution of Single- and Multiple-Dose Vials

Sulfamethoxazole and trimethoprim injection must be diluted. Each 5 mL should be added to 125 mL of 5% dextrose in water. After diluting with 5% dextrose in water, the solution should not be refrigerated and should be used within 6 hours.

If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours. In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours.

If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

Do NOT mix sulfamethoxazole and trimethoprim injection in 5% dextrose in water with drugs or solutions in the same container.

Multiple-dose Vials (Handling)

After initial entry into the vial, the remaining contents must be used within 48 hours.

Infusion Systems for Intravenous Administration

The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

3 DOSAGE FORMS AND STRENGTHS

Sulfamethoxazole and trimethoprim injection, USP is available as an injection containing 80 mg/mL of sulfamethoxazole and 16 mg/mL of trimethoprim in 5 mL single-dose, 10 mL single-dose and 30 mL multiple-dose vials.

4 CONTRAINDICATIONS

Sulfamethoxazole and trimethoprim injection is contraindicated in the following situations:

  • Known hypersensitivity to trimethoprim or sulfonamides [see Warnings and Precautions (5.2)]
  • History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides [see Warnings and Precautions (5.3)]
  • Documented megaloblastic anemia due to folate deficiency [see Warnings and Precautions (5.10)]
  • Pediatric patients less than two months of age [see Use in Specific Populations (8.4)]
  • Marked hepatic damage [see Warnings and Precautions (5.10, 5.13)]
  • Severe renal insufficiency when renal function status cannot be monitored [see Warnings and Precautions (5.10, 5.13)]
  • Concomitant administration with dofetilide2,3 [see Drug Interactions (7)]

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-fetal Toxicity

Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim injection 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 injection 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 Use in Specific Populations (8.1)].

5.2 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 injection [see Adverse Reactions (6.1)].

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 injection 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 injection, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim.

Sulfamethoxazole and trimethoprim injection 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 more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis or serious blood disorder. Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions.

5.3 Thrombocytopenia

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

5.4 Streptococcal Infections and Rheumatic Fever

Avoid use of sulfamethoxazole and trimethoprim injection in the treatment of streptococcal pharyngitis. Clinical studies have documented that patients with group A β-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with sulfamethoxazole and trimethoprim injection than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. Therefore, Sulfamethoxazole and trimethoprim injection will not prevent sequelae such as rheumatic fever.

5.5 Clostridium difficile-Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim injection, 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.6 Sulfite Sensitivity

Sulfamethoxazole and trimethoprim injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

5.7 Benzyl Alcohol Toxicity in Pediatric Patients (“Gasping Syndrome”)

Sulfamethoxazole and trimethoprim injection contains benzyl alcohol as a preservative. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved formulations in infusion solutions, including Sulfamethoxazole and trimethoprim injection. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Sulfamethoxazole and trimethoprim injection is contraindicated in pediatric patients less than two months of age [see Contraindications (4)].

When prescribing sulfamethoxazole and trimethoprim injection in pediatric patients (two months of age and older), consider the combined daily metabolic load of benzyl alcohol from all sources including sulfamethoxazole and trimethoprim injection (contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4)].

5.8 Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia

Treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim injection 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 injection and leucovorin during treatment of P. jirovecii pneumonia.

5.9 Propylene Glycol Toxicity

Sulfamethoxazole and trimethoprim injection contains propylene glycol as a solvent (40% v/v). When administered at high doses as for the treatment of P. jirovecii pneumonia and concomitantly with other products that contain propylene glycol, hyperosmolarity with anion gap metabolic acidosis, including lactic acidosis can occur. Propylene glycol toxicity can lead to acute kidney injury, CNS toxicity, and multi-organ failure. Monitor for the total daily intake of propylene glycol from all sources and for acid-base disturbances. Discontinue sulfamethoxazole and trimethoprim injection if propylene glycol toxicity is suspected [see Adverse Reactions (6)].

5.10 Folate Deficiency

Avoid use of sulfamethoxazole and trimethoprim injection in patients with impaired renal or hepatic function, in those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and in those with severe allergies or bronchial asthma.

Hematologic changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy [see Use in Specific Populations (8.5)].

5.11 Hemolysis

In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

5.12 Infusion Reactions

Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with sulfamethoxazole and trimethoprim injection. If these occur the infusion should be discontinued and restarted at another site.

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