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DESCRIPTION
Sulfamethoxazole and trimethoprim injection USP, a sterile solution for intravenous infusion only, is a synthetic antibacterial combination product. Each mL contains: sulfamethoxazole, USP 80 mg; trimethoprim, USP 16 mg; alcohol 12.3% (v/v); propylene glycol 400 mg; benzyl alcohol 10 mg as a preservative; diethanolamine 3 mg; sodium metabisulfite 1 mg as an antioxidant; water for injection q.s.; air replaced with nitrogen; pH adjusted with sodium hydroxide and/or hydrochloric acid if necessary. pH: 9.5 to 10.5.
Sulfamethoxazole, USP is N 1-(5-methyl-3-isoxazolyl)sulfanilamide. It is an almost white, odorless, tasteless compound with the following structural formula:
Trimethoprim, USP is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to light yellow, odorless, bitter compound with the following structural formula:
CLINICAL PHARMACOLOGY
Following a 1 hour intravenous infusion of a single dose of 800 mg sulfamethoxazole and 160 mg trimethoprim to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs) the peak plasma concentrations of sulfamethoxazole and trimethoprim were 46.3 ± 2.7 mcg/mL and 3.4 ± 0.3 mcg/mL, respectively. Following repeated intravenous administration of the same dose at 8 hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 70.6 ± 7.3 mcg/mL and 105.6 ± 10.9 mcg/mL for sulfamethoxazole and 5.6 ± 0.6 mcg/mL and 8.8 ± 0.9 mcg/mL for trimethoprim. The mean plasma half-life was 12.8 ± 1.8 hours for sulfamethoxazole and 11.3 ± 0.7 hours for trimethoprim. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years).1
Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in the following table.2
|
Age (years) |
No. of Patients |
Mean TMP Half-life (hours) |
| < 1 |
2 |
7.67 |
| 1 to 10 |
9 |
5.49 |
| 10 to 20 |
5 |
8.19 |
| 20 to 63 |
6 |
12.82 |
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).
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 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.
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 percent of dose excreted in urine over a 12 hour period following the intravenous administration of the first dose of 1200 mg of sulfamethoxazole and 240 mg of trimethoprim on day 1 ranged from 7% to 12.7% as free sulfamethoxazole and 17% to 42.4% as free trimethoprim; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.
Microbiology
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, this combination blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.
In vitro studies have shown that bacterial resistance develops more slowly with this combination than with either sulfamethoxazole or trimethoprim alone.
In vitro serial dilution tests have shown that the spectrum of antibacterial activity of sulfamethoxazole and trimethoprim injection includes common bacterial pathogens with the exception of Pseudomonas aeruginosa. The following organisms are usually susceptible: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, indole-positive Proteus species including Proteus vulgaris, Haemophilus influenzae (including ampicillin-resistant strains), Streptococcus pneumoniae, Shigella flexneri and Shigella sonnei. It should be noted, however, that there are little clinical data on the use of sulfamethoxazole and trimethoprim injection in serious systemic infections due to Haemophilus influenzae and Streptococcus pneumoniae.
REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATION VALUES FOR SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION-SUSCEPTIBLE ORGANISMS (MIC-mcg/mL)
SMX = sulfamethoxazole TMP = trimethoprim
*Rudoy RC, Nelson JD, Haltalin KC. Antimicrob Agents Chemother. May 1974; 5:439-443. |
| Bacteria |
TMP alone |
SMX alone |
TMP/SMX TMP |
(1:20) SMX |
| Escherichia coli |
0.05 to 1.5 |
1 to 245 |
0.05 to 0.5 |
0.95 to 9.5 |
Proteus species
(indole positive) |
0.5 to 5 |
7.35 to 300 |
0.05 to 1.5 |
0.95 to 28.5 |
| Morganella morganii |
0.5 to 5 |
7.35 to 300 |
0.05 to 1.5 |
0.95 to 28.5 |
| Proteus mirabilis |
0.5 to 1.5 |
7.35 to 30 |
0.05 to 0.15 |
0.95 to 2.85 |
| Klebsiella species |
0.15 to 5 |
2.45 to 245 |
0.05 to 1.5 |
0.95 to 28.5 |
| Enterobacter species |
0.15 to 5 |
2.45 to 245 |
0.05 to 1.5 |
0.95 to 28.5 |
| Haemophilus influenzae |
0.15 to 1.5 |
2.85 to 95 |
0.015 to 0.15 |
0.285 to 2.85 |
| Streptococcus pneumoniae |
0.15 to 1.5 |
7.35 to 24.5 |
0.05 to 0.15 |
0.95 to 2.85 |
| Shigella flexneri* |
< 0.01 to 0.04 |
< 0.16 to > 320 |
< 0.002 to 0.03 |
0.04 to 0.625 |
| Shigella sonnei* |
0.02 to 0.08 |
0.625 to > 320 |
0.004 to 0.06 |
0.08 to 1.25 |
The recommended quantitative disc susceptibility method may be used for estimating the susceptibility of bacteria to sulfamethoxazole and trimethoprim.3, 4 With this procedure, a report from the laboratory of “Susceptible to sulfamethoxazole and trimethoprim” indicates that the infection is likely to respond to therapy with this product. If the infection is confined to the urine, a report of “Intermediate susceptibility to sulfamethoxazole and trimethoprim” also indicates that the infection is likely to respond. A report of “Resistant to sulfamethoxazole and trimethoprim” indicates that the infection is unlikely to respond to therapy with this product.
INDICATIONS AND USAGE
PneumocystisJiroveci Pneumonia
Sulfamethoxazole and trimethoprim injection USP is indicated in the treatment of Pneumocystis jiroveci pneumonia in children and adults.
Shigellosis
Sulfamethoxazole and trimethoprim injection USP is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in children and adults.
Urinary Tract Infections
Sulfamethoxazole and trimethoprim injection USP is indicated in the treatment of severe or complicated urinary tract infections due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii and Proteus species when oral administration of sulfamethoxazole and trimethoprim is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract.
Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.
CONTRAINDICATIONS
Sulfamethoxazole and trimethoprim are contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and trimethoprim are also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and trimethoprim are contraindicated in pediatric patients less than 2 months of age.
WARNINGS
Hypersensitivity and Other Fatal Reactions
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 AND TRIMETHOPRIM INJECTION, 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 disorders (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.
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 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
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including SMX and TMP injection, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of ‘antibiotic-associated colitis’.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration would be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.
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 and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Benzyl Alcohol
Contains benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal.
Adjunctive Treatment With Leucovorin for Pneumocystis Jiroveci Pneumonia
Treatment failure and excess mortality were observed when trimethoprim and sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystisjiroveci pneumonia in a randomized placebo controlled trial.5 Coadministration of trimethoprim and sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.
PRECAUTIONS
General
Folate Deficiency
Sulfamethoxazole and trimethoprim should be given with caution to patients with impaired renal or hepatic function, to 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 to those with severe allergies or bronchial asthma.
Hematological 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.
Hemolysis
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.
Infusion Reactions
Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with sulfamethoxazole and trimethoprim. If these occur the infusion should be discontinued and restarted at another site.
Use in the Elderly
There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections) or a specific decrease in platelets (with or without purpura) are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Appropriate dosage adjustments should be made for patients with impaired kidney function (see DOSAGE AND ADMINISTRATION section).
Use in the Treatment of Pneumocystis JiroveciPneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS)
AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim therapy in AIDS patients who are being treated for Pneumocystis jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in non-AIDS patients.
Coadministration of sulfamethoxazole and trimethoprim and leucovorin should be avoided with Pneumocystis jiroveci pneumonia (see WARNINGS).
Laboratory Tests
Appropriate culture and susceptibility studies should be performed before and throughout treatment. Complete blood counts should be done frequently in patients receiving sulfamethoxazole and trimethoprim; if a significant reduction in the count of any formed blood element is noted, sulfamethoxazole and trimethoprim 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
In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. 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.
Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. 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.
Sulfonamides can also displace methotrexate from plasma protein binding sites, thus increasing free methotrexate concentrations.
Drug/Laboratory Test Interactions
Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole and trimethoprim injection.
Mutagenesis
Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim injection. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.
Impairment of Fertility
Sulfamethoxazole and trimethoprim injection has not been studied in animals for evidence of impairment of fertility. However, studies in rats at oral dosages as high as 350 mg/kg sulfamethoxazole plus 70 mg/kg trimethoprim daily showed no adverse effects on fertility or general reproductive performance.
Pregnancy
Teratogenic Effects
Pregnancy Category C
In rats, oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratological effects manifested mainly as cleft palates.
The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered separately. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In one study, however, cleft palates were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim.
In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses of trimethoprim six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,6 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral sulfamethoxazole and trimethoprim. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.
Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, sulfamethoxazole and trimethoprim injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pediatric Use
Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months of age (see CONTRAINDICATIONS section).
ADVERSE REACTIONS
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 AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Local reaction, pain and slight irritation on IV administration are infrequent. Thrombophlebitis has rarely been observed.
Hematologic
Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.
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, conjunctival and scleral injection, photosensitivity, 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.
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
Pulmonary infiltrates.
Miscellaneous
Weakness, fatigue, insomnia.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of trimethoprim and sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- Thrombotic thrombocytopenia purpura
- Idiopathic thrombocytopenic purpura
OVERDOSAGE
Acute
Since there has been no extensive experience in humans with single doses of sulfamethoxazole and trimethoprim injection in excess of 25 mL (2000 mg sulfamethoxazole and 400 mg trimethoprim), the maximum tolerated dose in humans is unknown. 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 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 trimethoprim and sulfamethoxazole.
Chronic
Use of sulfamethoxazole and trimethoprim injection 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.
Animal Toxicity
The LD50 of sulfamethoxazole and trimethoprim injection in mice is 700 mg/kg or 7.3 mL/kg; in rats and rabbits the LD50 is > 500 mg/kg or > 5.2 mL/kg. The vehicle produced the same LD50 in each of these species as the active drug.
The signs and symptoms noted in mice, rats and rabbits with sulfamethoxazole and trimethoprim or its vehicle at the high IV doses used in acute toxicity studies included ataxia, decreased motor activity, loss of righting reflex, tremors or convulsions, and/or respiratory depression.
DOSAGE AND ADMINISTRATION
SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION ISCONTRAINDICATED IN PEDIATRIC PATIENTS LESS THAN 2 MONTHS OF AGE. CAUTION—SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION MUST BE DILUTED IN 5% DEXTROSE IN WATER SOLUTION PRIOR TO ADMINISTRATION. DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION WITH OTHER DRUGS OR SOLUTIONS. RAPID INFUSION OR BOLUS INJECTION MUST BE AVOIDED.
Dosage
Children and Adults
PneumocystisJiroveci Pneumonia
Total daily dose is 15 to 20 mg/kg (based on the trimethoprim component) given in 3 or 4 equally divided doses every 6 to 8 hours for up to 14 days. One investigator noted that a total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function.7
Severe Urinary Tract Infections and Shigellosis
Total daily dose is 8 to 10 mg/kg (based on the trimethoprim component) given in 2 or 4 equally divided doses every 6, 8 or 12 hours for up to 14 days for severe urinary tract infections and 5 days for shigellosis. The maximum recommended daily dose is 60 mL per day.
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 to 30 |
1⁄2 the usual regimen |
| Below 15 |
Use not recommended |
Method of Preparation
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. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.
Multidose Vials
After initial entry into the vial, the remaining contents must be used within 48 hours.
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.
Dilution
EACH 5 ML OF SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER.
Note: 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 5% DEXTROSE IN WATER WITH DRUGS OR SOLUTIONS IN THE SAME CONTAINER.
Administration
The solution should be given by intravenous infusion over a period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. Sulfamethoxazole and trimethoprim injection should not be given intramuscularly.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
HOW SUPPLIED
Sulfamethoxazole and trimethoprim injection USP, 80 mg and 16 mg are supplied as follows:
5 mL single dose amber vials packaged 10 per carton.
10 mL multiple dose amber vials packaged 10 per carton. |
| NDC Numbers |
Sulfamethoxazole, USP |
Trimethoprim, USP |
Size |
| 0703-9503-03 |
80 mg/mL |
16 mg/mL |
5 mL
Single
dose vial
|
|
| 0703-9514-03 |
80 mg/mL |
16 mg/mL |
10 mL
Multiple
dose vial
|
|
|
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
DO NOT REFRIGERATE.
REFERENCES
- Grose WE, Bodey GP, Loo TL. Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole. Antimicrob Agents Chemother. Mar 1979;15:447-451.
- Siber GR, Gorham C, Durbin W, Lesko L, Levin MJ. Pharmacology of Intravenous Trimethoprim-Sulfamethoxazole in Children and Adults. Current Chemotherapy and Infectious Diseases, American Society for Microbiology, Washington, D.C., 1980, Vol. 1, pp. 691-692.
- Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic Susceptibility Testing by a Standardized Single Disk Method. Am J Clin Pathol. Apr 1966;45:493-496.
- National Committee for Clinical Laboratory Standards. Performance Standards For Antimicrobial Disc Susceptibility Test. 771 East Lancaster Avenue, Villanova, Pennsylvania 19085: Approved Standard ASM-2.
- 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.
- Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973;128 (Suppl):S657–S663.
- Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim- Sulfamethoxazole for the Treatment of Pneumocystis carinii pneumonia. Ann Intern Med. June 1980;92:762-769.
Manufactured In Israel By:
Teva Pharmaceutical Ind. Ltd.
Kfar Saba, 44102, Israel
Manufactured For:
Teva Pharmaceuticals USA
Sellersville, PA 18960
Rev. E 9/2012
PRINCIPAL DISPLAY PANEL, Part 1 of 2
PRINCIPAL DISPLAY PANEL, Part 2 of 2
Sulfamethoxazole and Trimethoprim Injection, USP 5 mL Single Dose Vial, 10 Vial Carton Text
NDC 0703-9503-03 Rx only
Sulfamethoxazole and Trimethoprim
Injection, USP
Sulfamethoxazole 400 mg/5 mL (80 mg/mL)
Trimethoprim 80 mg/5 mL (16 mg/mL)
For IV Infusion Only
5 mL Single Dose Vial
10 Vials
Must be diluted with 5% dextrose injection prior to administration.
TEVA
PRINCIPAL DISPLAY PANEL, Part 1 of 2
PRINCIPAL DISPLAY PANEL, Part 2 of 2
Sulfamethoxazole and Trimethoprim Injection, USP 10 mL Multiple Dose Vial, 10 Vial Carton Text
NDC 0703-9514-03 Rx only
Sulfamethoxazole and Trimethoprim
Injection, USP
Sulfamethoxazole 800 mg/10 mL (80 mg/mL)
Trimethoprim 160 mg/10 mL (16 mg/mL)
For IV Infusion Only
10 mL Multiple Dose Vial
10 Vials
Must be diluted with 5% dextrose injection prior to administration.
TEVA
SULFAMETHOXAZOLE AND TRIMETHOPRIM
sulfamethoxazole and trimethoprim injection, solution
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SULFAMETHOXAZOLE AND TRIMETHOPRIM
sulfamethoxazole and trimethoprim injection, solution
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Revised: 11/2012 Teva Parenteral Medicines, Inc.