The following text is complete prescribing information based on official labeling in effect June 2000.
Bactrim (trimethoprim and sulfamethoxazole) IV Infusion, a sterile solution for intravenous infusion only, is a synthetic antibacterial combination product. Each 5 mL contains 80 mg trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80 mg/mL) compounded with 40% propylene glycol, 10% ethyl alcohol and 0.3% diethanolamine; 1% benzyl alcohol and 0.1% sodium metabisulfite added as preservatives, water for injection, and pH adjusted to approximately 10 with sodium hydroxide.
Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3.
Sulfamethoxazole is N 1 -(5-methyl-3-isoxazolyl)sulfanilamide. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28.
Following a 1-hour intravenous infusion of a single dose of 160 mg trimethoprim and 800 mg sulfamethoxazole to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs), the peak plasma concentrations of trimethoprim and sulfamethoxazole were 3.4 ± 0.3 µg/mL and 46.3 ± 2.7 µg/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 5.6 ± 0.6 µg/mL and 8.8 ± 0.9 µg/mL for trimethoprim and 70.6 ± 7.3 µg/mL and 105.6 ± 10.9 µg/mL for sulfamethoxazole. The mean plasma half-life was 11.3 ± 0.7 hours for trimethoprim and 12.8 ± 1.8 hours for sulfamethoxazole. 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
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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 trimethoprim and sulfamethoxazole exist in the blood as unbound, protein-bound and metabolized forms; sulfamethaxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N 4 -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 trimethoprim and sulfamethoxazole are considered to be the therapeutically active forms. Approximately 44% of trimethoprim and 70% of sulfamethoxazole 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 trimethoprim and sulfamethoxazole is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfamethoxazole 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 240 mg of trimethoprim and 1200 mg of sulfamethoxazole on day 1 ranged from 17% to 42.4% as free trimethoprim; 7% to 12.7% as free sulfamethoxazole; and 36.7% to 56% as total (free plus the N 4 -acetylated metabolite) sulfamethoxazole. When administered together as Bactrim, neither trimethoprim nor sulfamethoxazole affects the urinary excretion pattern of the other. Both trimethoprim and sulfamethoxazole 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, Bactrim 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 Bactrim than with either trimethoprim or sulfamethoxazole alone.
In vitro serial dilution tests have shown that the spectrum of antibacterial activity of Bactrim 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 Bactrim IV Infusion in serious systemic infections due to Haemophilus influenzae and Streptococcus pneumoniae.
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The recommended quantitative disc susceptibility method may be used for estimating the susceptibility of bacteria to Bactrim. 3,4 With this procedure, a report from the laboratory of "Susceptible to trimethoprim and sulfamethoxazole" indicates that the infection is likely to respond to therapy with Bactrim. If the infection is confined to the urine, a report of "Intermediate susceptibility to trimethoprim and sulfamethoxazole" also indicates that the infection is likely to respond. A report of "Resistant to trimethoprim and sulfamethoxazole" indicates that the infection is unlikely to respond to therapy with Bactrim.
Pneumocystis Carinii Pneumonia : Bactrim IV Infusion is indicated in the treatment of Pneumocystis carinii pneumonia in children and adults.
Shigellosis: Bactrim IV Infusion is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in children and adults.
Urinary Tract Infections: Bactrim IV Infusion 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 Bactrim 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.
Bactrim is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Bactrim is also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Bactrim is contraindicated in infants less than 2 months of age.
BACTRIM SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. Clinical signs, such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions. In rare instances a skin rash may be followed by more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis or serious blood disorder. Complete blood counts should be done frequently in patients receiving sulfonamides.
BACTRIM SHOULD NOT BE USED IN THE TREATMENT OF STREPTOCOCCAL PHARYNGITIS. Clinical studies have documented that patients with group A (beta)-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with Bactrim than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area.
Bactrim IV Infusion 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.
General: Bactrim should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (eg, 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. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently doserelated.
Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with Bactrim IV Infusion. 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, eg, impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see 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 Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS): AIDS patients may not tolerate or respond to Bactrim in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values, with Bactrim therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Bactrim in non-AIDS patients.
Laboratory Tests: Appropriate culture and susceptibility studies should be performed before and throughout treatment. Complete blood counts should be done frequently in patients receiving Bactrim; if a significant reduction in the count of any formed blood element is noted, Bactrim 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 Bactrim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Bactrim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.
Bactrim may inhibit the hepatic metabolism of phenytoin. Bactrim, 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: Bactrim, 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 trimethoprim and sulfamethoxazole may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been conducted with Bactrim IV Infusion.
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 Bactrim. Observations of leukocytes obtained from patients treated with Bactrim revealed no chromosomal abnormalities.
Impairment of Fertility: Bactrim IV Infusion has not been studied in animals for evidence of impairment of fertility. However, studies in rats at oral dosages as high as 70 mg/kg trimethoprim plus 350 mg/kg sulfamethoxazole 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 trimethoprim and sulfamethoxazole in pregnant women, Brumfitt and Pursell, 5 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. 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 trimethoprim and sulfamethoxazole. 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 trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Bactrim IV Infusion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: See CONTRAINDICATIONS section.
Nursing Mothers: See CONTRAINDICATIONS section.
Pediatric Use: Bactrim IV Infusion is not recommended for infants younger than two months of age (see CONTRAINDICATIONS section).
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 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, pseudomembraneous 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.
Acute: Since there has been no extensive experience in humans with single doses of Bactrim IV Infusion in excess of 25 mL (400 mg trimethoprim and 2000 mg sulfamethoxazole), 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 intraveneous 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 Bactrim IV Infusion 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 LD 50 of Bactrim IV Infusion in mice is 700 mg/kg or 7.3 mL/kg; in rats and rabbits the LD 50 is >500 mg/kg or >5.2 mL/kg. The vehicle produced the same LD 50 in each of these species as the active drug.
The signs and symptoms noted in mice, rats and rabbits with Bactrim IV Infusion 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.
CONTRAINDICATED IN INFANTS LESS THAN 2 MONTHS OF AGE. CAUTION--BACTRIM IV INFUSION MUST BE DILUTED IN 5% DEXTROSE IN WATER SOLUTION PRIOR TO ADMINISTRATION. DO NOT MIX BACTRIM IV INFUSION WITH OTHER DRUGS OR SOLUTIONS. RAPID INFUSION OR BOLUS INJECTION MUST BE AVOIDED.
Pneumocystis Carinii 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. 6
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:
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Method of Preparation: Bactrim IV Infusion 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 BACTRIM IV INFUSION 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 BACTRIM IV INFUSION-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. Bactrim IV Infusion should not be given intramuscularly.
10-mL Vials, containing 160 mg trimethoprim (16 mg/mL) and 800 mg sulfamethoxazole (80 mg/mL) for infusion with 5% dextrose in water. Boxes of 10 (NDC 0004-1955-01).
30-mL Multidose Vials, each 5 mL containing 80 mg trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80 mg/mL) for infusion with 5% dextrose in water. Boxes of 1 (NDC 0004-1958-01).
STORE AT ROOM TEMPERATURE (15°-30°C or 59°-86°F). DO NOT REFRIGERATE.
Bactrim is also available as DS (double strength) Tablets (white, notched, capsule shaped), containing 160 mg trimethoprim and 800 mg sulfamethoxazole--bottles of 100 (NDC 0004-0117-01), 250 (NDC 0004-0117-04) and 500 (NDC 0004-0117-14). Imprint on tablets: (front) BACTRIM-DS; (back) ROCHE.
Tablets (light green, scored, capsule shaped), containing 80 mg trimethoprim and 400 mg sulfamethoxazole--bottles of 100 (NDC 0004-0050-01). Imprint on tablets: (front) BACTRIM; (back) ROCHE.
Pediatric Suspension (pink, cherry flavored), containing 40 mg trimethoprim and 200 mg sulfamethoxazole per teaspoonful (5 mL)--bottles of 16 oz (1 pint) (NDC 0004-1033-28).
Revised: March 1994