| BACTRIM™ ROCHE® |
|Trimethoprim - Sulfamethoxazole |
|Action And Clinical Pharmacology: Trimethoprim plus sulfamethoxazole block 2 consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by reversibly inhibiting the required enzyme, dihydrofolate reductase.
The effect of the dual consecutive action is to reduce the minimum inhibitory concentration of each agent (synergism) and to convert a bacteriostatic action to a bactericidal action.
Indications And Clinical Uses: For treatment of the following infections when associated with the gram-positive and gram-negative organisms: H. influenzae, N. gonorrhoeae, E. coli, Klebsiella, E. aerogenes, P. mirabilis, P. vulgaris, S. typhi, S. paratyphi, S. typhimurium, S. enteritidis, Shigella species, S. pyogenes, S. viridans, S. albus, S. aureus and S. pneumoniae.
Upper and lower respiratory tract infections (particularly chronic bronchitis and including acute and chronic otitis media).
Acute, recurrent, and chronic urinary tract infections.
Genital tract infections (uncomplicated gonococcal urethritis).
Gastrointestinal tract infections.
P. carinii pneumonitis.
The local prevalence of resistance to Bactrim among bacteria relevant to the infection should be known when Bactrim is prescribed on an empiric basis to exclude resistance, especially in infections likely to be caused by a partially sensitive pathogen, the isolate should be tested for sensitivity. Sensitivity to Bactrim can be determined by standardized methods such as the disk or dilution tests recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The following criteria (see Table I) for susceptibility are recommended by the NCCLS.
Bactrim for Infusion is indicated for the treatment of serious systemic infections such as meningitis and septicemia caused by susceptible organisms as well as in the treatment of Pneumocystis carinii pneumonitis, when oral administration is not practical.
The combination of trimethoprim plus sulfamethoxazole is not indicated in infections associated with Pseudomonas, Mycoplasma or viruses. It should not be used in the treatment of group A beta-hemolytic streptococcal pharyngitis.
Contra-Indications: In patients with evidence of known hypersensitivity to trimethoprim or sulfonamides or any of the excipients, marked liver parenchymal damage, blood dyscrasias or marked renal impairment when measurements of drug concentrations cannot be done (see Warnings and Precautions).
Bactrim should not be given to premature neonates or infants less than 2 months of age (see Precautions).
Pregnancy and Lactation: Not to be used in pregnancy or during nursing. If pregnancy cannot be excluded, the possible risks should be balanced against the expected therapeutic effect.
Manufacturers' Warnings In Clinical States: 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.
There is an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, for example, impaired kidney and/or liver function or concomitant use of other drugs (in which case the risk may be related to the dosage and duration of treatment). Severe skin reactions, generalized bone marrow suppression or a specific decrease in platelets (with or without purpura) are the most frequently reported severe adverse reactions in elderly patients. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
Patients with Acquired Immunodeficiency Syndrome (AIDS) may not tolerate or respond to the combination of trimethoprim plus sulfamethoxazole in the same manner as non-AIDS patients because of their unique immune dysfunction. The incidence of side effects, particularly rash, fever and leukopenia, with trimethoprim plus sulfamethoxazole therapy in AIDS patients who are being treated for Pneumocystis carinii pneumonitis has been reported to be greatly increased compared with the incidence normally associated with the use of trimethoprim plus sulfamethoxazole in non-AIDS patients.
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. Therefore, Bactrim should not be given to patients with G6PD deficiency unless absolutely essential, and then only in minimal doses.
Precautions: As with other sulfonamide preparations, critical appraisal of benefit versus risk should be done in patients with liver or renal damage, urinary obstruction, blood dyscrasias, allergies or bronchial asthma. Clinical signs such as rash, sore throat, fever, pallor, purpura or jaundice may be early indications of severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia or other blood dyscrasias. In rare instances, a skin rash may be followed by a severe reaction. Therefore, Bactrim should be discontinued immediately at the first appearance of skin rash or any sign of serious adverse reaction. As a general precaution, complete blood counts should be done frequently in patients receiving sulfonamides.
Urinalysis and renal function tests should be performed regularly in patients undergoing long-term treatment wiht Bactrim (particularly in patients with kidney failure). During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria and stone formation.
Interference with folate metabolism is possible in patients on long-term therapy, in patients predisposed to folate deficiency (i.e., the elderly, chronic alcoholics and rheumatoid arthritics), in malabsorption syndromes, in malnutrition states or during the treatment of epilepsy with anticonvulsant drugs such as phenytoin, primidone or barbiturates. Regular blood counts are advised in these patients. Changes indicative of folic acid impairment have, in certain specific situations, been reversed by folinic acid therapy.
In order to minimize the risk of undesirable reactions, the duration of treatment with Bactrim should be as short as possible, particularly in elderly patients.
If Bactrium is given over a prolonged period, regular blood counts are required. If a significant reduction in the count of any formed blood element is noted, Bactrim should be discontinued. Other than in exceptional cases, Bactrim should not be given to patients with serious hematological disorders.
The possibility of superinfection with a non-sensitive organism should be borne in mind.
Local irritation and inflammation due to extravascular infiltration have been observed with Bactrim for Infusion. If these occur, the infusion should be discontinued and restarted at another site.
Neonatal Infants: If Bactrim for Infusion is administered on an emergency basis to neonatal infants, a potential complication in this age group is kernicterus.
Pregnancy and Lactation: Because both trimethoprim and sulfamethoxazole cross the placental barrier and thus may interfere with folic acid metabolism, Bactrim should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It is recommended that pregnant women who are being treated with Bactrim should be given 5 to 10 mg of folic acid daily. During the last stage of pregnancy, treatment with Bactrim should be avoided because of the risk of kernicterus in the neonate.
Both trimethoprim and sulfamethoxazole pass into breast milk. Although the quantity of Bactrim ingested by a breast-fed infant is small, possible risks for the infant (kernicterus, hypersensitivity) should be weighed against the expected therapeutic benefits for the mother.
Patients with Special Diseases and Conditions: In patients with renal impairment, a reduced or less frequent dosage is recommended in order to avoid accumulation of trimethoprim and sulfamethoxazole in the blood (see Dosage). For such patients, serum drug concentration measurements are necessary. Bactrim should not be used when the creatinine clearance is <15 mL/min in order to avoid possible permanent impairment of renal function.
Drug Interactions: PABA or its derivatives antagonize the action of sulfamethoxazole.
Plasma protein binding displacement and/or inhibition of hepatic metabolism may account for a number of interactions between Bactrim and other drugs. Phenylbutazone, oxyphenbutazone, salicylates, sulfinpyrazone, and highly bound oral anticoagulants and sulfonylurea hypoglycemics may increase sulfamethoxazole free plasma concentrations. Bactrim may increase the free plasma concentrations of lesser bound oral anticoagulants and sulfonylurea hypoglycemics and methotrexate. It has been reported that Bactrim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. The coagulation time should be reassessed when Bactrim is administered to patients on anticoagulation therapy. Sulfonamides may enhance the hypoglycemic effects of sulfonylurea hypoglycemics.
An increased incidence of thrombocytopenia with purpura has been observed in elderly patients concurrently receiving certain diuretics, primarily thiazides (see Warnings).
Increased digoxin levels can occur with Bactrim therapy, especially in elderly patients. Serum digoxin levels should be monitored.
Bactrim given at common clinical dosage increased the half-life of phenytoin by 39% and decreased the metabolic clearance of phenytoin by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Reversible deterioration of renal function, manifested by increased serum creatinine, has been observed in patients treated with trimethoprim-sulfamethoxazole and cyclosporin following renal transplantation. This combined effect is presumably due to the trimethoprim component. A reversible decrease in creatinine clearance in renal function has been observed in patients with normal renal function. This is probably due to reversible inhibition of the tubular secretion of creatinine.
The efficacy of tricyclic antidepressants can decrease when co-administered with Bactrim.
Sulfonamides, including sulfamethoxazole, can compete with protein binding and also with renal transport of methotrexate, thus increasing the free-methotrexate fraction and the systemic exposure to methotrexate.
Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if Bactrim is prescribed concurrently.
Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.
Increased sulfamethoxazole blood concentrations may occur in patients who are receiving urinary acidifiers.
Drug Laboratory Test Interactions : Bactrim, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay.
The presence of trimethoprim and sulfamethoxazole may also interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% of the range of normal values.
Adverse Reactions: The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as skin rash and urticaria).
Gastrointestinal: Nausea, vomiting and gastric intolerance have been observed most frequently. Diarrhea, constipation, flatulence, anorexia, pyrosis, gastritis and gastroenteritis occur infrequently. Glossitis, stomatitis, dyspepsia, dry mouth and black tongue have been occasionally reported. Pseudomembranous enterocolitis, pancreatitis and abdominal pain have also been reported.
Allergic: Skin rash has been observed most frequently. Urticaria, erythema (including erythema multiforme), edema, angioneurotic edema, pruritus, toxicoderma, photosensitivity, dyspnea, drug fever and anaphylactoid reactions (sweating and collapse) have been occasionally reported. Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic myocarditis, exfoliative dermatitis, angioedema, chills, Henoch-Schönlein purpura, serum sickness-like syndrome, generalized allergic reactions, hypersensitivity reactions, generalized skin eruptions, conjunctival and scleral injection, periarteritis nodosa and systemic lupus erythematosus have also been reported. Pulmonary infiltrates as occurs in eosinophilic or allergic alveolitis have been reported in rare instances. They may manifest themselves through symptoms such as cough or shortness of breath. Should such symptoms appear or unexpectedly worsen, the patient should be re-evaluated and discontinuation of Bactrim therapy considered.
Hematologic: Hematological changes have been observed in some patients, particularly the elderly. The great majority of these changes were mild, asymptomatic, and proved reversible on withdrawal of the drug. The reported changes were primarily neutropenia and thrombocytopenia. Those observed less frequently include: leukopenia, aplastic and hemolytic anemia, purpura, agranulocytosis and bone marrow depression. Megaloblastic anemia, hypoprothombinemia, methemoglobinemia, pancytopenia, purpura and eosinophilia have also been reported.
Hepatic: Liver changes (as indicated by abnormal elevations in alkaline phosphatase and serum transaminase levels) occur infrequently. Jaundice has been occasionally reported. Hepatic necrosis and elevation of bilirubin levels have also been reported. Rare cases of hepatitis and cholestasis have been reported.
Genitourinary: Dysuria, oliguria, anuria, hematuria, urgency and functional kidney changes (as indicated by abnormal elevations in blood urea nitrogen, blood non-protein nitrogen, serum creatinine and urine protein concentrations) have been reported occasionally. Renal failure, interstitial nephritis and toxic nephrosis have been reported. Diuresis has occurred rarely in patients receiving sulfonamides, particularly in patients with edema of cardiac origin. Crystalluria has also been reported.
CNS: Headache occurs infrequently. Tremor and vertigo have been occasionally reported. Aseptic meningitis or meningitis-like symptoms, convulsions, peripheral neuritis, ataxia, tinnitus, hallucinations, depression, apathy, nervousness and insomnia have also been reported.
Metabolic Disorders: High dose trimethoprim, as used in patients with P. carinii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even at recommended doses, trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, renal insufficiency, or who are receiving drugs which induce hyperkalemia. Close monitoring of serum potassium is warranted in these patients. Cases of hypoglycemia in non- diabetic patients treated with trimethoprim-sulfamethoxazole are rarely seen, usually after a few days of therapy. Patients with impaired renal function, liver disease or malnutrition or receiving high doses of trimethoprim-sulfamethoxazole are particularly at risk.
Musculoskeletal: Arthalgia and myalgia have been reported.
Miscellaneous: Tiredness (fatigue), weakness, vision troubles, alopecia and epistaxis have been occasionally reported. Goiter and hypoglycemia have occurred rarely in patients receiving sulfonamides.
Local Tolerance with Bactrim Solution for Infusion: Local reaction, pain and slight irritation on i.v. administration are infrequent. Thrombophlebitis has rarely been observed.
Symptoms And Treatment Of Overdose: Symptoms: Symptoms of acute overdosage may include nausea, vomiting, diarrhea, headache, vertigo, dizziness, mental and visual disturbances; crystalluria, hematuria, and anuria may occur in severe cases. In chronic overdosage bone marrow depression, as manifested as thrombocytopenia or leukopenia, and other blood dyscrasias due to folinic acid deficiency may occur. tag_Treatment
Treatment: Remove the drug from the stomach by gastric lavage and/or emesis. If renal function is normal, force fluids orally or parenterally to promote excretion (alkalinization of urine increases sulfamethoxazole excretion). Hemodialysis may be considered in patients with impaired renal function. Peritoneal dialysis is ineffective. The patient should be monitored with blood counts and appropriate blood chemistries. Blood dyscrasias and jaundice are potential late manifestations of overdosage.
There is no known antidote for sulfonamide poisoning; however, calcium folinate (3 to 6 mg i.m. for 5 to 7 days) is an effective antidote for adverse effects in the hemopoietic system caused by trimethoprim.
There has been no experience with deliberate or inadvertent overdosage in humans with Bactrim for Infusion. When repeated doses are required, large volumes of infusion solution may induce fluid overload. Appropriate therapy, e.g., diuretics, may be required.
Dosage And Administration: Oral: Bacterial Infections: Adults and children over 12 years: 2 adult tablets or 1 DS tablet twice daily. In severe infections, the dosage may be increased to 3 adult or 1.5 DS tablets twice daily.
Children under 12 years: 3 mg trimethoprim/kg+15 mg sulfamethoxazole/kg twice daily.
Therapy should be continued for at least 5 days or until the patient is asymptomatic for 48 hours or, in the case of urinary infections, until the urine becomes sterile.
As prophylaxis and for Salmonella carriers, 1 adult tablet or 1/2 DS tablet twice daily.
In acute salmonellosis, therapy should be continued for at least 7 days after defervescence. Carriers should continue therapy until repeated stool cultures are negative.
Uncomplicated Gonorrhea: Adults and children, 2 adult or 1 DS tablet 4 times daily for 2 days.
P. Carinii Pneumonitis: Adults and children, 5 mg trimethoprim/kg+25 mg sulfamethoxazole/kg 4 times daily for at least 14 days.
I.V. Infusion: Bactrim for Infusion may be used in patients who cannot take oral medication or need rapid attainment of high serum concentrations (see Table II).
Parenteral treatment should be terminated and oral treatment instituted as soon as possible.
Method of Dilution: Caution: Bactrim for Infusion must be diluted prior to infusion administration. Direct i.v. injection is not recommended. Do not mix the prepared infusion solution with other drugs or solutions.
Each mL should be diluted with 25 mL of 5% dextrose in water or Ringer's solution or sodium chloride 0.9% solution. The prepared solution must be kept at room temperature (15 to 30°C) and administration should be started within 1 hour of preparation. It should be infused over 1/2 to 1 hour (after proper dilution).
Note: In those instances where fluid restriction is desirable, each mL of Bactrim for Infusion may be added to 15 mL of 5% dextrose in water or Ringer's solution or sodium chloride 0.9% solution. Under these circumstances the solution should be mixed just prior to use and administration should be completed within 1 hour.
If upon visual inspection there is cloudiness or evidence of precipitation after mixing, the solution should be discarded and a fresh solution prepared.
P. Carinii Pneumonitis: Children and Adults: The recommended daily i.v. dosage is 20 mg trimethoprim/kg+100 mg sulfamethoxazole/kg. This daily dosage is to be divided into 4 equal doses and administered at 6 hour intervals, until oral therapy can be instituted.
Serious Systemic Infections: Adults: The i.v. dosage depends on the severity of the infection. A dose of 160 to 240 mg trimethoprim+800 to 1 200 mg sulfamethoxazole (10 to 15 mL of undiluted solution) may be given every 6, 8 or 12 hours. The dosage must be properly diluted (see Method of Dilution) and infused.
Children: The recommended daily dosage for children is 5 to 10 mg trimethoprim/kg/day and 25 to 50 mg sulfamethoxazole/kg/day. This daily dosage is to be properly diluted and administered in equally divided doses by infusion (see Table III).
SuppliedSupplied: Adult Tablets: Each white, round, biconvex, tablet with ROCHE on one face and indented score on the other, contains: trimethoprim 80 mg and sulfamethoxazole 400 mg. Nonmedicinal ingredients: magnesium stearate, povidone, sodium docusate and sodium starch glycolate. Energy: 0.9 kJ (0.2 kcal). Sodium: <1 mmol (2.8 mg). Paraben-, sulfite-, tartrazine-, lactose-, and gluten-free. Bottles of 100.
DS Tablets: Each film-coated, white, oval, biconvex tablet with ROCHE 800+160 on one face and indented score on the other, contains: trimethoprim 160 mg and sulfamethoxazole 800 mg. Nonmedicinal ingredients: hydroxypropylmethylcellulose, magnesium stearate, polyethylene glycol, povidone, sodium docusate, sodium starch glycolate, talc and titanium dioxide. Energy: 1.7 kJ (0.4 kcal). Sodium: <1 mmol (6.0 mg). Gluten-, lactose-, paraben-, sulfite- and tartrazine-free. Bottles of 100.
Solution for Infusion: Each mL contains: sulfamethoxazole 80 mg, trimethoprim 16 mg, benzyl alcohol 10 mg as preservative, propylene glycol 400 mg, alcohol 100 mg, sodium metabisulfite 1 mg, diethanolamine 3 mg, and sodium hydroxide to adjust the pH to 10, for infusion with 5% dextrose in water or Ringer's solution or sodium chloride 0.9% solution. Sodium: <1 mmol (8.1 mg)/mL. Paraben-free. Vials of 10 mL, packs of 10. Vials of 30 mL.
Suspension: Each 5 mL of sweet, pink, cherry-flavored suspension contains: trimethoprim 40 mg and sulfamethoxazole 200 mg. Nonmedicinal ingredients: amaranth, ethanol 0.24%, flavor, glycerin, methylparaben, microcrystalline cellulose, polysorbate 80, ponceau 4R, propylparaben, sodium carboxymethylcellulose, sodium cyclamate, sorbitol and water. Energy: 50.9 kJ (12.1 kcal). Sodium: <1 mmol. Gluten-, lactose-, sucrose-, sulfite- and tartrazine-free. Bottles of 400 mL. Shake well before using.
Store all dosage forms at 15 to 30°C in a light-resistant container. Protect from light.
(Shown in Product Recognition Section)