Source: FDA, National Drug Code (US) Revision Year: 2021
BACTRIM is contraindicated in the following situations:
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 BACTRIM (see ADVERSE REACTIONS).
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 BACTRIM 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 BACTRIM, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim.
BACTRIM 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 a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis, or serious blood disorders (see PRECAUTIONS and ADVERSE REACTIONS). Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions.
BACTRIM-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 BACTRIM.
The sulfonamides should not be used for treatment of group A β-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.
Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Treatment failure and excess mortality were observed when BACTRIM 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 BACTRIM and leucovorin during treatment of P. jirovecii pneumonia.
The following adverse reactions associated with the use of BACTRIM or sulfamethoxazole and trimethoprim were identified in clinical trials, postmarketing or published reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). Fatalities and serious adverse reactions, including severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including BACTRIM.
Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura.
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, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) (see WARNINGS).
Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.
Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, renal insufficiency, oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine.
Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities), metabolic acidosis.
Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.
Psychiatric: Hallucinations, depression, apathy, nervousness.
Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred.
Musculoskeletal: Arthralgia, myalgia, rhabdomyolysis.
Respiratory: Cough, shortness of breath and pulmonary infiltrates, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratory failure (see WARNINGS).
Cardiovascular System: QT prolongation resulting in ventricular tachycardia and torsades de pointes, circulatory shock (see WARNINGS).
Miscellaneous: Weakness, fatigue, insomnia.
Prescribing Bactrim (sulfamethoxazole and trimethoprim) tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Avoid use of BACTRIM 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.
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 (see PRECAUTIONS, Geriatric Use).
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.
Cases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of BACTRIM are particularly at risk.
The trimethoprim component of BACTRIM has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.
Like other drugs containing sulfonamides, BACTRIM can precipitate porphyria crisis and hypothyroidism. Avoid use of BACTRIM in patients with porphyria or thyroid dysfunction.
AIDS patients may not tolerate or respond to BACTRIM in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for P. jirovecii pneumonia has been reported to be increased compared with the incidence normally associated with the use of BACTRIM in non-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign of adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with BACTRIM (see WARNINGS).
Avoid coadministration of BACTRIM and leucovorin during treatment of P. jirovecii pneumonia (see WARNINGS).
High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients.
Severe and symptomatic hyponatremia can occur in patients receiving BACTRIM, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.
During treatment, ensure adequate fluid intake and urinary output to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides.
Patients should be counseled that antibacterial drugs including Bactrim (sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Bactrim (sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets or other antibacterial drugs in the future.
Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Complete blood counts and clinical chemistry testing should be done frequently in patients receiving BACTRIM. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. Discontinue BACTRIM if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted.
Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of BACTRIM with drugs that are substrates of CYP2C8 and 2C9 or OCT2.
Table 1. Drug Interactions with BACTRIM:
| Drug(s) | Recommendation | Comments |
|---|---|---|
| Diuretics | Avoid concurrent use | In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. |
| Warfarin | Monitor prothrombin timeand INR | It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when BACTRIM is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. |
| Phenytoin | Monitor serum phenytoin levels | BACTRIM may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). 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. |
| Methotrexate | Avoid concurrent use | Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. |
| Cyclosporine | Avoid concurrent use | There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients. |
| Digoxin | Monitor serum digoxin levels | Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. |
| Indomethacin | Avoid concurrent use | Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. |
| Pyrimethamine | Avoid concurrent use | Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed. |
| Tricyclic Antidepressants(TCAs) | Monitor therapeutic response and adjust dose of TCA accordingly | The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM. |
| Oral Hypoglycemics | Monitor blood glucose more frequently | Like other sulfonamide-containing drugs, BACTRIM potentiates the effect of oral hypoglycemic that are metabolized by CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide) or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be warranted. |
| Amantadine | Avoid concurrent use | In the literature, a single case of toxic delirium has been reported after concomitant intake of BACTRIM and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. |
| Angiotensin Converting-Enzyme Inhibitors | Avoid concurrent use | In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of BACTRIM and an angiotensin converting enzyme inhibitor.5,6 |
| Zidovudine | Monitor for hematologic toxicity | Zidovudine and BACTRIM are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when coadministered.7 |
| Dofetilide | Concurrent administration is contraindicated | Elevated plasma concentrations of dofetilide have been reported following concurrent administration of trimethoprim and dofetilide. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes.8,9 |
| Procainamide | Closely monitor for clinical and ECG signs of procainamide toxicity and/or procainamide plasma concentration if available | Trimethoprim increases the plasma concentrations of procainamide and its active N-acetyl metabolite (NAPA) when trimethoprim and procainamide are coadministered. The increased procainamide and NAPA plasma concentrations that resulted from the pharmacokinetic interaction with trimethoprim are associated with further prolongation of the QTc interval.10 |
While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,11 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or 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, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole and trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole and trimethoprim exposure and specific malformations.
In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. 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 some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.
See CONTRAINDICATIONS section.
Levels of sulfamethoxazole and trimethoprim in breast milk are approximately 2–5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when BACTRIM is administered to a nursing woman, especially when breastfeeding jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.
BACTRIM is contraindicated for infants younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS sections).
Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia 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. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.
Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics).
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 BACTRIM may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
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