Sulfamethoxazole and Trimethoprim (Page 3 of 6)

Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia

Treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with P. jirovecii pneumonia in a randomized placebo-controlled trial.4 Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia.

PRECAUTIONS

Development of Drug Resistant Bacteria

Prescribing sulfamethoxazole and trimethoprim oral suspension 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.

Folate Deficiency

Avoid use of sulfamethoxazole and trimethoprim 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).

Hemolysis

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

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk.

Impaired Phenylalanine Metabolism

The trimethoprim component of sulfamethoxazole and trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

Porphyria and Hypothyroidism

Like other drugs containing sulfonamides, sulfamethoxazole and trimethoprim can precipitate porphyria crisis and hypothyroidism. Avoid use of sulfamethoxazole and trimethoprim in patients with porphyria or thyroid dysfunction.

Potential Risk in the Treatment of Pneumocystis jirovecii Pneumonia 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 adverse reactions, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim (see WARNINGS).

Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia (see WARNINGS).

Electrolyte Abnormalities

Hyperkalemia: 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.

Hyponatremia: Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole and trimethoprim, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

Crystalluria: 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.

Information for Patients

Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim oral suspension is 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 sulfamethoxazole and trimethoprim oral suspension 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.

Laboratory Tests

Complete blood counts and clinical chemistry testing should be done frequently in patients receiving sulfamethoxazole and trimethoprim. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. Discontinue sulfamethoxazole and trimethoprim if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted.

Drug Interactions

Potential for sulfamethoxazole and trimethoprim to Affect Other Drugs

Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of sulfamethoxazole and trimethoprim with drugs that are substrates of CYP2C8 and 2C9 or OCT2.

Table 1: Drug Interactions with Sulfamethoxazole and Trimethoprim Oral Suspension

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 time and INR

It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). 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.

Phenytoin

Monitor serum phenytoin levels

Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). 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.

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 sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients.

Digoxin

Monitor serum digoxin levels

Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim is prescribed.

Tricyclic Antidepressants (TCAs)

Monitor therapeutic response and adjust dose of TCA accordingly

The efficacy of tricyclic antidepressants can decrease when coadministered with Sulfamethoxazole and trimethoprim oral suspension.

Oral Hypoglycemics

Monitor blood glucose more frequently

Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim and an angiotensin converting enzyme inhibitor.5,6

Zidovudine

Monitor for hematologic toxicity

Zidovudine and sulfamethoxazole and trimethoprim 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

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