Sulfamethoxazole-Trimethoprim (sulfamethoxazole/trimethoprim)

Dosage of co-trimoxazole is expressed in terms of the trimethoprim content of the fixed combination containing 5 mg of sulfamethoxazole to 1 mg of trimethoprim.

If trimethoprim is used for treatment of acute, uncomplicated urinary tract infections in adults with creatinine clearances of 15-30 mL/minute, dosage of the drug should be reduced to 50 mg every 12 hours. The drug is not recommended in patients with creatinine clearances less than 15 mL/minute.

For information on dosage of the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.

In patients with impaired renal function, doses and/or frequency of administration of co-trimoxazole must be modified in response to the degree of renal impairment, severity of the infection, susceptibility of the causative organism, and serum concentrations of the drug. The manufacturers recommend that the usual adult daily dosage of co-trimoxazole be reduced 50% in patients with creatinine clearances of 15-30 mL/minute. Although the manufacturers recommend not using the drug in patients with creatinine clearances less than 15 mL/minute, some clinicians suggest using the drug in reduced dosages in these patients.

Trimethoprim is administered orally. Trimethoprim also is administered orally or IV as a fixed-combination preparation with sulfamethoxazole. (For information on the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.)

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Selected Antibiotics/Cholera Vaccine Live

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine.(1)

CLINICAL EFFECTS: Concurrent or recent antibiotic use may make the cholera vaccine ineffective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of live cholera vaccine states that it should not be administered to patients who have received antibiotics within 14 days prior to vaccination.(1) If antimalarial prophylaxis with chloroquine is required, administer the live cholera vaccine at least 10 days before beginning chloroquine.(1) Antibiotics linked to this monograph are: macrolides, quinolones, tetracyclines, ampicillin, cefprozil, chloramphenicol, furazolidone, sulfamethoxazole-trimethoprim, and sulfametrole-trimethoprim.(2,3)

DISCUSSION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine, rendering the vaccine ineffective.

Selected Photosensitizers/Tretinoin-Mequinol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tretinoin, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of tretinoin in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), methotrexate, phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

Sulfonamides/Methenamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Methenamine is hydrolyzed to formaldehyde in acidic urine. Sulfonamides may form an insoluble precipitate with formaldehyde in the urine.(1,2)

CLINICAL EFFECTS: The concurrent administration of methenamine and sulfamethizole or sulfathiazole is likely to form a precipitate in the urine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Methenamine should not be administered to patients receiving sulfonamides.(1-3)

DISCUSSION: Methenamine is hydrolyzed to formaldehyde in acidic urine. An in vitro study showed that addition of methenamine and mandelic acid to saturated solutions of sulfamethizole at pH 5.0 and 6.0 produced a precipitate in one hour.(4)

Trimethoprim/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The active tubular secretion of dofetilide is inhibited by trimethoprim.(1)

CLINICAL EFFECTS: The concurrent administration of dofetilide with trimethoprim may result in elevated levels and increased effects of dofetilide, including QT prolongation or torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with trimethoprim (alone or in combination with sulfamethoxazole) is contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting trimethoprim.(1)

DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Trimethoprim is believed to inhibit the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with trimethoprim-sulfamethoxazole (160 mg-800 mg twice daily) for four days resulted in an increase in dofetilide area-under-curve (AUC) and maximum concentration (Cmax) by 93% and 103%, respectively.(1) Therefore, the manufacturer of dofetilide states that the concurrent administration of dofetilide and trimethoprim is contraindicated.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Iodide/Radioactive Iodide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Agents That Affect Iodide/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

Dihydrofolate Reductase Inhibitors/Sepiapterin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dihydrofolate reductase (DHFR) inhibitors (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate) may decrease conversion of sepiapterin to its active metabolite, tetrahydrobiopterin (BH4).(1)

CLINICAL EFFECTS: Concurrent use of DHFR inhibitors and sepiapterin may result in decreased levels of BH4 (the active metabolite of sepiapterin) and reduced or loss of efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of DHFR inhibitors and sepiapterin should be avoided. If concurrent use cannot be avoided, monitor blood phenylalanine levels.(1)

DISCUSSION: Sepiapterin is metabolized by dihydrofolate reductase (DHFR) to its pharmacologically active form, tetrahydrobiopterin (BH4). Inhibitors of DHFR may reduce the metabolism of sepiapterin to BH4.(1) DHFR inhibitors linked to this monograph include: methotrexate, pemetrexed, pralatrexate, raltitrexed, trimethoprim, and trimetrexate.

Mate Inhibitors/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may inhibit the renal tubular secretion of chloroquine or hydroxychloroquine via the MATE1 transporter.(1,2,3)

CLINICAL EFFECTS: Concurrent use of MATE inhibitors may result in increased levels of and toxicity from chloroquine or hydroxychloroquine, including irreversible retinopathy, potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP), hypoglycemia, or myopathy.(1,2)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturers of chloroquine and hydroxychloroquine state that concomitant use of MATE inhibitors should be avoided.(1,2) The Israeli manufacturer of hydroxychloroquine states that hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine. Caution is advised when coadministering hydroxychloroquine with MATE inhibitors.(5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of healthy volunteers, cimetidine (400 mg daily for 4 days) decreased the clearance of single-dose chloroquine (300 mg) by 53% and half-life by 49%, compared to subjects not on cimetidine.(6) MATE inhibitors linked to this monograph include: bictegravir, brepocitinib, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(7)

Selected Photosensitizers/Aminolevulinic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

Selected Photosensitizers/Methoxsalen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1)

DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)

Selected Photosensitizers/Porfimer

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1)

PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer.

DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)

Sulfonamide Antibac; Trimethoprim/Methotrexate; Pralatrexate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sulfonamide antibacterials and/or trimethoprim may decrease the renal clearance of methotrexate and pralatrexate or produce a synergistically-induced folate deficiency. Sulfonamide antibacterials and/or trimethoprim may decrease protein binding of methotrexate.

CLINICAL EFFECTS: Concurrent use of sulfonamide antibacterials and/or trimethoprim may increase levels of and toxicity from methotrexate and pralatrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate or pralatrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Concurrent use of sulfonamide antibiotics or trimethoprim with methotrexate or pralatrexate should be avoided. If coadministration cannot be avoided, closely monitor patients who are receiving concurrent therapy or patients who have recently finished methotrexate or pralatrexate therapy and who are beginning sulfonamide therapy for signs of toxicity, including bone marrow suppression, pancytopenia, thrombocytopenia, and stomatitis.

DISCUSSION: In one study in pediatric leukemia patients, concurrent administration of methotrexate and trimethoprim-sulfamethoxazole resulted in an increase in free methotrexate and a decrease in free methotrexate clearance. These changes resulted in a 66% increase in systemic exposure to methotrexate, although there were no significant changes in total methotrexate clearance or methotrexate half-life. In another study in pediatric leukemia patients, concurrent therapy with methotrexate and trimethoprim-sulfamethoxazole did not alter the intestinal absorption, degree of plasma protein binding, or average concentration of methotrexate. Case reports have documented methotrexate toxicities such as bone marrow hypoplasia, pancytopenia, thrombocytopenia, and stomatitis during concurrent therapy and during therapy with trimethoprim-sulfamethoxazole following the conclusion of methotrexate therapy. Some of these reports involved patients receiving low-dose methotrexate for rheumatoid arthritis. Methotrexate plasma protein binding and renal clearance have been shown to be decreased by the concurrent administration of sulfisoxazole. In a retrospective cohort study of 3204 adults taking low-dose methotrexate, the risk of all-cause hospitalization (Risk Ratio (RR) 1.49 (95% Confidence Interval (CI) 1.13-1.97) and infection (RR 2.78 (95% CI 1.30 - 5.95)) was higher in adults treated with trimethoprim-sulfamethoxazole (n=1602) than those treated with cephalosporins (n=1602). This interaction has also been reported in patients receiving concurrent methotrexate and trimethoprim without concurrent sulfamethoxazole.

Sulfonamide Antibact/Selected Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism may involve several processes. Some sulfonamides, e.g. cotrimoxazole, sulfamethizole, sulfaphenazole, inhibit the CYP2C9 mediated metabolism of warfarin. Sulfonamides have also been shown to displace plasma protein bound warfarin. The use of sulfonamides may decrease vitamin-K producing bacteria in the gastrointestinal tract. Disease related factors such as fever, decreased oral intake and acute illness may also play a role in bleeding risk.

CLINICAL EFFECTS: Concurrent use of anticoagulants and sulfonamides may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Numerous studies and case reports have documented an interaction between warfarin and sulfamethoxazole/trimethoprim. The effects are generally seen within two to six days and may or may not be accompanied by increased warfarin concentrations. Case reports also document an interaction between warfarin and sulfisoxazole and sulfamethizole resulting in increased bleeding, warfarin half-life and decreased warfarin clearance rates. Because of the proposed mechanism, it is prudent to expect similar results during the concurrent administration of warfarin and other sulfonamides. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with sulfonamides (OR=2.41; 95% CI 1.42-4.10).

Sulfonamides/Cyclosporine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Both cyclosporine and sulfonamides can cause serum creatinine and BUN elevations and nephrotoxicity.(1,2)

CLINICAL EFFECTS: Coadministration of sulfonamides and cyclosporine may produce additive nephrotoxicity.(1,2)

PREDISPOSING FACTORS: The risk of nephrotoxicity is higher with elderly patients and increasing doses of cyclosporine.

PATIENT MANAGEMENT: The manufacturer of trimethoprim/sulfamethoxazole states that concurrent use of cyclosporine should be avoided.(1) The manufacturer of cyclosporine states that concurrent use of drugs that may cause additive or synergistic renal impairment should be approached with caution. Renal function (especially serum creatinine) should be closely monitored. In all patients treated with cyclosporine, renal function should be assessed repeatedly by measurement of serum creatinine and BUN.(2)

DISCUSSION: It is not unusual for cyclosporine to cause elevations in serum creatinine and BUN.(2) There have been reports of marked but reversible nephrotoxicity with coadministration of trimethoprim/sulfamethoxazole (TMP/SMX) and cyclosporine in renal transplant patients.(1,3-4) A double-blind controlled trial of 132 renal transplant recipients on cyclosporine and randomized for prophylactic TMP/SMX therapy found that patients on TMP/SMX had 15% higher serum creatinine than control patients (p<0.01). However, the difference reflected trimethoprim inhibition of tubular excretion of creatinine and was reversible. There was no evidence that TMP/SMX augmented nephrotoxicity.(5)

Trimethoprim/Ace Inhibitors; Arbs

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), and trimethoprim have all been proven to increase serum potassium levels. The increase is achieved by reduction in potassium elimination by trimethoprim(1,2) and a decrease in angiotensin activity by ACE Inhibitors and ARBs. The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(1-5)

CLINICAL EFFECTS: Concurrent use of trimethoprim and ACE Inhibitors or Angiotensin Receptor Blockers may result in increased serum potassium levels,(1-5) which may be fatal.(2)

PREDISPOSING FACTORS: The interaction may be more significant in elderly patients and patients with renal insufficiency.(1)

PATIENT MANAGEMENT: Use trimethoprim with caution in patients maintained on ACE Inhibitors or ARBs. Patients using these medications concurrently should have their serum potassium monitored. In the elderly or renally impaired, alternative antibiotic therapy should be considered.

DISCUSSION: In a retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB who were admitted to a hospital for hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion, 371 patients were identified. More than half of the patients with hyperkalemia had received SMX-TMP. Patients receiving SMX-TMP had a 7-fold increased risk of hyperkalemia compared to patients receiving other antibiotics. No risk was found with the other antibiotics.(1) A retrospective review of patients in Ontario maintained on an ACE inhibitor or ARB examined those who died within 7 days of filling an outpatient prescription for amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin, or SMX-TMP. Patients receiving SMX-TMP had an increased risk of death (adjusted odds ratio 1.38) compared to amoxicillin. Risk was slightly higher at 14 days (adjusted odds ration 1.54). This corresponded to 3 sudden deaths within 14 days per 1000 SMX-TMP prescriptions.(2) A review of nine case reports of hyperkalemia with SMX-TMP found that 2 patients were receiving concurrent ACE inhibitors (enalapril and benazepril). One of these patients had severe hyperkalemia with a peak potassium level of 7.4 mEq/l.(3) Hyperkalemia has also been reported with concurrent SMX-TMP and enalapril(4) and with quinapril.(5)

Trimethoprim/Aldosterone Receptor Antagonists

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eplerenone, finerenone, spironolactone, and trimethoprim have all been proven to increase serum potassium levels.(1-7) The increase is achieved by reduction in potassium elimination by trimethoprim(4,5) and inhibition of aldosterone by eplerenone, finerenone, and spironolactone.(2,3,8) The use of these medications in combination can have an additive effect on serum potassium resulting in potentially dangerous levels.(9)

CLINICAL EFFECTS: Concurrent use of trimethoprim and aldosterone antagonists may result in increased serum potassium levels(9) and risk of sudden death.(10)

PREDISPOSING FACTORS: Interaction risk appears to be greater in patients with renal insufficiency, heart failure, when receiving other drugs associated with hyperkalemia risk (e.g. ACE Inhibitors, non-steroidal antiinflammatory agents(NSAIDs), angiotensin II receptor antagonists), and/or in older patients.(1,2,3,6,9,10)

PATIENT MANAGEMENT: Alternative antibiotic therapy should be considered for patients who have renal impairment, heart failure, or take other meds associated with hyperkalemia risk.(1,2,9,10) Patients using trimethoprim and an aldosterone antagonist concurrently should have their serum potassium monitored at baseline and during treatment. Peak potassium increase is delayed and generally occurs after 4 or more days of therapy.(6)

DISCUSSION: A nested case-control study of elderly patients chronically treated with spironolactone evaluated hospital admissions due to hyperkalemia within 14 days of receiving a prescription for SMX-TMP, amoxicillin, norfloxacin, or nitrofurantion. 248 patients were identified. Two thirds of the patients with hyperkalemia on admission had received SMX-TMP, a 12-fold increased risk compared to patients receiving amoxicillin or norfloxacin.(9) A nested case-control study of elderly patients chronically treated with spironolactone evaluated sudden death within 14 days of receiving a prescription for SMX-TMP, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantion. 328 patients were identified and matched to up to 4 case controls. Compared with amoxicillin, use of SMX-TMP was associated with a more than 2-fold (2.46 adjusted OR) increased risk of death.(10)

Trimethoprim/Digoxin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Trimethoprim may inhibit the renal tubular clearance of digoxin.(1-3)

CLINICAL EFFECTS: Concurrent use of trimethoprim may result in elevated levels of and toxicity from digoxin.(1,2) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: The manufacturer of digoxin states if concurrent therapy is warranted, monitor serum digoxin levels before initiating concurrent trimethoprim therapy and observe the patient for symptoms of digoxin toxicity. Upon adding trimethoprim, digoxin should first be decreased by approximately 15-30% of the current dose or by modifying the dosing frequency in anticipation of interaction. Continue monitoring digoxin levels and further adjust the dosing as necessary.(1)

DISCUSSION: In a study of nine patients (median age 78 years, range 62-92) treated with a constant oral dosage of digoxin (0.125-0.25 mg daily), trimethoprim (200 mg twice daily) increased serum digoxin concentrations by 22% during concurrent therapy (p < 0.05).(3) In a single dose study of 6 healthy subjects (median age 29 years, range 24-31) treated with trimethoprim and digoxin (1 mg intravenous), trimethoprim (200 mg twice daily) administration did not affect total body clearance of digoxin. The renal clearance of digoxin decreased by 17% (p < 0.05) and the extrarenal clearance of digoxin increased by 14%.(3) In a retrospective, population-based cohort study of 47,961 patients receiving digoxin (median age 80 years, range 74-86) and initiated on trimethoprim-sulfamethoxazole (TMP-SMX) (n=10,273) or amoxicillin (n=37,688), the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in older adults who were prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Of 10,273 patients co-prescribed digoxin and TMP-SMX, 492 (5%) had evidence of a digoxin dose reduction when the prescription for TMP-SMX was started. A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted risk ratio, 5.71 (95% confidence interval, 3.9 to 10.24)).(4)

Trimethoprim/Potassium Supplements

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Trimethoprim may increase serum potassium levels by reduction in potassium elimination.(1-3) The combination of trimethoprim and potassium supplements can have an additive effect on serum potassium resulting in potentially dangerous levels.

CLINICAL EFFECTS: Concurrent use of trimethoprim and potassium supplements may result in hyperkalemia, which may be severe.

PREDISPOSING FACTORS: Patients who are elderly, have any degree of renal insufficiency or heart failure have an increased risk for hyperkalemia.(1-9) Concomitant use with other drugs associated with hyperkalemia risk (e.g. ACE Inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, NSAIDs) and high doses of trimethoprim further increase the risk for hyperkalemia.(1-8) Interaction risk and severity is greater in patients with multiple risk factors.

PATIENT MANAGEMENT: Assure adequate monitoring for hyperkalemia.(1-9) Patients receiving trimethoprim and a potassium supplement concurrently should have their serum potassium monitored at baseline and during treatment. Potassium supplementation may need to be held during antibiotic therapy, especially when other predisposing factors for hyperkalemia are present. Peak potassium increase due to trimethoprim is delayed and generally occurs after 4 or more days of therapy.(3,5,6) When possible, alternative antibiotic therapy should be considered in patients with one or more risk factors for hyperkalemia, e.g. renal impairment, heart failure, age > 65 years, and/or receiving additional meds associated with hyperkalemia risk (e.g. ACE inhibitors, angiotensin II receptor blockers, aldosterone antagonists, NSAIDs).(6)

DISCUSSION: A nested case-control study evaluated the risk for hyperkalemia in 19,194 patients with newly diagnosed heart failure. Over a mean follow-up of 3.9 years 2,176 cases of hyperkalemia (96.7% with a potassium value of => 5.5 mmol/L) were identified. Study authors found that trimethoprim independently increased the risk for hyperkalemia (OR 2.82; 95% CI 1.88-4.23).(4) A retrospective cohort study evaluated the risk for hospitalization due to hyperkalemia in 393,039 elderly women (age >65 years) treated for a urinary tract infection (UTI) with trimethoprim-sulfamethoxazole (TMP-SMX) or another antibiotic (amoxicillin, ciprofloxacin, norfloxacin, nitrofurantoin). Baseline renal function was similar in all five antibiotic groups. When compared with amoxicillin, TMP-SMX use was associated with a 3.3-fold increased risk for hospitalization due to hyperkalemia. Ciprofloxacin, norfloxacin, and nitrofurantoin were not associated with a risk for hyperkalemia.(9) A prospective study of hospitalized patients evaluated the risk for hyperkalemia in patients who received standard dose TMP-SMX (<= 320 mg trimethoprim, <= 1600 mg sulfamethoxazole daily) versus a control group who received a different antibiotic for at least 5 days. The two groups were similar in age, renal function and use of potassium altering medications. Serum potassium concentration increased in TMP-SMX patients by 1.21 mmol/L (CI 1.09 - 1.32 mmol/L), a change which was statistically significant in patients with a pretreatment serum creatinine = or > 1.2. In control patients, serum potassium decreased during antibiotic therapy (change not quantitated by authors).(5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents That Increase Potassium/Baxdrostat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The combination of baxdrostat and agents that increase potassium such as aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements can have an additive effect on serum potassium levels.

CLINICAL EFFECTS: Concurrent use of baxdrostat and agents that increase potassium may result in hyperkalemia, which may be severe.

PREDISPOSING FACTORS: More frequent monitoring is recommended for patients at increased risk of hyperkalemia (e.g., patients greater than or equal to 65 years or age, those with diabetes mellitus or chronic kidney disease).(1)

PATIENT MANAGEMENT: The manufacturer of baxdrostat states concurrent use with medications that may increase potassium warrants more frequent monitoring of serum potassium.(1) Assess serum potassium prior to initiation of baxdrostat and monitor periodically during treatment. Correct serum potassium abnormalities prior to initiation of baxdrostat.(1) If hyperkalemia occurs, treat hyperkalemia and consider interrupting or discontinuing baxdrostat. Consider more frequent monitoring of serum potassium in patients who restart baxdrostat after experiencing hyperkalemia. Permanently discontinue baxdrostat if clinically significant hyperkalemia recurs.(1)

DISCUSSION: Baxdrostat may increase potassium. Concurrent use with aldosterone receptor antagonists, potassium-sparing diuretics, and potassium supplements may have additive effects on serum potassium levels, resulting in hyperkalemia. The risk of hyperkalemia can be reduced by monitoring serum potassium more frequently when baxdrostat is administered concomitantly with these agents.

Mate Inhibitors/Flecainide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal elimination of flecainide.(1)

CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from flecainide.(1)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Monitor serum flecainide concentrations and observe the patients for signs of toxicity. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a pharmacokinetic study, concurrent use of cimetidine (1 gram daily) increased flecainide levels by 30% and increased half-life by 10%.(1) MATE inhibitors linked include: abemaciclib, bictegravir, brepocitinib, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(4,5)

Mate Inhibitors/Oxaliplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may inhibit the renal transport of oxaliplatin.(1) Oxaliplatin is a MATE substrate.(2,3)

CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from oxaliplatin, including QT prolongation and neutropenia.(1)

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Concurrent use of oxaliplatin with MATE renal transporter inhibitors should be approached with caution and monitored closely. If concurrent use is warranted, monitor for toxicities of oxaliplatin and consider dosage reduction based on toxicity dose recommendations.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Oxaliplatin is a MATE substrate.(2,3) MATE inhibitors include: abemaciclib, bictegravir, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(6,7)

Mate Inhibitors/Procainamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal elimination of procainamide and its active metabolite, N-acetylprocainamide (NAPA).

CLINICAL EFFECTS: The pharmacological and toxic effects of procainamide and NAPA may be increased, including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).

PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).

PATIENT MANAGEMENT: Monitor serum procainamide and NAPA concentrations and observe the patients for signs of toxicity. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Administration of trimethoprim to patients receiving procainamide produced an increase in the area under the concentration-time curve and a decrease in the clearance of procainamide. At the same time, serum NAPA concentrations and clearance were decreased. MATE inhibitors include: pyrimethamine, risdiplam, and trimethoprim.(4)

Oct2 Inhibitors/Cisplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of cisplatin by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicities from cisplatin, including nephrotoxicity, ototoxicity, neuropathy, and myelosuppression.(1,2)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, and dehydration may increase the risk of nephrotoxicity.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of cisplatin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor closely for toxicities of cisplatin and consider dosage reduction of cisplatin.(1,2)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)

Oct2 Inhibitors/Clofarabine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of clofarabine by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from clofarabine, including myelosuppression, serious hemorrhages, enterocolitis, nephrotoxicity, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of clofarabine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of the clofarabine and consider dosage reduction of clofarabine.(1)

DISCUSSION: In an animal study, cimetidine, an OCT2 inhibitor, decreased the clearance of clofarabine in rats by 61%. The clinical implications of this finding are unclear.(1,2) In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, cimetidine, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(5)

Oct2 Inhibitors/Dalfampridine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of dalfampridine by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from dalfampridine.(1,2)

PREDISPOSING FACTORS: The risk of seizures from dalfampridine may be increased in patients with a history of head trauma or prior seizure; CNS tumor; CNS infections; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of dalfampridine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of dalfampridine and consider dosage reduction of dalfampridine.(1,2)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)

Selected Sulfonamide Antibacterials; Trimethoprim/Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Trimethoprim and selected sulfonamides may inhibit the CYP2C9 mediated metabolism of phenytoin and possibly other hydantoins.

CLINICAL EFFECTS: Concurrent use of trimethoprim or selected sulfonamides may result in elevated levels of and toxicity from the hydantoin. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.

PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting). If available, monitor hydantoin serum levels. Adjust the dose of hydantoins if needed.

DISCUSSION: In a case-control cohort study, elderly patients hospitalized due to phenytoin toxicity were more than twice as likely to have had concurrent use of trimethoprim-sulfamethoxazole in the previous 30 days (729 subjects) as compared to concurrent use of amoxicillin in the previous 30 days (3148 subjects). The adjusted odds ratio was 2.11 with a 95% CI of 1.24, 3.60. In another study, concurrent administration of phenytoin and trimethoprim as well as phenytoin and trimethoprim-sulfamethoxazole have been reported to increase the half-life of phenytoin by 50% and 39%, respectively. Concomitant administration of phenytoin with sulfamethoxazole alone produced small increases in the half-life of phenytoin. The severity of this interaction appears to vary with the different sulfonamides and is subject to large individual variability.

Sulfamethoxazole-Trimethoprim/Azathioprine; Mercaptopurine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The combination of antimetabolite properties of either azathioprine or mercaptopurine with the inhibition of dihydrofolate reductase by sulfamethoxazole-trimethoprim may result in cytopenias.(1)

CLINICAL EFFECTS: Concurrent use of either azathioprine or mercaptopurine with sulfamethoxazole-trimethoprim may result in leucopenia,(2,3) neutropenia, or thrombocytopenia,(1)

PREDISPOSING FACTORS: Renal transplant patients(2), especially those within 60 days of transplant,(3) may be predisposed to this interaction. Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(4)

PATIENT MANAGEMENT: Patients receiving this combination should be closely monitored for cytopenias. The Australian manufacturer of sulfamethoxazole-trimethoprim states that alternatives to sulfamethoxazole-trimethoprim should be considered for patients receiving azathioprine or mercaptopurine.(6)

DISCUSSION: In a retrospective review of 40 renal transplant patients, 25 received azathioprine alone, 6 received azathioprine with sulfamethoxazole-trimethoprim prophylaxis, and 9 received sulfamethoxazole-trimethoprim for treatment of a urinary tract infection (UTI). Patients in the prophylaxis group had an increased incidence and duration of neutropenia and thrombocytopenia compared to patients receiving azathioprine alone. There were no differences in the incidence or duration of neutropenia or thrombocytopenia between patients receiving azathioprine alone or with concurrent sulfamethoxazole-trimethoprim for UTI treatment. In a study of renal transplant patients, 4 of 14 patients maintained on azathioprine developed leucopenia following the addition of sulfamethoxazole-trimethoprim for the treatment of UTI. In 3 patients, the leucopenia developed within 2 days of the initiation of sulfamethoxazole-trimethoprim.(3) In contrast to these reports, a retrospective review of 94 renal transplant patients found that the incidence of leucopenia with concurrent azathioprine and sulfamethoxazole-trimethoprim was not significantly different than the incidence with concurrent azathioprine and other antibiotics.(5)

Sulfonamide Antibacterials/Antidiabetics, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. However, it is speculated that sulfonamides may inhibit hepatic metabolism and/or displace oral antidiabetics from plasma protein binding sites.

CLINICAL EFFECTS: Increased serum levels of antidiabetics with potentiation of hypoglycemic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed.

DISCUSSION: Additional documentation is necessary to confirm this interaction.

Sulfonamide Antibacterials/Paba

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sulfonamide antibacterials are structurally similar to PABA (p-aminobenzoic acid). PABA is an essential precursor for synthesis of tetrahydrofolate. Sulfonamides competitively inhibit utilization of PABA and therefore disrupt tetrahydrofolate biosynthesis. Supplementation with PABA antagonizes sulfonamide antibacterials.

CLINICAL EFFECTS: Reduced antibacterial effectiveness of sulfonamides with concomitant use.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs.

DISCUSSION: This interaction is well documented.

Trimethoprim-Sulfamethoxazole/Leucovorin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Leucovorin may protect Pneumocystis jirovecii from the effects of trimethoprim-sulfamethoxazole by providing a source of folate.(1,2)

CLINICAL EFFECTS: Concurrent use of leucovorin in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci pneumonia (formerly called Pneumocystic carinii) with trimethoprim-sulfamethoxazole has been associated with treatment failure and increased mortality.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of leucovorin and trimethoprim-sulfamethoxazole should be avoided in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci (formerly carinii) pneumonia.(1-4) The Australian manufacturer of leucovorin states simultaneous administration of folinic acid and folic acid antagonists (e.g. trimethoprim-sulfamethoxazole, pyrimethamine) is contraindicated because the folinic acid can completely negate the effect of the folic acid antagonist.(5) Leucovorin is an effective treatment for trimethoprim-sulfamethoxazole induced bone marrow suppression.(3)

DISCUSSION: In a prospective, double-blind study in 92 AIDS patients with Pneumocystis jiroveci (formerly carinii) pneumonia, concurrent use of leucovorin with trimethoprim-sulfamethoxazole resulted in an increase in treatment failure (15% versus 0) and death (11% versus 0). Leucovorin was also associated with a shorter time to therapeutic failure. Patients receiving leucovorin did have a lower incidence of neutropenia; however, there was no difference in the time to occurrence of neutropenia.(4) In a study in 12 AIDS/ARC patients, leucovorin had no effect on trimethoprim-sulfamethoxazole induced cytopenia.(6) In a study in HIV patients with no history of Pneumocystis jiroveci pneumonia, administration of leucovorin had no effect on patient tolerance to trimethoprim-sulfamethoxazole.(7) In a case report, two renal transplant patients with Pneumocystis jiroveci pneumonia failed to respond to treatment with trimethoprim-sulfamethoxazole until concurrent leucovorin was discontinued.(1) In a case report, an AIDS patient developed Pneumocystis jiroveci pneumonia despite a regimen of concurrent trimethoprim-sulfamethoxazole and leucovorin.(2)

Trimethoprim/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transport. Trimethoprim inhibits elimination by these pathways.

CLINICAL EFFECTS: Use of trimethoprim may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin and/or trimethoprim be adjusted as needed. Consider the benefits and risks of concomitant use.(1) Evaluate patient's renal function and consider discontinuation of one or both agents in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Trimethoprim was found to cause significant inhibition of net transcellular chloroquine transport in canine kidney-OCT2-MATE1 cells. Chloroquine is eliminated by renal tubular secretion involving multidrug and toxin extrusion protein 1 (MATE1). Trimethoprim caused concentration-dependent inhibition of net metformin intake in HEK293-MATE1 cells (human embryonic kidney). (2) A randomized, open-label, two-phase crossover study found that trimethoprim inhibited OCT2, MATE1, and MATE2-K-dependent transport of metformin. Trimethoprim increased metformin area under the curve (AUC) by 29.4% and decreased metformin renal clearance by 26.4%. (3) 24 healthy volunteers received metformin 500 mg three times daily for ten days and trimethoprim 200 mg twice daily from days 5-10. Trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h and renal metformin clearance from 31 to 21 l/h. Metformin half-life was prolonged from 2.7 to 3.6h. The metformin plasma concentration (Cmax) increased 38% and the AUC by 37%. Trimethoprim was also associated with a decrease in creatinine clearance and an increase in plasma lactate. (4)

Trimethoprim/Pioglitazone; Repaglinide; Rosiglitazone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Trimethoprim, a weak CYP2C8 inhibitor, may inhibit the metabolism of pioglitazone,(1,2) repaglinide,(3) and rosiglitazone.(4,5)

CLINICAL EFFECTS: Concurrent use of trimethoprim may result in increased levels of and effects from pioglitazone,(1,2) repaglinide,(3) and rosiglitazone.(4,5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent trimethoprim and pioglitazone, repaglinide, or rosiglitazone should be monitored for signs and symptoms of hypoglycemia. The dosage of the antidiabetic agent may need to be adjusted during and following trimethoprim therapy.

DISCUSSION: In a randomized, cross-over study in 16 healthy subjects, trimethoprim (160 mg twice daily for 6 days) increased the area-under-curve (AUC) of a single dose of pioglitazone (15 mg) by 42%.(1) Trimethoprim was shown to inhibit pioglitazone metabolism in vitro in human liver microsomes.(1,2) In a randomized, double-blind, cross-over study in 9 healthy subjects, trimethoprim (160 mg twice daily for 3 days) increased the AUC and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 61% and 41%, respectively. Trimethoprim also inhibited repaglinide metabolism in vitro in a concentration-dependent manner.(3) In a randomized, cross-over study in 8 healthy subjects, trimethoprim (200 mg twice daily for 5 days) increased the AUC of a single dose of rosiglitazone (8 mg) by 31%. An in vitro study in human liver microsomes showed that trimethoprim inhibited troglitazone metabolism.(4) In a randomized, cross-over study in 10 healthy subjects, trimethoprim (160 mg twice daily for 4 days) increased the AUC of a single dose of troglitazone (4 mg) by 37%.(5)

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• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Folic acid deficient megaloblastic anemia
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Pregnancy
• Pregnancy- third trimester

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Clostridioides difficile infection
• Folic acid deficient megaloblastic anemia
• Hyponatremia
• Neutropenic disorder
• Porphyria
• Severe hepatic disease
• Thrombocytopenic disorder

• Disease of liver
• Folate deficiency
• Hyperkalemia
• Hypoglycemic disorder
• Hypothyroidism
• Kidney disease with reduction in glomerular filtration rate (GFr)
• NAt2 poor metabolizer
• Neutropenic disorder

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More Frequent

• Drug fever
• Skin photosensitivity

Less Frequent

• Hepatitis

Rare or Very Rare

• Acidosis
• Acute generalized exanthematous pustulosis
• Acute respiratory failure
• Acute respiratory failure
• Agranulocytosis
• Alveolitis
• Anaphylaxis
• Anaphylaxis
• Angioedema
• Anuria
• Aplastic anemia
• Behcet syndrome
• Cauda equina syndrome
• Clostridioides difficile infection
• Clostridioides difficile infection
• Crystalluria
• Cyanosis
• DRESS syndrome
• Dyspnea
• Enterocolitis
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Erythema multiforme
• Erythema nodosum
• Exfoliative dermatitis
• Exfoliative dermatitis
• Gastrointestinal hemorrhage
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency anemia
• Goiter
• Granulocytopenic disorder
• Guillain-barre syndrome
• Hematuria
• Hemolytic anemia
• Hemolytic uremic syndrome
• Hemophagocytic lymphohistiocytosis
• Hemophagocytic lymphohistiocytosis
• Hepatic necrosis
• Hepatic necrosis
• Hepatocellular damage
• Hyperkalemia
• Hypofibrinogenemia
• Hyponatremia
• Hyponatremia
• Hypoprothrombinemia
• Hypothyroidism
• IgA vasculitis
• Interstitial lung disease
• Interstitial nephritis
• Intracranial hypertension
• Leukopenia
• Leukopenia
• Lupus-like syndrome
• Megaloblastic anemia
• Megaloblastic anemia
• Methemoglobinemia
• Methemoglobinemia
• Myelodysplastic syndrome
• Myocarditis
• Neutropenic disorder
• Neutropenic disorder
• Non-infective meningitis
• Obstructive hyperbilirubinemia
• Oliguria
• Pancreatitis
• Pancreatitis
• Pericarditis
• Periorbital edema
• Pleuritis
• Polyarteritis nodosa
• Proteinuria
• Pulmonary infiltrates
• Renal tubular acidosis
• Renal tubular necrosis
• Seizure disorder
• Serum sickness
• Shock
• Stevens-johnson syndrome
• Stevens-johnson syndrome
• Sweet's syndrome
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura
• Toxic epidermal necrolysis
• Toxic epidermal necrolysis
• Urolithiasis
• Uveitis
• Vasculitis

More Frequent

• Anorexia
• Diarrhea
• Dizziness
• Headache disorder
• Lethargy
• Nausea
• Pruritus of skin
• Pruritus of skin
• Skin rash
• Skin rash
• Vomiting

Less Frequent

• Cough
• Nausea
• Skin photosensitivity
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Acute abdominal pain
• Acute cognitive impairment
• Alopecia
• Arthralgia
• Ataxia
• Black tarry stools
• Candidiasis
• Chills
• Constipation
• Cough
• Depression
• Drowsy
• Drug-induced psychosis
• Fatigue
• Fever
• Flatulence
• Gastroenteritis
• General weakness
• Glossitis
• Glossitis
• Hallucinations
• Headache disorder
• Hearing loss
• Hypoglycemic disorder
• Indifference
• Insomnia
• Nervousness
• Paresthesia
• Peripheral neuropathy
• Porphyria
• Stomatitis
• Stomatitis
• Symptoms of anxiety
• Tinnitus
• Urticaria
• Urticaria
• Uveitis
• Vertigo

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Trimethoprim has been shown to be teratogenic in rats when given in doses 40 times the usual human dose; in rabbits, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose. Although there are no adequate and controlled studies to date using trimethoprim in humans, a retrospective study that reported the outcome of 186 pregnancies suggested that the incidence of congenital abnormalities in those who received the fixed combination containing trimethoprim and sulfamethoxazole (co-trimoxazole) was similar to that in those who received a placebo. Because trimethoprim may interfere with folic acid metabolism, the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.

Trimethoprim and sulfamethoxazole, alone and in combination, have produced teratogenic effects, manifested principally as cleft palate, in some (but not all) studies in rats receiving dosages exceeding the usual human dosages. In addition, in some rabbit studies, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose. Although there are no adequate and controlled studies to date in humans, studies in pregnant women suggest that the incidence of congenital abnormalities in those who received co-trimoxazole was similar to that in those who received a placebo; there were no abnormalities in 10 children whose mothers had received the drug during the first trimester. In one report, there were no congenital abnormalities in 35 children whose mothers had received co-trimoxazole at the time of conception or shortly thereafter. Because co-trimoxazole crosses the placenta and may interfere with folic acid metabolism, the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Because sulfonamides may cause kernicterus in neonates, the manufacturers state that use of co-trimoxazole in pregnant women is contraindicated.

Trimethoprim is distributed into milk. Because trimethoprim may interfere with folic acid metabolism, the drug should be used with caution in nursing women.

Co-trimoxazole is distributed into milk. Because co-trimoxazole may interfere with folic acid metabolism, the drug should be used in nursing women only if the potential benefits justify the possible risks to the infant. Because sulfonamides may cause kernicterus in infants younger than 2 months of age, a decision should be made whether to discontinue nursing or co-trimoxazole or to use an alternative drug, taking into account the importance of co-trimoxazole to the woman.

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