Primsol (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.

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.)

No dosing information is available for this tab.

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)

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.

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)

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.

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.

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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• Folic acid deficient megaloblastic anemia
• Pregnancy

• Neutropenic disorder
• Porphyria
• Thrombocytopenic disorder

• Disease of liver
• Folate deficiency
• Hyperkalemia
• Kidney disease with reduction in glomerular filtration rate (GFr)

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Rare or Very Rare

• Acute respiratory failure
• Anaphylaxis
• Clostridioides difficile infection
• Erythema multiforme
• Exfoliative dermatitis
• Hemophagocytic lymphohistiocytosis
• Hepatic necrosis
• Hyperkalemia
• Hyponatremia
• Leukopenia
• Megaloblastic anemia
• Methemoglobinemia
• Neutropenic disorder
• Non-infective meningitis
• Obstructive hyperbilirubinemia
• Pancreatitis
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Uveitis

More Frequent

• Pruritus of skin
• Skin rash

Less Frequent

• Cough
• Nausea
• Skin photosensitivity
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Candidiasis
• Constipation
• Fever
• Glossitis
• Headache disorder
• Porphyria
• Stomatitis
• Urticaria

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

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