Please wait while the formulary information is being retrieved.
Drug overview for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
Generic name: BENAZEPRIL HCL/HYDROCHLOROTHIAZIDE (ben-AZ-e-pril/HYE-droe-KLOR-oh-THYE-a-zide)
Drug class: Angiotensin Converting Enzyme (ACE) Inhibitors
Therapeutic class: Cardiovascular Therapy Agents
Benazepril is an angiotensin-converting enzyme (ACE) inhibitor. Hydrochlorothiazide is a thiazide diuretic and antihypertensive agent.
Benazepril hydrochloride is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.
Generic name: BENAZEPRIL HCL/HYDROCHLOROTHIAZIDE (ben-AZ-e-pril/HYE-droe-KLOR-oh-THYE-a-zide)
Drug class: Angiotensin Converting Enzyme (ACE) Inhibitors
Therapeutic class: Cardiovascular Therapy Agents
Benazepril is an angiotensin-converting enzyme (ACE) inhibitor. Hydrochlorothiazide is a thiazide diuretic and antihypertensive agent.
Benazepril hydrochloride is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.
DRUG IMAGES
BENAZEPRIL-HCTZ 20-12.5 MG TAB
The following indications for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide) have been approved by the FDA:
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
Indications:
Hypertension
Professional Synonyms:
Elevated blood pressure
Essential hypertension
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Systemic arterial hypertension
The following dosing information is available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
Dosage of hydrochlorothiazide should be individualized according to the patient's requirements and response. The lowest dosage necessary to produce the desired clinical effect should be used. If hydrochlorothiazide is added to the regimen of a patient stabilized on a potent hypotensive agent, dosage of the hypotensive agent should initially be reduced to avoid the possibility of severe hypotension.
Dosage of benazepril hydrochloride must be adjusted according to patient tolerance and response. Because of the risk of inducing hypotension, initiation of benazepril therapy requires consideration of recent and current antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. If blood pressure is not controlled adequately with the ACE inhibitor alone, a low dosage of a diuretic may be added.
For the management of hypertension in adults, the manufacturers recommend an initial hydrochlorothiazide dosage of 12.5-25 mg once daily and a usual maximum dosage of 50 mg daily (in 1 or 2 divided doses). Dosages of 25-100 mg daily (in 1 or 2 divided doses) have been used in randomized controlled studies; experts recommend a dosage of 25-50 mg daily for optimal balance between efficacy and safety in the management of hypertension in adults.
Dosages exceeding 50 mg daily usually are associated with marked hypokalemia; some manufacturers state that such dosages are not recommended.
In children 6 months to 12 years of age, the usual dosage of hydrochlorothiazide for the management of hypertension or for diuresis is 1-2 mg/kg daily given as a single dose or in 2 divided doses. Infants younger than 6 months of age may require up to 3 mg/kg daily in 2 divided doses. The total daily dosage should not exceed 37.5
mg for children up to 2 years of age or 100 mg for children 2-12 years of age. Experts recommend initiation of the drug at the low end of the dosage range; the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Because an increased incidence of adverse effects to hydrochlorothiazide and excessive reduction in blood pressure may occur in geriatric patients (older than 65 years of age), hydrochlorothiazide should be initiated at the lowest dosage (12.5 mg daily); dosage may be adjusted in increments of 12.5 mg if needed.
Dosage of benazepril hydrochloride must be adjusted according to patient tolerance and response. Because of the risk of inducing hypotension, initiation of benazepril therapy requires consideration of recent and current antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. If blood pressure is not controlled adequately with the ACE inhibitor alone, a low dosage of a diuretic may be added.
For the management of hypertension in adults, the manufacturers recommend an initial hydrochlorothiazide dosage of 12.5-25 mg once daily and a usual maximum dosage of 50 mg daily (in 1 or 2 divided doses). Dosages of 25-100 mg daily (in 1 or 2 divided doses) have been used in randomized controlled studies; experts recommend a dosage of 25-50 mg daily for optimal balance between efficacy and safety in the management of hypertension in adults.
Dosages exceeding 50 mg daily usually are associated with marked hypokalemia; some manufacturers state that such dosages are not recommended.
In children 6 months to 12 years of age, the usual dosage of hydrochlorothiazide for the management of hypertension or for diuresis is 1-2 mg/kg daily given as a single dose or in 2 divided doses. Infants younger than 6 months of age may require up to 3 mg/kg daily in 2 divided doses. The total daily dosage should not exceed 37.5
mg for children up to 2 years of age or 100 mg for children 2-12 years of age. Experts recommend initiation of the drug at the low end of the dosage range; the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Because an increased incidence of adverse effects to hydrochlorothiazide and excessive reduction in blood pressure may occur in geriatric patients (older than 65 years of age), hydrochlorothiazide should be initiated at the lowest dosage (12.5 mg daily); dosage may be adjusted in increments of 12.5 mg if needed.
Hydrochlorothiazide is administered orally. Benazepril hydrochloride is administered orally. For adult or pediatric patients unable to swallow tablets or those children for whom the daily dose does not correspond exactly to the strength of commercially available tablets, benazepril hydrochloride may be administered orally as an extemporaneously prepared suspension.
An extemporaneous suspension containing benazepril hydrochloride 2 mg/mL can be prepared in the following manner. First, 75 mL of suspending vehicle (Ora-Plus(R)) is added to an amber polyethylene terephthalate (PET) bottle containing fifteen 20-mg tablets of benazepril hydrochloride, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 60 minutes following reconstitution, and then should be shaken for an additional minute.
The concentrated suspension of benazepril hydrochloride should be diluted with 75 mL of syrup (Ora-Sweet(R)), and the container then shaken to disperse the ingredients. The suspension should be shaken before dispensing each dose. The extemporaneous suspension is stable for 30 days when stored at 2-8degreesC.
An extemporaneous suspension containing benazepril hydrochloride 2 mg/mL can be prepared in the following manner. First, 75 mL of suspending vehicle (Ora-Plus(R)) is added to an amber polyethylene terephthalate (PET) bottle containing fifteen 20-mg tablets of benazepril hydrochloride, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 60 minutes following reconstitution, and then should be shaken for an additional minute.
The concentrated suspension of benazepril hydrochloride should be diluted with 75 mL of syrup (Ora-Sweet(R)), and the container then shaken to disperse the ingredients. The suspension should be shaken before dispensing each dose. The extemporaneous suspension is stable for 30 days when stored at 2-8degreesC.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| BENAZEPRIL-HCTZ 5-6.25 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 10-12.5 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 20-12.5 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 20-25 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| BENAZEPRIL-HCTZ 20-12.5 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 5-6.25 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 20-25 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
| BENAZEPRIL-HCTZ 10-12.5 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
The following drug interaction information is available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
There are 3 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Dofetilide/Thiazide Diuretics 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: Thiazide diuretics may decrease the excretion of dofetilide and may decrease potassium levels.(1) CLINICAL EFFECTS: Concurrent use of dofetilide with a thiazide diuretic may result in elevated levels and clinical effects of dofetilide, as well as prolongation of the QT interval.(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, and 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 use of dofetilide with hydrochlorothiazide, alone or in combination with triamterene, is contraindicated.(1) Other thiazides should also be considered contraindicated as well. If concurrent therapy is deemed medically necessary, 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, hydrochlorothiazide (50 mg daily) alone or hydrochlorothiazide/triamterene (50 mg/100 mg daily) was administered with dofetilide (500 mcg twice daily) for 5 days following 2 days of diuretic use at half-dose. In patients receiving hydrochlorothiazide alone, the area-under-curve (AUC) and maximum concentration (Cmax) of dofetilide increased by 27% and by 21%, respectively. The pharmacodynamic effects of dofetilide increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients on combination hydrochlorothiazide/triamterene, dofetilide AUC and Cmax increased by 30% and by 16%, respectively. The pharmacodynamic effects of dofetilide increased by 190% (QTc increase over time) and by 84% (maximum QTc increase).(1) Dofetilide clearance was 16% lower in patients receiving thiazide diuretics.(1) |
DOFETILIDE, TIKOSYN |
| Sacubitril/ACE Inhibitors 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: Sacubitril is a neprilysin inhibitor. Overlapping inhibition of Angiotensin Converting Enzyme (ACE) and neprilysin may increase the risk of angioedema.(1,2) CLINICAL EFFECTS: Concurrent use may result in angioedema.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of sacubitril and an ACE inhibitor is contraindicated. Allow a 36 hour washout period when switching between an ACE inhibitor and sacubitril.(1-3) Monitor patients for signs of angioedema (swelling of the face, lips, tongue, and/or throat).(2) DISCUSSION: Higher incidence of angioedema was seen in clinical trials with omapatrilat, a combined ACE and neprilysin inhibitor. In the OCTAVE trial, the incidence and severity of angioedema was worse with omapatrilat (2.2%) than with enalapril (0.7%).(2) For this reason, overlap of sacubitril, a neprilysin inhibitor, with an ACE inhibitor is contraindicated and a 36 hour washout period is recommended when switching agents. The 36 hour window is designed to cover at least three half-lives of all ACE inhibitors.(1) |
ENTRESTO, ENTRESTO SPRINKLE |
| Selected Nephrotoxic Agents/Bacitracin 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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3) CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3) PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1) PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3) DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3) |
BACITRACIN, BACITRACIN MICRONIZED, BACITRACIN ZINC |
There are 12 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Lithium/Thiazide Diuretics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lithium is eliminated unchanged by the kidney; thiazide induced sodium elimination may lead to decreased renal clearance of lithium. CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal. PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors. PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. If a thiazide diuretic is started, or if the dose is increased in a patient stabilized on lithium therapy, consider empirically lowering the lithium dose, and recheck lithium levels 5 to 7 days after diuretic initiation. Adjust lithium or thiazide dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on a thiazide diuretic, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing. DISCUSSION: This interaction is well documented.(1-15) |
LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID |
| ACE Inhibitors; ARBs/Lithium SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blocker (ARB)-induced sodium loss or volume depletion may result in decreased renal clearance of lithium.(1) CLINICAL EFFECTS: Concurrent use of ACEI or ARBs may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(1) PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors. PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. The onset of lithium toxicity due to concomitant therapy with an ACEI or ARB may be delayed for 3-5 weeks.(2) Patients receiving this combination should be observed for signs of lithium toxicity when the ACEI or ARB dose is increased or if additional risk factors for lithium toxicity emerge. If an ACEI or ARB is required in a patient stabilized on lithium therapy, check baseline lithium concentration, consider empirically lowering the lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB initiation. Adjust lithium, ACEI or ARB dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on an ACEI or ARB, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged.(1) Monitor lithium concentrations frequently until stabilized on the combination. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(1) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing. DISCUSSION: Elevated lithium levels and lithium toxicity have been reported during concomitant administration of lithium and an ACEI(3-17) or an ARB(18-20). Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction. |
LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID |
| Colistimethate/Selected Nephrotoxic Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3) CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects. PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness. PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1) DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5) |
COLISTIMETHATE, COLISTIMETHATE SODIUM, COLY-MYCIN M PARENTERAL |
| Methenamine-Sodium Phosphate/Thiazides; Carbonic Anhydrase Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Thiazide diuretics and carbonic anhydrase inhibitors may elevate urinary ph preventing the conversion of methenamine to formaldehyde and mandelic acid.(1) CLINICAL EFFECTS: Concurrent administration may result in alkalinization of the urine causing methenamine to be less effective.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for urinary ph and any worsening symptoms of their infection, including dysuria, flank pain, or fever.(1) DISCUSSION: Administration of thiazide diuretics and carbonic anhydrase inhibitors may result in alkalinization of the urine resulting in therapeutic failure of methenamine. Formaldehyde is released by acid hydrolysis from methenamine resulting in bactericidal concentrations at urinary ph 5.0 to 5.5. Above urinary ph 6.0 there is insufficient quantities of formaldehyde and methenamine released to achieve a therapeutic response.(1) |
UROQID-ACID NO.2 |
| Sodium Phosphate Bowel Cleanser/Diuretics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on diuretics may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as diuretics. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8) |
MB CAPS, SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA |
| Sodium Phosphate Bowel Cleanser/ACE Inhibitors; ARBs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on angiotensin converting enzyme (ACE) inhibitors, angiotension receptor blockers (ARBs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, ARBs, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8) |
MB CAPS, SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA |
| ACE Inhibitors; ARBs/Trimethoprim 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) |
BACTRIM, BACTRIM DS, PRIMSOL, SULFAMETHOXAZOLE-TRIMETHOPRIM, SULFATRIM, TRIMETHOPRIM, TRIMETHOPRIM MICRONIZED |
| Aliskiren/ACE Inhibitors; ARBs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: In the ALTITUDE study, concurrent use of aliskiren for 18-24 months in patients maintained on either an ACE inhibitor or an ARB resulted in an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2) PREDISPOSING FACTORS: Patients with Type II diabetes and/or renal impairment may be at a higher risk from this combination.(1) PATIENT MANAGEMENT: Novartis no longer recommends the concurrent use of aliskiren with either an ACE inhibitor or an ARB.(1,3) Hypertension regimens of patients receiving concurrent therapy should be re-evaluated.(1) Concurrent use of aliskiren in diabetic patients receiving either an ACE inhibitor or an ARB is contraindicated.(2,4) Avoid the combination in patients with CrCl less than 60 ml/min.(5) DISCUSSION: ALTITUDE was a multinational study designed to evaluate the use of aliskiren for more than 1 year in patients with Type II diabetes and renal impairment, who are known to have a high risk for cardiovascular and renal events. Aliskiren was given with optimal cardiovascular treatment, including an ACE inhibitor or ARB. After 18-24 months of concurrent therapy with aliskiren and either an ACE inhibitor or an ARB, there was an increase in non-fatal stroke, renal complications, hyperkalemia, and hypotension.(1,2) |
ALISKIREN, TEKTURNA |
| ACE Inhibitors/mTOR Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: ACE inhibitors cause reduced bradykinin metabolism, leading to an increase in bradykinin which can cause vasodilation. mTOR inhibitors may also cause a reduction in bradykinin metabolism. CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk. PREDISPOSING FACTORS: History of previous angioedema. PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor. Consider switching the patient to an angiotensin receptor blocker. Monitor patients receiving concurrent therapy with ACE inhibitors and mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately. DISCUSSION: A retrospective, single center analysis looked at renal allograft recipients treated with mTOR inhibitors and ACE inhibitors over an 8 year-period. Out of 137 patients on concomitant ACE inhibitor and mTOR inhibitor therapy, 9 patients (6.6%) developed angioedema. Concomitant ACE inhibitor and mTOR inhibitor therapy increased the risk of developing angioedema 3.7-fold. Eight of these patients tolerated therapy with an angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR inhibitor and ARB therapy developed angioedema. Treatment with an ACE inhibitor or mTOR inhibitor alone resulted in a significantly lower incidence of angioedema.(1) In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.(2) There are case reports of patients on concomitant ACE inhibitor and sirolimus/everolimus that developed angioedema. In the majority of cases, patients had tolerated chronic therapy with an ACE inhibitor before the addition of sirolimus/everolimus.(3-7) The interaction may be dose-dependent.(7) |
AFINITOR, AFINITOR DISPERZ, EVEROLIMUS, FYARRO, SIROLIMUS, TEMSIROLIMUS, TORISEL, TORPENZ, ZORTRESS |
| Aminolevulinic Acid/Selected Photosensitizers 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) |
AMINOLEVULINIC ACID HCL, GLEOLAN |
| Porfimer/Selected Photosensitizers 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) |
PHOTOFRIN |
| Methoxsalen/Selected Photosensitizers 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) |
METHOXSALEN, UVADEX |
There are 19 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Digitalis Glycosides/Kaluretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Potassium-losing diuretics may result in potassium depletion which can predispose patients to digitalis toxicity. CLINICAL EFFECTS: May observe increased arrhythmias, resulting from an increase in the cardiac response to digitalis. 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: Monitor serum potassium status and give potassium replacements as needed. DISCUSSION: This interaction is well documented. Most patients taking diuretics do not develop significant potassium depletion if they are on low doses of diuretics and have adequate potassium intake. |
DIGITEK, DIGOXIN, DIGOXIN MICRONIZED, LANOXIN, LANOXIN PEDIATRIC |
| Thiazide & Related Diuretics/Cholestyramine; Colestipol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cholestyramine and colestipol, anionic exchange resins, bind thiazides and furosemide, preventing their absorption. CLINICAL EFFECTS: Concurrent administration may result in decreased absorption of the diuretic, as well as decreased clinical effects. Decreased absorption of furosemide by 80-90% has been reported. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Available data suggest that colestipol may be preferable to cholestyramine. Separating administration times lessens the the extent of this interaction but still remains significant. Separate the administration of cholestyramine and the thiazide by at least four hours and that of colestipol by at least two hours. Separate the administration of furosemide and cholestyramine or colestipol by two to three hours. DISCUSSION: Administration of cholestyramine or colestipol decreased total urinary excretion of hydrochlorothiazide by 85% and 43% respectively. These studies indicate that no dosing schedule will eliminate this interaction. Even four hours of separation reduces the absorption of hydrochlorothiazide by 35%. Similar reductions occurred to serum hydrochlorothiazide concentrations. In a study in six subjects, the concurrent administration of cholestyramine and furosemide resulted in a decrease in furosemide area-under-curve (AUC) by 90% and a decrease in furosemide's diuretic effects. Concurrent administration of furosemide and colestipol resulted in a decrease in furosemide AUC by 80% and a decrease in furosemide's diuretic effects. |
CHOLESTYRAMINE, CHOLESTYRAMINE LIGHT, CHOLESTYRAMINE RESIN, COLESTID, COLESTIPOL HCL, PREVALITE, QUESTRAN, QUESTRAN LIGHT |
| Thiazides/Antidiabetics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Thiazides antagonize hypoglycemic effects of antidiabetics due to intrinsic hyperglycemic activity. CLINICAL EFFECTS: Impaired glucose tolerance and diminished hypoglycemic effects of antidiabetics may occur. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Caution when starting or stopping thiazides in diabetic patients. Adjust the antidiabetic dose as needed based on blood glucose levels. DISCUSSION: This interaction is likely to occur based upon well documented properties of the interacting drugs. However, there is individual variability in its occurrence. A cross-sectional study of 425 outpatients found 46 patients with 86 suspected drug interactions resulting in uncontrolled glycemia. Recorded drug interactions included hydrochlorothiazide-gliclazide (22.1%), hydrochlorothiazide-insulins (2.3%), and chlorothiazide-gliclazide (1.2%). Using the drug interaction probability scale (DIPS), these drug interactions were categorized as possible.(2) |
ACARBOSE, ADMELOG, ADMELOG SOLOSTAR, AFREZZA, APIDRA, APIDRA SOLOSTAR, BASAGLAR KWIKPEN U-100, BASAGLAR TEMPO PEN U-100, DUETACT, FIASP, FIASP FLEXTOUCH, FIASP PENFILL, FIASP PUMPCART, GLIMEPIRIDE, GLIPIZIDE, GLIPIZIDE ER, GLIPIZIDE XL, GLIPIZIDE-METFORMIN, GLYBURIDE, GLYBURIDE MICRONIZED, GLYBURIDE-METFORMIN HCL, HUMALOG, HUMALOG JUNIOR KWIKPEN, HUMALOG KWIKPEN U-100, HUMALOG KWIKPEN U-200, HUMALOG MIX 50-50 KWIKPEN, HUMALOG MIX 75-25, HUMALOG MIX 75-25 KWIKPEN, HUMALOG TEMPO PEN U-100, HUMULIN R U-500, HUMULIN R U-500 KWIKPEN, INSULIN ASPART, INSULIN ASPART FLEXPEN, INSULIN ASPART PENFILL, INSULIN ASPART PROT MIX 70-30, INSULIN DEGLUDEC, INSULIN DEGLUDEC PEN (U-100), INSULIN DEGLUDEC PEN (U-200), INSULIN GLARGINE MAX SOLOSTAR, INSULIN GLARGINE SOLOSTAR, INSULIN GLARGINE-YFGN, INSULIN LISPRO, INSULIN LISPRO JUNIOR KWIKPEN, INSULIN LISPRO KWIKPEN U-100, INSULIN LISPRO PROTAMINE MIX, LANTUS, LANTUS SOLOSTAR, LYUMJEV, LYUMJEV KWIKPEN U-100, LYUMJEV KWIKPEN U-200, LYUMJEV TEMPO PEN U-100, MERILOG, MERILOG SOLOSTAR, MIGLITOL, MYXREDLIN, NATEGLINIDE, NOVOLOG, NOVOLOG FLEXPEN, NOVOLOG MIX 70-30, NOVOLOG MIX 70-30 FLEXPEN, NOVOLOG PENFILL, PIOGLITAZONE-GLIMEPIRIDE, PRECOSE, REZVOGLAR KWIKPEN, SEMGLEE (YFGN), SEMGLEE (YFGN) PEN, SOLIQUA 100-33, TOUJEO MAX SOLOSTAR, TOUJEO SOLOSTAR, TRESIBA, TRESIBA FLEXTOUCH U-100, TRESIBA FLEXTOUCH U-200, XULTOPHY 100-3.6 |
| ACE Inhibitors; ARBs/Loop Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. The initial hypotensive effect of the ACE inhibitors is mainly the result of suppression of the renin-angiotensin-aldosterone system. The ACE inhibitors inhibit the formation of angiotensin II and angiotensin II receptor antagonists block the action of angiotensin II, thereby lowering aldosterone levels with subsequent sodium and water depletion. Agents such as the loop diuretics that cause sodium and water loss may exaggerate the hypotensive state. CLINICAL EFFECTS: The addition of an ACE inhibitor to a patient receiving a loop diuretic may result in severe postural hypotension. This effect is transient and is not expected to occur during long-term dosing. Symptomatic hypotension may result in patients treated with loop diuretics who are started on an angiotensin II receptor antagonist. Concurrent use of a renin-angiotensin system (RAS) inhibitor with diuretics and NSAIDs may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Addition of an ACE inhibitor or an angiotensin II receptor antagonist to a patient already receiving a diuretic or who is sodium depleted. Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individual's susceptibility to AKI. PATIENT MANAGEMENT: In patients without heart failure, it may be advisable to discontinue the diuretic, reduce the dose of the diuretic, or increase salt intake prior to the initiation of the ACE inhibitor. If hypotension occurs, place the patient in a supine position. Hypotension is most likely when the ACE inhibitor is initiated. However, if subsequent hypotension occurs, a dosage adjustment or discontinuation of one agent may be required. Intravascular volume depletion should be corrected in patients prior to the initiation of an angiotensin II receptor antagonist. Concurrent use of a RAS inhibitor with loop diuretics and NSAIDs should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (6) Severe postural hypotension(1,2) and transient postural hypotension(3) has been reported in patients receiving concurrent captopril and furosemide. The effect is transient and may be more prevalent in patients who are sodium depleted.(8) Reversible renal failure(9) and decreased renal function(10) have been reported in patients receiving concurrent administration with enalapril and furosemide. In a study in which electrolytes were replaced with saline or Ringer's solution, no postural hypotension was noted; however, significant decreases in diastolic blood pressure occurred at three, four, and six hours after concurrent administration.(11) |
BUMETANIDE, EDECRIN, ETHACRYNATE SODIUM, ETHACRYNIC ACID, FUROSCIX, FUROSEMIDE, FUROSEMIDE-0.9% NACL, LASIX, SOAANZ, TORSEMIDE |
| Azathioprine/ACE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine-induced impairment of hematopoiesis and ACE inhibitor-induced decreases in erythropoietin may result in additive effects on bone marrow.(1,2) CLINICAL EFFECTS: The concurrent use of azathioprine and an ACE inhibitor may result in anemia or leucopenia.(1-6) ACE inhibitors have been used to correct post-transplantation erythrocytosis in patients who also received azathioprine.(7) PREDISPOSING FACTORS: 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.(8) PATIENT MANAGEMENT: Patients receiving concurrent therapy with azathioprine and an ACE inhibitor should be closely monitored for hematological changes. One of the agents may need to be discontinued. DISCUSSION: In a study in 15 kidney-transplant patients receiving azathioprine, enalapril and captopril were replaced by nifedipine or clonidine. Hematocrit and hemoglobin levels increased from 37.5% to 39.7% and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE inhibitor withdrawal. Reticulocytes and erythropoietin concentrations rose from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively. There were no changes in azathioprine levels.(1) A retrospective review compared azathioprine-treated patients to patients receiving azathioprine and ACE inhibitors. Hematocrit, hemoglobin, and haptoglobin levels were significantly lower in the group receiving ACE inhibitors, 19.7%, 17.2%, and 45%, respectively.(2) Three case reports document the development of leucopenia during the concurrent administration of captopril and azathioprine.(3-5) Another case report documented the development of anemia with concurrent enalapril and azathioprine.(6) Enalapril has been used to treat post-renal transplant erythrocytosis in patients receiving azathioprine.(7) |
AZASAN, AZATHIOPRINE, AZATHIOPRINE SODIUM, IMURAN, MERCAPTOPURINE, PURIXAN |
| ACE Inhibitors/High-Dose Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Aspirin's inhibition of prostaglandin synthesis may inhibit the release of vasodilating prostaglandins by ACE inhibitors. CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ACETYL SALICYLIC ACID, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BUTALBITAL-ASPIRIN-CAFFEINE, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, DURLAZA, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, YOSPRALA |
| Drospirenone/ACE Inhibitors; ARBs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. ACE inhibitors and angiotensin II receptor antagonists may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and ACE inhibitors or angiotensin II receptor antagonists may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with either an ACE inhibitor or an angiotensin II receptor antagonist should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of ACE inhibitors or angiotensin II receptor antagonists may also increase potassium levels.(1) In a study in 24 mildly hypertensive postmenopausal women who received concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean serum potassium levels were 0.22 mEq/L higher than in the placebo group. On day 14 of concurrent therapy, the ratios for serum potassium maximum concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010, respectively. No patient developed hyperkalemia.(1) |
ANGELIQ, BEYAZ, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, JASMIEL, LO-ZUMANDIMINE, LORYNA, NEXTSTELLIS, NIKKI, OCELLA, SAFYRAL, SLYND, SYEDA, VESTURA, YASMIN 28, YAZ, ZARAH, ZUMANDIMINE |
| Zoledronic Acid/Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of zoledronic acid and a diuretic may have adverse effects on the renal system.(1,2) CLINICAL EFFECTS: Concurrent use of zoledronic acid and a diuretic may result in renal dysfunction. Deterioration in renal function, acute renal failure requiring dialysis, and death have been reported.(1) PREDISPOSING FACTORS: The interaction may be more likely in elderly patients, patients who are taking other drugs that impact renal function, patients with pre-existing renal compromise, and patients who are dehydrated.(1) PATIENT MANAGEMENT: Patients should be adequately hydrated with 500 ml (2 glasses of water) before and after zoledronic acid administration.(1) Creatinine clearance should be monitored before and after therapy and zoledronic acid should not be administered in patients with a creatinine clearance less than 35 ml/min.(1,3) DISCUSSION: Zoledronic acid has been associated with renal dysfunction, including deterioration in renal function, acute renal failure requiring dialysis, and death. Risk factors include advanced age, concomitant nephrotoxic agents, and dehydration.(1) The FDA has received 16 reports of fatal acute renal failure and 9 reports of renal injury requiring dialysis following the administration of Reclast (zoledronic acid).(3) |
RECLAST, ZOLEDRONIC ACID |
| Topiramate/Hydrochlorothiazide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Hydrochlorothiazide may increase levels of topiramate. Also, both agents may decrease potassium levels.(1,2) CLINICAL EFFECTS: Concurrent use of hydrochlorothiazide may result in elevated levels of topiramate and hypokalemia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor serum potassium and topiramate in patients receiving concurrent therapy. The dosage of topiramate may need to be adjusted, an alternative diuretic or potassium supplement may be needed. DISCUSSION: In a study in 23 healthy subjects, concurrent hydrochlorothiazide (25 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of topiramate (96 mg BID) by 27% and 29%, respectively. During concurrent therapy, 61% of patients had a serum potassium level less than 3.5 mEq/L, compared with 27% with topiramate alone and 25% with hydrochlorothiazide alone. During concurrent therapy, the mean decrease in serum potassium levels was -0.60 mEq/L, compared with -0.25 mEq/L with topiramate alone and -0.12 mEq/L with hydrochlorothiazide alone.(1) |
EPRONTIA, PHENTERMINE-TOPIRAMATE ER, QSYMIA, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TOPIRAMATE ER SPRINKLE, TROKENDI XR |
| Selected MAOIs/Selected Antihypertensive Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2) CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension. DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine and sparsentan. |
NARDIL, PARNATE, PHENELZINE SULFATE, TRANYLCYPROMINE SULFATE |
| Desmopressin/Agents with Hyponatremia Risk SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3) CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3) PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics). PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1) DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4) |
DDAVP, DESMOPRESSIN ACETATE, NOCDURNA |
| Tizanidine/Selected ACE Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with ACE inhibitors may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4) |
TIZANIDINE HCL, ZANAFLEX |
| Selected ACE Inhibitors/Indomethacin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with an ACE inhibitor, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
INDOCIN, INDOMETHACIN, INDOMETHACIN ER |
| ACE Inhibitors/Acemetacin; Proglumetacin; Salsalate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with an ACE inhibitor, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
DISALCID, SALSALATE |
| ACE Inhibitors/Selected NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of ACE inhibitors with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ACE inhibitors with NSAIDs and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI. PATIENT MANAGEMENT: Patients maintained on ACE inhibitors should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of ACE inhibitors. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(30,31) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(32) Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, BISMUTH SUBSALICYLATE, BROMFENAC SODIUM, BUPIVACAINE-KETOROLAC-KETAMINE, CALDOLOR, CELEBREX, CELECOXIB, CHOLINE MAGNESIUM TRISALICYLAT, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DOLOBID, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, MB CAPS, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, OXAPROZIN, PHENYL SALICYLATE, PHENYLBUTAZONE, PIROXICAM, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RELAFEN DS, ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, SODIUM SALICYLATE, SPRIX, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TOXICOLOGY SALIVA COLLECTION, TRESNI, TREXIMET, URELLE, URETRON D-S, URIBEL TABS, URIMAR-T, URNEVA, URO-MP, URO-SP, VIMOVO, VIVLODEX, XIFYRM, ZIPSOR, ZORVOLEX, ZYNRELEF |
| Selected ACE Inhibitors/Potassium Sparing Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium. CLINICAL EFFECTS: Concurrent use of potassium sparing diuretics with an ACE inhibitor may result in hyperkalemia. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with a potassium sparing diuretic and an ACE inhibitors. In all patients taking eplerenone who start taking an ACE inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy. DISCUSSION: In a nested case-control study of heart failure patients receiving continuous ACE inhibitor/ARB therapy (n = 1,491,894), the risk of hyperkalemia was significantly associated with concomitant spironolactone use (odds ratio (OR) = 13.59; confidence interval (CI) = 11.63-15.88).(20) In a systemic literature review and meta-analysis of 20 randomized controlled studies, it was found that treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L).(21) A retrospective cohort study in patients with hypertension, diabetes, and albuminuria between 2008 and 2018 examined the efficacy and safety of mineralocorticoid receptor antagonists eplerenone and spironolactone in combination with ACEI/ARB compared to ACEI/ARB alone. Hyperkalemia was more frequent in combination therapy patients (n=1,282) versus monotherapy (n=5,484) (22.3 vs 10.9 per 100 person-years for combination and monotherapy, respectively; HR = 1.78, 95% CI: 1.42, 2.24).(22) Several studies have indicated that serum potassium levels increase when ACE inhibitors and ARB therapy is initiated and decrease when the drug is lowered. There are case reports of hyperkalemia during concurrent therapy with ARBs and spironolactone and with aliskiren and spironolactone. Based on this data, serum potassium levels should be monitored in patients receiving concomitant ACE inhibitors with potassium sparing diuretics. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril. |
ALDACTONE, AMILORIDE HCL, AMILORIDE-HYDROCHLOROTHIAZIDE, CAROSPIR, DYRENIUM, EPLERENONE, INSPRA, KERENDIA, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ, TRIAMTERENE, TRIAMTERENE-HYDROCHLOROTHIAZID |
| Selected ACE Inhibitors/Potassium Supplements SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: ACE inhibitors may decrease the renal excretion of potassium. CLINICAL EFFECTS: Concurrent use of potassium supplements with ACE inhibitors may result in hyperkalemia. PREDISPOSING FACTORS: Impaired renal function; diabetes mellitus. PATIENT MANAGEMENT: Monitor serum potassium and adjust the dosage accordingly in patients receiving concurrent therapy with potassium supplements and ACE inhibitors. DISCUSSION: Several studies have indicated that serum potassium levels increase when ACE inhibitors is initiated and decrease when the drug is lowered. Based on this data, serum potassium levels should be monitored in patients receiving potassium supplements with ACE inhibitors. Selected ACE inhibitors linked to this monograph include: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril. |
CLINIMIX E, DEXTROSE 5%-ELECTROLYTE #48, EFFER-K, K-PHOS NO.2, K-PHOS ORIGINAL, KABIVEN, KCL-D5W-0.2% NACL, KCL-D5W-0.225% NACL, KCL-D5W-0.45% NACL, KCL-D5W-0.9% NACL, KLOR-CON, KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, KLOR-CON-EF, NUTRILYTE, PERIKABIVEN, POKONZA, POTASSIUM ACETATE, POTASSIUM CHLORIDE, POTASSIUM CHLORIDE IN D5LR, POTASSIUM CHLORIDE-0.45% NACL, POTASSIUM CHLORIDE-0.9% NACL, POTASSIUM CHLORIDE-DEXTROSE 5%, POTASSIUM CHLORIDE-WATER, POTASSIUM CITRATE, POTASSIUM CITRATE ER, POTASSIUM CL-LIDOCAINE-NS, POTASSIUM GLUCONATE, POTASSIUM PHOSPHATE, POTASSIUM PHOSPHATE-0.9% NACL, POTASSIUM PHOSPHATES, TPN ELECTROLYTES, UROCIT-K |
| Apomorphine/Selected Antihypertensives and Vasodilators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1) PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1) |
APOKYN, APOMORPHINE HCL, ONAPGO |
| Allopurinol/Thiazide Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. Allopurinol has been documented to cause Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), and Drug reaction with eosinophilia and systemic symptoms (DRESS).(1) CLINICAL EFFECTS: Concurrent administration of allopurinol with thiazides may result in an increased incidence of rash which may be severe. PREDISPOSING FACTORS: Patients who are HLA-B*58:01 positive or have impaired renal function may be at increased risk. PATIENT MANAGEMENT: The manufacturer of allopurinol recommends monitoring renal function and reducing the dose of allopurinol in patients with concomitant thiazide diuretic use and impaired renal function. Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when used with thiazide diuretics. Instruct patients to seek medical attention for any peeling skin rash or blisters.(1) DISCUSSION: There are case reports of patients on concurrent thiazide diuretics and allopurinol developing SJS, TEN, or DRESS.(1,2) |
ALLOPURINOL, ALLOPURINOL SODIUM, ALOPRIM, DUZALLO, ZYLOPRIM |
The following contraindication information is available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
Drug contraindication overview.
Benazepril is contraindicated in patients with known hypersensitivity to benazepril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation; those with a history of angioedema with or without prior ACE inhibitor therapy; and in patients with diabetes mellitus who are receiving aliskiren therapy. Benazepril also is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril) and should not be administered within 36 hours of switching to or from sacubitril/valsartan.
Benazepril is contraindicated in patients with known hypersensitivity to benazepril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation; those with a history of angioedema with or without prior ACE inhibitor therapy; and in patients with diabetes mellitus who are receiving aliskiren therapy. Benazepril also is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril) and should not be administered within 36 hours of switching to or from sacubitril/valsartan.
There are 6 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Angioedema |
| Anuria |
| Head and neck angioedema |
| Hereditary angioedema |
| Intestinal angioedema |
| Pregnancy |
There are 18 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Bone marrow depression |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Dehydration |
| Gout |
| Hepatic failure |
| Hymenoptera venom desensitization therapy |
| Hyperkalemia |
| Hyperuricemia |
| Hypochloremic alkalosis |
| Hypokalemia |
| Hypomagnesemia |
| Hyponatremia |
| Hypotension |
| Hypovolemia |
| Neonatal hyperbilirubinemia |
| Neutropenic disorder |
| Renal artery stenosis |
There are 10 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Basal cell carcinoma of skin |
| Diabetes mellitus |
| Hemodialysis with high-flux membrane |
| Hypercalcemia |
| Hypercholesterolemia |
| Hyperparathyroidism |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Squamous cell carcinoma of skin |
| Sympathectomy |
| Systemic lupus erythematosus |
The following adverse reaction information is available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
Adverse reaction overview.
Adverse effects reported in at least 2% of patients receiving benazepril and at an incidence more than 1% greater than that with placebo include headache, dizziness, somnolence, and postural dizziness. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with hydrochlorothiazide and possibly or probably study drug-related include dizziness, fatigue, postural dizziness, headache, cough, hypertonia, vertigo, nausea, impotence, and somnolence. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with amlodipine and possibly or probably drug-related include cough, headache, dizziness, and edema.
Adverse effects reported in at least 2% of patients receiving benazepril and at an incidence more than 1% greater than that with placebo include headache, dizziness, somnolence, and postural dizziness. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with hydrochlorothiazide and possibly or probably study drug-related include dizziness, fatigue, postural dizziness, headache, cough, hypertonia, vertigo, nausea, impotence, and somnolence. Adverse effects reported in greater than 1% of patients receiving benazepril in fixed combination with amlodipine and possibly or probably drug-related include cough, headache, dizziness, and edema.
There are 52 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Hypochloremic alkalosis Hypokalemia Hyponatremia Hypotension |
Hyperglycemia Hyperkalemia Hypomagnesemia Hypotension Kidney disease with reduction in glomerular filtration rate (GFr) Nephrotoxicity |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute pancreatitis Acute renal failure Acute respiratory distress syndrome Agranulocytosis Anaphylaxis Angioedema Aplastic anemia Black tarry stools Cardiac arrhythmia Choroidal effusion Drug-induced hepatitis Erythema multiforme Exfoliative dermatitis Gout Head and neck angioedema Hemolytic anemia Hepatitis Hypercalcemia Hyperparathyroidism Hypersensitivity angiitis Hypersensitivity pneumonitis Hypertonia Hyperuricemia Interstitial nephritis Interstitial pneumonitis Intestinal angioedema Jaundice Laryngeal edema Leukopenia Myopia Neutropenic disorder Obstructive hyperbilirubinemia Pemphigus Purpura Secondary angle-closure glaucoma Squamous cell carcinoma of skin Stevens-johnson syndrome Systemic lupus erythematosus Thrombocytopenic disorder Toxic epidermal necrolysis Vasculitis |
There are 54 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Cough Headache disorder |
Abdominal pain with cramps Abnormal sexual function Anorexia Diarrhea Dizziness Drowsy Fatigue Nausea Orthostatic hypotension Skin rash Vomiting |
| Rare/Very Rare |
|---|
|
Alopecia Angina Arthralgia Arthritis Asthma Basal cell carcinoma of skin Blurred vision Bronchitis Constipation Dysgeusia Dyspnea Erectile dysfunction Fever Flushing Gastritis Gastrointestinal irritation General weakness Headache disorder Hypercholesterolemia Hyperhidrosis Hypertriglyceridemia Increased urinary frequency Infection Insomnia Libido changes Muscle spasm Myalgia Nervousness Paresthesia Pruritus of skin Sialoadenitis Sinusitis Skin photosensitivity Skin rash Symptoms of anxiety Urinary tract infection Urticaria Vertigo Vision impairment Vomiting Xanthopsia |
The following precautions are available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
If oliguria or hypotension occurs in neonates with a history of in utero exposure to benazepril, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.) Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means. There are occasional reports of benefit from these maneuvers with another ACE inhibitor; however, experience is limited.
Safety and efficacy of benazepril have not been established in children younger than 6 years of age and in pediatric patients with creatinine clearances of less than 30 mL/minute. Safety and efficacy of benazepril in fixed combination with amlodipine or hydrochlorothiazide have not been established in children. The long-term effects of benazepril on growth and development in children have not been studied.
Although the safety profile of benazepril in pediatric patients is similar to that in adults, because of the potential for adverse effects on kidney development, ACE inhibitors should not be administered to pediatric patients younger than 1 year of age. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Safety and efficacy of benazepril have not been established in children younger than 6 years of age and in pediatric patients with creatinine clearances of less than 30 mL/minute. Safety and efficacy of benazepril in fixed combination with amlodipine or hydrochlorothiazide have not been established in children. The long-term effects of benazepril on growth and development in children have not been studied.
Although the safety profile of benazepril in pediatric patients is similar to that in adults, because of the potential for adverse effects on kidney development, ACE inhibitors should not be administered to pediatric patients younger than 1 year of age. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Category D. (See Users Guide.) Benazepril can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Benazepril should be discontinued as soon as possible when pregnancy is detected. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Benazepril and benazeprilat are distributed into human milk in minimal amounts. Because of the unknown effects of benazepril or benazeprilat in nursing infants, a decision should be made whether to discontinue nursing or benazepril, taking into account the importance of the drug(s) to the woman.
No substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out. Because geriatric patients are more likely to have decreased renal function, dosage should be selected cautiously; it may be useful to monitor renal function in such patients.
The following prioritized warning is available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide):
WARNING: This drug can cause serious harm to an unborn baby (possibly fatal) if used during pregnancy. It is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control while taking this medication. If you are planning pregnancy, become pregnant, or think you may be pregnant, contact your doctor right away.
WARNING: This drug can cause serious harm to an unborn baby (possibly fatal) if used during pregnancy. It is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss the use of reliable forms of birth control while taking this medication. If you are planning pregnancy, become pregnant, or think you may be pregnant, contact your doctor right away.
The following icd codes are available for BENAZEPRIL-HYDROCHLOROTHIAZIDE (benazepril hcl/hydrochlorothiazide)'s list of indications:
| Hypertension | |
| I10 | Essential (primary) hypertension |
| I11 | Hypertensive heart disease |
| I11.0 | Hypertensive heart disease with heart failure |
| I11.9 | Hypertensive heart disease without heart failure |
| I12 | Hypertensive chronic kidney disease |
| I12.0 | Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal disease |
| I12.9 | Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13 | Hypertensive heart and chronic kidney disease |
| I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.1 | Hypertensive heart and chronic kidney disease without heart failure |
| I13.10 | Hypertensive heart and chronic kidney disease without heart failure, with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.11 | Hypertensive heart and chronic kidney disease without heart failure, with stage 5 chronic kidney disease, or end stage renal disease |
| I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
| I15.1 | Hypertension secondary to other renal disorders |
Formulary Reference Tool