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Feb.17.2021

Sacubitril; Valsartan

Indications/Dosage

Labeled

  • heart failure
  • reduction of cardiovascular mortality
  • reduction of heart failure hospitalizations

General dosing:

  • Allow a 36 hour washout period if switching from an ACE inhibitor to sacubitril; valsartan.
  • Use of an oral suspension prepared in a concentration of 4 mg/mL (sacubitril 1.96 mg; valsartan 2.04 mg/mL) is recommended in pediatric patients weighing less than 40 kg; recommended mg/kg doses are of the combined amount of both sacubitril and valsartan.
  • The oral suspension can also be substituted at the recommended tablet dosage in patients unable to swallow tablets.[59904]

Off-Label

    † Off-label indication

    For the treatment of heart failure

    for the reduction of cardiovascular mortality and reduction of heart failure hospitalizations in adults with chronic heart failure

    Oral dosage

    Adults

    In patients previously not taking or taking a low-dose of an ACE inhibitor or ARB, start at 24 mg sacubitril; 26 mg valsartan PO twice daily. In patients taking a high-dose of an ACE inhibitor or ARB, start at 49 mg sacubitril; 51 mg valsartan PO twice daily. Double the dose every 2 to 4 weeks as tolerated to the target maintenance dose of 97 mg sacubitril; 103 mg valsartan PO twice daily. LVEF is a variable measure; use clinical judgement when considering therapy initiation.[59904] Guidelines recommend an angiotensin receptor-neprilysin inhibitor (ARNI) and ARB in combination with an evidence-based beta blocker plus or minus an aldosterone antagonist in patients with chronic reduced ejection fraction heart failure (HFrEF) NYHA class II or III to reduce morbidity and mortality. In patients with chronic symptomatic HFrEF class II or III who tolerate an ACE inhibitor or ARB, replacement by ARNI therapy is recommended.[62661]

    for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients

    Oral dosage

    Children and Adolescents weighing 50 kg or more

    In patients previously not taking or taking a low dose of an ACE inhibitor or ARB, start at 24 mg sacubitril; 26 mg valsartan PO twice daily. In patients previously taking a high dose of an ACE inhibitor or ARB, start at 49 mg sacubitril; 51 mg valsartan PO twice daily. Titrate every 2 weeks as tolerated, first to 49 mg sacubitril; 51 mg valsartan PO twice daily in patients on 24 mg sacubitril; 26 mg valsartan PO twice daily, then to 72 mg sacubitril; 78 mg valsartan PO twice daily in all patients, and then to 97 mg sacubitril; 103 mg valsartan PO twice daily.[59904]

    Children and Adolescents weighing 40 to 49 kg

    In patients previously not taking or taking a low dose of an ACE inhibitor or ARB, start at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily. In patients on a high dose of an ACE inhibitor or ARB, start at 24 mg sacubitril; 26 mg valsartan. Titrate every 2 weeks as tolerated, first to 24 mg sacubitril; 26 mg valsartan PO twice daily in patients starting with 0.8 mg/kg twice daily, next to 49 mg sacubitril; 51 mg valsartan PO twice daily in all patients, and then to 72 sacubitril; 78 mg valsartan PO twice daily.[59904]

    Children and Adolescents weighing less than 40 kg

    In patients previously not taking or taking a low dose of an ACE inhibitor or ARB, start at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily. In patients taking a high-dose of an ACE inhibitor or ARB, start at 1.6 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily. Titrate every 2 weeks as tolerated, first to 1.6 mg/kg/dose PO twice daily in patients starting at 0.8 mg/kg twice daily, next to 2.3 mg/kg/dose PO twice daily in all patients, and then to 3.1 mg/kg/dose PO twice daily.[59904]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

      Sacubitril 97 mg; valsartan 103 mg PO twice daily.

    • Geriatric

      Sacubitril 97 mg; valsartan 103 mg PO twice daily.

    • Adolescents

      Weighing 50 kg or more: Sacubitril 97 mg; valsartan 103 mg PO twice daily.

      Weighing 40 to 49 kg: Sacubitril 72 mg; valsartan 78 mg PO twice daily.

      Weighing less than 40 kg: 3.1 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.

    • Children

      Weighing 50 kg or more: Sacubitril 97 mg; valsartan 103 mg PO twice daily.

      Weighing 40 to 49 kg: Sacubitril 72 mg; valsartan 78 mg PO twice daily.

      Weighing less than 40 kg: 3.1 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.

    • Infants

      Safety and efficacy have not been established.

    • Neonates

      Safety and efficacy have not been established.

    Patients with Hepatic Impairment Dosing

    Mild hepatic impairment: No dosage adjustment needed.

    Moderate hepatic impairment (Child-Pugh Class B): Initiate at half the usual recommended dose; thereafter, follow the recommended dose escalation. In pediatric patients weighing 40 to 49 kg, initiate at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.

    Severe hepatic impairment: Use not recommended.[59904]

    Patients with Renal Impairment Dosing

    eGFR 30 mL/minute/1.73 m2 or more: No dosage adjustment needed.

    eGFR less than 30 mL/minute/1.73 m2: Initiate at half the usual recommended dose; thereafter, follow the recommended dose escalation. In pediatric patients weighing 40 to 49 kg, initiate at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.[59904]

     

    Hemodialysis

    Sacubitril; valsartan is unlikely to be removed by hemodialysis due to high protein binding.[59904]

    † Off-label indication
    Revision Date: 02/17/2021, 01:00:56 PM

    References

    59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.62661 - Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2017;136:e137-e161.

    How Supplied

    Sacubitril, Valsartan Oral tablet

    ENTRESTO 24mg-26mg Tablet (00078-0659) (Novartis Pharmaceuticals Corporation) nullENTRESTO 24mg-26mg Tablet package photo

    Sacubitril, Valsartan Oral tablet

    ENTRESTO 49mg-51mg Tablet (00078-0777) (Novartis Pharmaceuticals Corporation) null

    Sacubitril, Valsartan Oral tablet

    ENTRESTO 97mg-103mg Tablet (00078-0696) (Novartis Pharmaceuticals Corporation) null

    Description/Classification

    Description

    Sacubitril; valsartan is a combination product containing sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Sacubitril; valsartan is indicated in adults to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. The benefits of sacubitril; valsartan therapy in adult patients with chronic heart failure are most evident in those patients with left ventricular ejection fraction (LVEF) below normal. In the PARADIGM-HF trial, sacubitril; valsartan was superior to enalapril in reducing the rate of cardiovascular death and hospitalizations related to heart failure in adults with symptomatic chronic heart failure (NYHA class II to IV) and systolic dysfunction (LVEF of 40% or less). Most patients were also receiving standard heart failure treatments including beta-blockers, diuretics, and mineralocorticoid antagonists.[59939] In the PARAGON-HF trials, the rate of the primary composite outcome (first and recurrent heart failure hospitalizations and cardiovascular death) was lower in the sacubitril; valsartan group at 12.8 events per 100 patient years compared to the valsartan group at 14.6 events per 100 patient years (RR = 0.87 (0.75, 1.01), p = 0.06). The PARAGON-HF trial enrolled adult patients with symptomatic heart failure with LVEF of 45% or higher and structural heart disease (either left atrial enlargement or left ventricular hypertrophy). Most patients were also receiving a beta-blockers and diuretics.[66422] In an analysis of both the PARADIGM-HF and PARAGON-HF studies, greater risk reductions were observed with patients with LVEF below normal treated with sacubitril; valsartan.[59904] In pediatric patients 1 year and older, sacubitril; valsartan is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction. Results from PANORAMA-HF trial showed a reduction from baseline in NT-proBNP of 44% in sacubitril; valsartan-treated patients compared to 33% in enalapril-treated patients. While not statistically significant, the reductions were similar or larger than what were seen in adult patients. This effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in the pediatric populations, as similar outcomes were seen in the PARADIGM-HF study. Sacubitril; valsartan is contraindicated with concomitant use of an ACE inhibitor; allow a 36-hour washout period between administration of the 2 drugs. The most common adverse effects reported include hypotension, hyperkalemia, cough, dizziness, and renal failure.[59904]

    Classifications

    • Cardiovascular System
      • Antihypertensives
        • Agents Acting On The Renin-Angiotensin System (RAS)
          • Angiotensin-II Receptor Blockers/ARBs Plain and in Combination
            • Angiotensin-II Receptor Blocker/ARBs and Neprilysin Inhibitor Combinations
    Revision Date: 02/19/2021, 04:37:53 PM

    References

    59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.59939 - McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.66422 - Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381:1609-1620.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Route-Specific Administration

    Oral Administration

    • Administer twice daily with or without food.[59904]

    Extemporaneous Compounding-Oral

    Preparation of 4 mg/mL (sacubitril 1.96 mg; valsartan 2.04 mg/mL) oral suspension

    • Transfer 8 sacubitril 49 mg; valsartan 51 mg tablets into a mortar and crush into a fine powder using a pestle.
    • Add 60 mL of Ora-Plus into the mortar and gently triturate with a pestle for 10 minutes to form a uniform suspension.
    • Add 140 mL of Ora-Sweet SF into the mortar and triturate with a pestle for another 10 minutes to form a uniform suspension.
    • Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle.
    • Shake well before each use.
    • Storage: Store up to 15 days. Do not store above 77 degrees F (25 degrees C) and do not refrigerate.[59904]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 10/03/2019, 11:04:54 AM

      References

      59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.

      Adverse Reactions

      Severe

      • anaphylactoid reactions
      • angioedema
      • azotemia
      • hyperkalemia
      • laryngeal edema
      • oliguria
      • renal failure (unspecified)
      • rhabdomyolysis
      • teratogenesis

      Moderate

      • hypotension
      • orthostatic hypotension

      Mild

      • cough
      • dizziness
      • pruritus
      • rash

      Angioedema has been reported with the use of sacubitril; valsartan. During clinical trials, angioedema was reported in 0.5% of patients treated with sacubitril; valsartan compared to 0.2% of those treated with enalapril. The incidence of angioedema was higher in Black patients at 2.4% with sacubitril; valsartan compared to 0.5% with enalapril. If angioedema occurs, immediately discontinue sacubitril; valsartan therapy, provide appropriate therapy, and monitor for airway compromise. Do not readminister sacubitril; valsartan to patients who have experienced angioedema with its use. In cases where swelling was confined to the face and lips, the condition generally resolved without treatment; however, antihistamines have been used for symptom relief. Laryngeal edema may be fatal. If there is involvement of the tongue, glottis, or larynx, administer appropriate therapy (e.g., epinephrine) to ensure airway patency. During the postmarketing surveillance of sacubitril; valsartan, rash, pruritus, and anaphylactoid reactions have been reported.[59904]

      Drugs which affect the renin-angiotensin system have been associated with fetal and neonatal abnormalities when administered to pregnant women. Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, oligohydramnios, and death. Oligohydramnios has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Due to the potential for teratogenesis, every effort should be made to discontinue sacubitril; valsartan and consider alternative therapy during pregnancy.[59904]

      Hypotension has been reported with the use of sacubitril; valsartan. During controlled clinical trials, hypotension was reported in 18% of patients treated with sacubitril; valsartan and in 12% of those receiving enalapril. Hypotension was reported as serious in 1.5% of patients in both treatment arms. Orthostatic hypotension was reported in 2.1% of patients receiving sacubitril; valsartan and 1.1% of patients in the enalaparil group. Falls were reported in 1.9% of those receiving sacubitril; valsartan compared to 1.3% of those receiving enalapril. Dizziness was reported in 6% of patients in the sacubitril; valsartan group and 5% in the enalapril group. Volume and salt depletion should be corrected prior to initiating therapy. If hypotension is anticipated, initiating therapy at a lower dose may be necessary. If hypotension occurs during therapy, ensure hypovolemia has not occurred and consider dose adjustments of diuretics and other concomitant antihypertensive drugs. If hypotension persists despite such measures, reduce the dosage or temporarily discontinue sacubitril; valsartan; permanent discontinuation of therapy is usually not required.[59904]

      Decrease in renal function has been reported with the use of sacubitril; valsartan. During the PARADIGM-HF clinical trial, renal failure (unspecified) was reported in 5% of patients in both the sacubitril; valsartan and enalapril groups. Increases in serum creatinine of more than 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the sacubitril; valsartan run-in period. During the double-blind period, increases in serum creatinine of more than 50% were reported in approximately 16% of both treatment groups. In the PARAGON-HF trial, increases in serum creatinine of more than 50% were reported in approximately 17% of sacubitril; valsartan patients and 21% of valsartan patients. Oliguria, progressive azotemia, and, rarely, acute renal failure and death have been associated in patients receiving angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). If a clinically significant decrease in renal function develops, closely monitor serum creatinine and decrease the dose or interrupt sacubitril; valsartan therapy. In addition, serum creatinine and blood urea concentrations may increase in patients with bilateral or unilateral renal artery stenosis.[59904]

      Hyperkalemia was reported in 12% of patients treated with sacubitril; valsartan and 14% of patients treated with enalapril during controlled trials. Potassium concentrations more than 5.5 mEq/L were reported in approximately 4% of patients in both the enalapril and sacubitril; valsartan run-in periods. During the double-blind period in the PARADIGM-HF trial, approximately 16% of both treatment groups reported potassium concentrations more than 5.5 mEq/L. During the double-blind period in the PARAGON-HF trial, approximately 18% of sacubitril; valsartan patients and 20% of valsartan patients reported potassium concentrations more than 5.5 mEq/L. Monitor serum potassium periodically and treat appropriately. Dosage reduction or interruption of therapy may be required.[59904]

      During controlled clinical trials, cough was reported in 9% of patients receiving sacubitril; valsartan compared to 13% of those in the enalapril group.[59904]

      Rhabdomyolysis has been reported with the postmarketing use of sacubitril; valsartan. During clinical trials, evidence of possible muscle harm was noted.[63529]

      Revision Date: 02/17/2021, 08:11:23 PM

      References

      59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.63529 - Institute for Safe Medication Practices (ISMP). Acute Care ISMP Medication Safety Alert 2018;23:1-2.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • ACE-inhibitor induced angioedema
      • angioedema
      • Black patients
      • breast-feeding
      • diabetes mellitus
      • hepatic disease
      • hereditary angioedema
      • hyperkalemia
      • hypotension
      • hypovolemia
      • pregnancy
      • renal artery stenosis
      • renal failure
      • renal impairment

      Sacubitril; valsartan is contraindicated in patients with hypersensitivity to any component of the product.[59904]

      Sacubitril; valsartan is contraindicated in patients with a history of ACE-inhibitor induced angioedema and in those with angiotensin II receptor blocker (ARB) therapy induced angioedema. Sacubitril; valsartan should not be used in patients with hereditary angioedema. Angioedema was reported during clinical trials of sacubitril; valsartan. Black patients and patients with a prior history of angioedema may be at increased risk of angioedema with sacubitril; valsartan.[59904]

      Use sacubitril; valsartan with caution in patients with hypovolemia and in patients who exhibit signs of hypotension. Sacubitril; valsartan lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system including patients who are volume or salt depleted (e.g., those treated with diuretics) are at an increased risk of developing hypotension. Correct volume or salt depletion prior to initiating of therapy or start sacubitril; valsartan at a lower dose.[59904]

      Sacubitril; valsartan may decrease renal function in patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). Treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and reduce the dose or interrupt sacubitril; valsartan in patients who develop a clinically significant decrease in renal function. Similar to other drugs that affect the renin-angiotensin-aldosterone system, sacubitril; valsartan may increase blood urea and serum creatinine concentrations in patients with bilateral or unilateral renal artery stenosis. Monitor renal function in patients with renal artery stenosis.[59904]

      Sacubitril; valsartan therapy may result in hyperkalemia and should be used cautiously in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or a high potassium diet. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia. Dosage reduction or interruption of sacubitril; valsartan therapy may be required.[59904]

      Administration of sacubitril; valsartan is not recommended in patients with severe hepatic disease (Child-Pugh class C), as no studies have been conducted in these patients. Dose adjustments are recommended in patients with moderate hepatic disease (Child-Pugh class B); no dose adjustment is required when administering sacubitril; valsartan to patients with mild hepatic impairment (Child-Pugh class A).[59904]

      When pregnancy is detected, discontinue sacubitril; valsartan as soon as possible. Once pregnancy is detected, every effort should be made to discontinue sacubitril; valsartan and consider alternative therapy. Women of child-bearing age should be made aware of the potential risk of fetal harm when amlodipine; valsartan is taken during pregnancy. When used during the second and third trimesters of pregnancy, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) can cause reduced fetal renal function and increased fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death. Retrospective data indicate that first-trimester use of ACE inhibitors has been associated with a potential risk of birth defects.[32294] [59904] However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated.[46406] An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa.[64367] Once pregnancy is detected, ultrasound examination should be performed if amlodipine; valsartan exposure occurs beyond the first trimester. In rare cases, when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios occurs, discontinue amlodipine; valsartan unless it is life-saving to the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained an irreversible injury. Closely observe newborns with histories of in utero exposure to sacubitril; valsartan for hypotension, oliguria, and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. The effect of sacubitril; valsartan on labor and delivery has not been evaluated.[59904]

      Breast-feeding is not recommended during treatment with sacubitril; valsartan. There are no data on the presence of sacubitril or valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. The ACE inhibitors captopril, enalapril, benazepril, and quinapril are excreted in human breast milk in very small quantities; therefore, a clinically significant risk to a breast-feeding infant is not expected unless high doses are required.[27500] [29147] [46352] [46354] [63903] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[59904]

      Revision Date: 02/17/2021, 03:44:59 PM

      References

      27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.29147 - Lotensin (benazepril) package insert. Parsippany, NJ: Validus Pharmaceuticals LLC; 2019 Jan.32294 - Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.46352 - Begg EJ, Robson RA, Gardiner SJ et al. Quinapril and its metabolite quinaprilat in human milk. Br J Clin Pharmacol 2001;51:478-81.46354 - National Institutes of Health (NIH). Quinapril monograph. LactMed: Drug and Lactation Database. Available at http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~nugSBG:1. Accessed October 24, 2011.46406 - Li D, Yang C, Andrade S, et al. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011;343:d5931.59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.63903 - American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin No. 203: Chronic Hypertension in Pregnancy. Obstet Gynecol 2019;133:e23-e50.64367 - Hoeltzenbein M, Tissen-Diabate T, Fietz AK, et al. Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study. Clin Res Cardiol 2018;107:679-687.

      Mechanism of Action

      Sacubitril is a neprilysin inhibitor, and valsartan antagonizes angiotensin II at the AT1 receptor subtype. Neprilysin degrades endogenous vasoactive peptides, including natriuretic peptide, bradykinin, and adrenomedullin. Inhibition of neprilysin results in increases concentrations of these proteins and their activities, resulting in vasodilation, natriuresis, diuresis, and inhibition of pathologic growth and fibrosis. Inhibition of neprilysin occurs via the active metabolite of sacubitril, LBQ657. Angiotensin II is a potent vasoconstrictor and also stimulates the production and release of aldosterone.[59939][59940] The cardiovascular and renal effects of sacubitril; valsartan in patients with heart failure are due to increased concentrations of peptides that are degraded by neprilysin and the simultaneous inhibition of angiotensin II and angiotensin II-dependent aldosterone release by valsartan.[59904]

      Revision Date: 07/14/2015, 01:22:37 PM

      References

      59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.59939 - McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.59940 - McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail 2015;17:242-247.

      Pharmacokinetics

      Sacubitril; valsartan is administered orally. Sacubitril and valsartan are highly bound to plasma proteins (more than 94%). Sacubitril is converted to its active metabolite, LBQ657, by plasma esterases and not further metabolized. Valsartan is minimally metabolized; approximately 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified at low concentrations (less than 10%) in plasma. LBQ657 crosses the blood brain barrier to a minimal extent (0.28%). The average volume of distribution of sacubitril and valsartan are 103 and 75 L, respectively. After oral administration, 52% to 68% of sacubitril (primarily as metabolite) and approximately 13% of valsartan and its metabolites are excreted in urine. The remaining drug and metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan exhibit a mean elimination half-life of approximately 1.4, 11.5, and 9.9 hours, respectively.[59904]

       

      In a 21-day study of patients with heart failure and reduced ejection fraction, sacubitril; valsartan administration resulted in significantly increased urine atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) and plasma cGMP, and decreased plasma N-terminal pro b-type natriuretic peptide (NT-proBNP), aldosterone, and endothelin-1. Sacubitril; valsartan blocked the AT1-receptor resulting in increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril; valsartan decreased NT-proBNP, increased BNP, and increased urine cGMP compared to enalapril. In the PARAMOUNT study that enrolled patients with heart failure with left ventricular ejection fraction (LVEF) of 45% or higher, sacubitril; valsartan (97 mg; 103 mg twice daily) decreased NT-proBNP by 17% compared to an 8% decrease with valsartan (160 mg twice daily) after 12 weeks of therapy. In the PARAGON-HF study, NT-proBNP was decreased by 24% at week 16 and 19% at week 48 in the sacubitril; valsartan group compared to 6% and 3%, respectively, in the valsartan group.[59904]

       

      Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, OATP1B1, OATP1B3, MRP2

      Valsartan does not inhibit CYP450 isoenzymes at clinically relevant concentrations. In vitro studies indicate CYP2C9 is the isoenzyme responsible for the formation of valeryl-4-hydroxy valsartan. An in vitro study with human liver tissue indicates that it is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.[29130][62719] In vitro data also indicate that sacubitril inhibits OATP1B1 and OSTP1B3 transporters.[59904]

      Route-Specific Pharmacokinetics

      Oral Route

      After oral administration, the peak plasma concentrations of sacubitril, its metabolite, and valsartan are reached in 0.5, 2, and 1.5 hours, respectively. Oral absolute bioavailability of sacubitril is estimated to be 60% or more. Valsartan when combined in the sacubitril; valsartan combination product is more bioavailable than valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril; valsartan is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed formulations. Steady state concentrations of sacubitril, its metabolite, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate; however, the metabolite of sacubitril accumulates by 1.6-fold. Food has no clinically significant effect on the systemic exposure of sacubitril; valsartan.[59904]

      Special Populations

      Pediatrics

      Pharmacokinetic data indicated that exposure to sacubitril; valsartan is similar in pediatric and adult patients.[59904]

      Revision Date: 02/19/2021, 04:34:31 PM

      References

      29130 - Diovan (valsartan) tablets package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021 Apr.59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.62719 - Valsartan oral solution package insert. New Brunswick, NJ; Lifsa Drugs LLC. 2022 Apr.

      Pregnancy/Breast-feeding

      pregnancy

      When pregnancy is detected, discontinue sacubitril; valsartan as soon as possible. Once pregnancy is detected, every effort should be made to discontinue sacubitril; valsartan and consider alternative therapy. Women of child-bearing age should be made aware of the potential risk of fetal harm when amlodipine; valsartan is taken during pregnancy. When used during the second and third trimesters of pregnancy, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) can cause reduced fetal renal function and increased fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death. Retrospective data indicate that first-trimester use of ACE inhibitors has been associated with a potential risk of birth defects.[32294] [59904] However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated.[46406] An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa.[64367] Once pregnancy is detected, ultrasound examination should be performed if amlodipine; valsartan exposure occurs beyond the first trimester. In rare cases, when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios occurs, discontinue amlodipine; valsartan unless it is life-saving to the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained an irreversible injury. Closely observe newborns with histories of in utero exposure to sacubitril; valsartan for hypotension, oliguria, and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. The effect of sacubitril; valsartan on labor and delivery has not been evaluated.[59904]

      breast-feeding

      Breast-feeding is not recommended during treatment with sacubitril; valsartan. There are no data on the presence of sacubitril or valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. The ACE inhibitors captopril, enalapril, benazepril, and quinapril are excreted in human breast milk in very small quantities; therefore, a clinically significant risk to a breast-feeding infant is not expected unless high doses are required.[27500] [29147] [46352] [46354] [63903] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.[59904]

      Revision Date: 10/03/2019, 02:12:35 PM

      References

      27500 - American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.29147 - Lotensin (benazepril) package insert. Parsippany, NJ: Validus Pharmaceuticals LLC; 2019 Jan.32294 - Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.46352 - Begg EJ, Robson RA, Gardiner SJ et al. Quinapril and its metabolite quinaprilat in human milk. Br J Clin Pharmacol 2001;51:478-81.46354 - National Institutes of Health (NIH). Quinapril monograph. LactMed: Drug and Lactation Database. Available at http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~nugSBG:1. Accessed October 24, 2011.46406 - Li D, Yang C, Andrade S, et al. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011;343:d5931.59904 - Entresto (sacubitril; valsartan) package insert. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; 2019 Oct.63903 - American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin No. 203: Chronic Hypertension in Pregnancy. Obstet Gynecol 2019;133:e23-e50.64367 - Hoeltzenbein M, Tissen-Diabate T, Fietz AK, et al. Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study. Clin Res Cardiol 2018;107:679-687.

      Interactions

      Level 1 (Severe)

      • Amlodipine; Benazepril
      • Angiotensin-converting enzyme inhibitors
      • Benazepril
      • Benazepril; Hydrochlorothiazide, HCTZ
      • Captopril
      • Captopril; Hydrochlorothiazide, HCTZ
      • Enalapril, Enalaprilat
      • Enalapril; Felodipine
      • Enalapril; Hydrochlorothiazide, HCTZ
      • Fosinopril
      • Fosinopril; Hydrochlorothiazide, HCTZ
      • Hydrochlorothiazide, HCTZ; Moexipril
      • Lisinopril
      • Lisinopril; Hydrochlorothiazide, HCTZ
      • Moexipril
      • Perindopril
      • Perindopril; Amlodipine
      • Quinapril
      • Quinapril; Hydrochlorothiazide, HCTZ
      • Ramipril
      • Trandolapril
      • Trandolapril; Verapamil
      • Tranylcypromine

      Level 2 (Major)

      • Aliskiren
      • Aliskiren; Amlodipine
      • Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ
      • Aliskiren; Hydrochlorothiazide, HCTZ
      • Aliskiren; Valsartan
      • Amifostine
      • Amiloride
      • Amiloride; Hydrochlorothiazide, HCTZ
      • Cocaine
      • Eplerenone
      • Ibritumomab Tiuxetan
      • Nesiritide, BNP
      • Oxymetazoline
      • Potassium Phosphate
      • Potassium Phosphate; Sodium Phosphate
      • Triamterene
      • Triamterene; Hydrochlorothiazide, HCTZ

      Level 3 (Moderate)

      • Acarbose
      • Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine
      • Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine
      • Acetaminophen; Chlorpheniramine; Phenylephrine
      • Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine
      • Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine
      • Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine
      • Acetaminophen; Dextromethorphan; Phenylephrine
      • Acetaminophen; Dextromethorphan; Pseudoephedrine
      • Acetaminophen; Dichloralphenazone; Isometheptene
      • Acetaminophen; Guaifenesin; Phenylephrine
      • Acetaminophen; Pseudoephedrine
      • Acrivastine; Pseudoephedrine
      • Aldesleukin, IL-2
      • Alemtuzumab
      • Alogliptin; Metformin
      • Alpha-glucosidase Inhibitors
      • Amobarbital
      • Amyl Nitrite
      • Angiotensin II
      • Apomorphine
      • Articaine; Epinephrine
      • Asenapine
      • Atazanavir
      • Atazanavir; Cobicistat
      • Baclofen
      • Brexpiprazole
      • Brompheniramine; Carbetapentane; Phenylephrine
      • Brompheniramine; Dextromethorphan; Phenylephrine
      • Brompheniramine; Hydrocodone; Pseudoephedrine
      • Brompheniramine; Phenylephrine
      • Brompheniramine; Pseudoephedrine
      • Brompheniramine; Pseudoephedrine; Dextromethorphan
      • Bupivacaine; Epinephrine
      • Cabergoline
      • Calcium Phosphate, Supersaturated
      • Canagliflozin; Metformin
      • Carbetapentane; Chlorpheniramine; Phenylephrine
      • Carbetapentane; Diphenhydramine; Phenylephrine
      • Carbetapentane; Guaifenesin; Phenylephrine
      • Carbetapentane; Phenylephrine
      • Carbetapentane; Phenylephrine; Pyrilamine
      • Carbetapentane; Pseudoephedrine
      • Carbidopa; Levodopa
      • Carbidopa; Levodopa; Entacapone
      • Carbinoxamine; Dextromethorphan; Pseudoephedrine
      • Carbinoxamine; Hydrocodone; Phenylephrine
      • Carbinoxamine; Hydrocodone; Pseudoephedrine
      • Carbinoxamine; Phenylephrine
      • Carbinoxamine; Pseudoephedrine
      • Cariprazine
      • Cetirizine; Pseudoephedrine
      • Chlophedianol; Dexchlorpheniramine; Pseudoephedrine
      • Chlophedianol; Guaifenesin; Phenylephrine
      • Chloroprocaine
      • Chlorpheniramine; Dextromethorphan; Phenylephrine
      • Chlorpheniramine; Dextromethorphan; Pseudoephedrine
      • Chlorpheniramine; Dihydrocodeine; Phenylephrine
      • Chlorpheniramine; Dihydrocodeine; Pseudoephedrine
      • Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine
      • Chlorpheniramine; Hydrocodone; Phenylephrine
      • Chlorpheniramine; Hydrocodone; Pseudoephedrine
      • Chlorpheniramine; Ibuprofen; Pseudoephedrine
      • Chlorpheniramine; Phenylephrine
      • Chlorpheniramine; Pseudoephedrine
      • Clofarabine
      • Clozapine
      • Co-Enzyme Q10, Ubiquinone
      • Codeine; Guaifenesin; Pseudoephedrine
      • Codeine; Phenylephrine; Promethazine
      • Cyclosporine
      • Daclatasvir
      • Dapagliflozin; Metformin
      • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
      • Desloratadine; Pseudoephedrine
      • Dexbrompheniramine; Pseudoephedrine
      • Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine
      • Dextromethorphan; Diphenhydramine; Phenylephrine
      • Dextromethorphan; Guaifenesin; Phenylephrine
      • Dextromethorphan; Guaifenesin; Pseudoephedrine
      • Dextromethorphan; Quinidine
      • Diazoxide
      • Diethylpropion
      • Digoxin
      • Dihydrocodeine; Guaifenesin; Pseudoephedrine
      • Diphenhydramine; Hydrocodone; Phenylephrine
      • Diphenhydramine; Phenylephrine
      • Drospirenone
      • Drospirenone; Estetrol
      • Drospirenone; Estradiol
      • Drospirenone; Ethinyl Estradiol
      • Drospirenone; Ethinyl Estradiol; Levomefolate
      • Duloxetine
      • Elexacaftor; tezacaftor; ivacaftor
      • Eltrombopag
      • Elvitegravir
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
      • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
      • Empagliflozin; Linagliptin; Metformin
      • Empagliflozin; Metformin
      • Enflurane
      • Ephedrine
      • Ephedrine; Guaifenesin
      • Epinephrine
      • Epoprostenol
      • Ertugliflozin; Metformin
      • Etomidate
      • Fexofenadine; Pseudoephedrine
      • Finerenone
      • Fish Oil, Omega-3 Fatty Acids (Dietary Supplements)
      • Fospropofol
      • General anesthetics
      • Glipizide; Metformin
      • Glyburide; Metformin
      • Guaifenesin; Hydrocodone; Pseudoephedrine
      • Guaifenesin; Phenylephrine
      • Guaifenesin; Pseudoephedrine
      • Haloperidol
      • Halothane
      • Hydralazine; Isosorbide Dinitrate, ISDN
      • Hydrocodone; Phenylephrine
      • Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine
      • Hydrocodone; Pseudoephedrine
      • Ibuprofen; Pseudoephedrine
      • Iloperidone
      • Iloprost
      • Incretin Mimetics
      • Indapamide
      • Insulins
      • Intravenous Lipid Emulsions
      • Isocarboxazid
      • Isoflurane
      • Isoproterenol
      • Isosorbide Dinitrate, ISDN
      • Isosorbide Mononitrate
      • Ketamine
      • Levodopa
      • Lidocaine; Epinephrine
      • Linagliptin; Metformin
      • Lithium
      • Loop diuretics
      • Lopinavir; Ritonavir
      • Loratadine; Pseudoephedrine
      • Lovastatin; Niacin
      • Lurasidone
      • Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate
      • Meglitinides
      • Metformin
      • Metformin; Repaglinide
      • Metformin; Rosiglitazone
      • Metformin; Saxagliptin
      • Metformin; Sitagliptin
      • Methohexital
      • Methylphenidate Derivatives
      • Miglitol
      • Milrinone
      • Naproxen; Pseudoephedrine
      • Nateglinide
      • Niacin, Niacinamide
      • Niacin; Simvastatin
      • Nitrates
      • Nitroglycerin
      • Nitroprusside
      • Nonsteroidal antiinflammatory drugs
      • Obeticholic Acid
      • Olanzapine
      • Olanzapine; Fluoxetine
      • Olanzapine; Samidorphan
      • Ombitasvir; Paritaprevir; Ritonavir
      • Oritavancin
      • Paliperidone
      • Pentoxifylline
      • Phenelzine
      • Phenylephrine
      • Pioglitazone; Metformin
      • Polyethylene Glycol; Electrolytes
      • Polyethylene Glycol; Electrolytes; Ascorbic Acid
      • Potassium
      • Pramlintide
      • Prazosin
      • Prilocaine; Epinephrine
      • Procainamide
      • Procaine
      • Promethazine; Phenylephrine
      • Propofol
      • Pseudoephedrine
      • Pseudoephedrine; Triprolidine
      • Quinidine
      • Rasagiline
      • Repaglinide
      • Risperidone
      • Sevoflurane
      • SGLT2 Inhibitors
      • Silodosin
      • Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous
      • Sodium picosulfate; Magnesium oxide; Anhydrous citric acid
      • Sofosbuvir; Velpatasvir; Voxilaprevir
      • Spironolactone
      • Spironolactone; Hydrochlorothiazide, HCTZ
      • Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole
      • Sulfonylureas
      • Tetracaine
      • Thiazolidinediones
      • Thiopental
      • Thiothixene
      • Tizanidine
      • Tolvaptan
      • Trimethoprim
      • Yohimbine

      Level 4 (Minor)

      • Alprostadil
      • Amphetamine; Dextroamphetamine Salts
      • Apraclonidine
      • Aprepitant, Fosaprepitant
      • Aripiprazole
      • Benzphetamine
      • Cobicistat
      • Darunavir; Cobicistat
      • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
      • Estradiol
      • Estradiol Cypionate; Medroxyprogesterone
      • Fenofibric Acid
      • Gemfibrozil
      • Heparin
      • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
      • Isoniazid, INH; Rifampin
      • Lisdexamfetamine
      • Mestranol; Norethindrone
      • Methamphetamine
      • Nefazodone
      • Nirmatrelvir; Ritonavir
      • Rifampin
      • Ritonavir
      • Simeprevir
      • Telithromycin
      • Trazodone
      • Zafirlukast
      • Ziprasidone
      Acarbose: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended. [31048] Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Aldesleukin, IL-2: (Moderate) Angiotensin II receptor antagonists may potentiate the hypotension seen with aldesleukin, IL 2. [41853] Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents. [27942] Aliskiren: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. [29130] [29132] [32198] [33200] [60860] [63923] Aliskiren; Amlodipine: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. [29130] [29132] [32198] [33200] [60860] [63923] Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. [29130] [29132] [32198] [33200] [60860] [63923] Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. [29130] [29132] [32198] [33200] [60860] [63923] Aliskiren; Valsartan: (Major) Aliskiren-containing products are contraindicated in combination with angiotensin II receptor antagonists (ARBs) in patients with diabetes mellitus. In general, avoid combined use of two renin-angiotensin-aldosterone system (RAAS) inhibitors, particularly in patients with CrCl less than 60 mL/minute. Combination therapy increases the risk for hyperkalemia, renal impairment, hypotension, and other side effects. Most patients receiving a comination of two RAAS inhibitors, such as ARBs and aliskiren, do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes if aliskiren must be combined with another RAAS inhibitor. In the ALTITUDE trial, patients with type 2 diabetes and renal impairment, a population at high risk for cardiovascular and renal events, were given aliskiren in addition to ACE inhibitors or ARBs. The trial was stopped early because aliskiren was associated with an increased risk of non-fatal stroke, renal complications, hyperkalemia, and hypotension. In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, no additional benefit over monotherapy was seen in patients receiving the combination of losartan and lisinopril compared to monotherapy; however, there was an increased incidence of hyperkalemia and acute renal injury. [29130] [29132] [32198] [33200] [60860] [63923] Alogliptin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Alpha-glucosidase Inhibitors: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as angiotensin II receptor antagonists (angiotensin receptor blockers, or ARBs), may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil. [30847] [30849] [55990] Amifostine: (Major) Patients receiving angiotensin II receptor antagonists should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine. [49124] Amiloride: (Major) Potassium-sparing diuretics, such as amiloride, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [29135] [43532] [60860] Amiloride; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as amiloride, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [29135] [43532] [60860] Amlodipine; Benazepril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration. [6532] Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. [29332] [53320] [60070] Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Angiotensin II: (Moderate) Angiotensin II receptor antagonists (angiotensin receptor blockers, or ARBs) may decrease the response to angiotensin II. Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. ARBs block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin receptor in many tissues. [62722] Angiotensin-converting enzyme inhibitors: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] (Major) Most patients receiving the combination of two renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs) do not obtain any additional benefit compared to monotherapy. Combination therapy has been associated with an increased risk of diarrhea, hypotension, syncope, hyperkalemia, and renal dysfunction resulting in dialysis, doubling of serum creatinine, and death in clinical studies. The risk of hyperkalemia is particularly high in patients with renal impairment (stage 3a or higher kidney disease). In general, avoid combined use of these drugs together. Patients who must receive concomitant therapy with ACE inhibitors and ARBs should be closely monitored for renal dysfunction, hypotension, and hyperkalemia. Closely monitor blood pressure, renal function, and electrolytes. [27991] [28608] [29147] [34997] [34998] [63923] Apomorphine: (Moderate) Use of angiotensin II receptor antagonists and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination. [28661] Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically. [6224] Aprepitant, Fosaprepitant: (Minor) Use caution if valsartan and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of valsartan. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Valsartan is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. [29130] [30676] [34686] [40027] Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. [31327] Articaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. [56575] Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known. [36343] Atazanavir: (Moderate) Concurrent use of atazanavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. [56579] [61511] [61512] Atazanavir; Cobicistat: (Moderate) Concurrent use of atazanavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. [56579] [61511] [61512] (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required. [30582] [57272] Benazepril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Benazepril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Benzphetamine: (Minor) Benzphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. [28456] [28477] Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. [59949] Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Brompheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. [56575] Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including angiotensin II receptor antagonists. Cabergoline has been associated with hypotension. Initial doses of cabergoline higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure. [27964] Calcium Phosphate, Supersaturated: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin II receptor antagonists, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous. [32159] [32160] Canagliflozin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Captopril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Captopril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbetapentane; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbetapentane; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. [28521] Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. [28521] Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Carbinoxamine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Carbinoxamine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs. [60164] Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. [28996] Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Chlorpheniramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and valsartan, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving valsartan. [29130] [54578] Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug. [28262] Cobicistat: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation. [6289] Codeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Codeine; Phenylephrine; Promethazine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. [34900] Cyclosporine: (Moderate) Coadministration of cyclosporine and an angiotensin II receptor antagonist, like valsartan, may increase the risk of hyperkalemia and reduced renal function. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. Also, cyclosporine can cause hyperkalemia, and inhibition of angiotensin II leads to reduced aldosterone concentrations, which can increase the serum potassium concentration. Closely monitor renal function and serum potassium concentrations in patients receiving cyclosporine concurrently with valsartan. Additionally, valsartan is a substrate of the hepatic uptake transporter OATP1B1 and cyclosporine is an inhibitor of OATP. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan. [28404] [29130] [29323] [29324] [39870] Daclatasvir: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects. [29130] [34686] [60001] Dapagliflozin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Darunavir; Cobicistat: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. [29130] [34686] [58664] [60002] (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Dexbrompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension. [28249] Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving beta-blockers, hydralazine, methyldopa, minoxidil, nitrites, prazosin, reserpine, or other antihypertensive agents. [29537] Diethylpropion: (Moderate) Diethylpropion has vasopressor effects and may limit the benefit of angiotensin II receptor antagonists. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications. [29114] Digoxin: (Moderate) Caution should be exercised when administering digoxin with drugs that may cause a significant deterioration in renal function including angiotensin II receptor antagonists. A decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Close monitoring of serum digoxin concentrations is essential to avoid enhanced toxicity. [28272] Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Diphenhydramine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function. [31698] [40219] [41929] [42068] [42851] Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function. [31698] [40219] [41929] [42068] [42851] Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function. [31698] [40219] [41929] [42068] [42851] Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function. [31698] [40219] [41929] [42068] [42851] Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium. The concurrent use of angiotensin II receptor antagonists (ARBs) may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if ARBs are used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function. [31698] [40219] [41929] [42068] [42851] Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary. [29934] Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for valsartan-related adverse reactions (i.e., hypotension) during coadministration of elexacaftor; tezacaftor; ivacaftor as concurrent use may increase exposure of valsartan. Valsartan is a substrate for the transporters OATP1B1 and OATP1B3; elexacaftor; tezacaftor; ivacaftor may inhibit uptake of OATP1B1 and OATP1B3. [56579] [64697] Eltrombopag: (Moderate) Use caution and monitor blood pressure closely if eltrombopag and valsartan are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as valsartan, may exhibit an increase in systemic exposure if coadministered with eltrombopag. [40392] Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with valsartan as there is a potential for decreased valsartan concentrations. Valsartan is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer. [29130] [35588] [51664] [58001] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when elvitegravir is administered with valsartan as there is a potential for decreased valsartan concentrations. Valsartan is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer. [29130] [35588] [51664] [58001] (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when elvitegravir is administered with valsartan as there is a potential for decreased valsartan concentrations. Valsartan is a substrate of CYP2C9; elvitegravir is a CYP2C9 inducer. [29130] [35588] [51664] [58001] (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP. [29130] [35588] [51664] [58000] [60860] Empagliflozin; Linagliptin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Empagliflozin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Enalapril, Enalaprilat: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Enalapril; Felodipine: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Enalapril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Ephedrine: (Moderate) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved. [26181] [29548] Ephedrine; Guaifenesin: (Moderate) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved. [26181] [29548] Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. [56575] Eplerenone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. [27990] Epoprostenol: (Moderate) Angiotensin II receptor antagonists can enhance the hypotensive effects of antihypertensive agents if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. [4892] Ertugliflozin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. [805] Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness. [805] Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid. [34686] [49952] Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Finerenone: (Moderate) Monitor serum potassium concentrations closely if finerenone and angiotensin II receptor antagonists are used together. Concomitant use may increase the risk of hyperkalemia. [28608] [29134] [60860] [66793] Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. [30536] [30537] [30538] [30539] [30540] Fosinopril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Fosinopril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Gemfibrozil: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan. [29130] [39870] General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Glipizide; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Glyburide; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Guaifenesin; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension. [5036] Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Heparin: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium. [29130] Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Hydrochlorothiazide, HCTZ; Moexipril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Hydrocodone; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Hydrocodone; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Ibritumomab Tiuxetan: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations. [49592] Ibuprofen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known. [36146] Iloprost: (Moderate) Angiotensin II receptor antagonists can enhance the hypotensive effects of antihypertensive agents if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. [7537] Incretin Mimetics: (Moderate) Angiotensin II receptor antagonists may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving these drugs concomitantly should be monitored for changes in glycemic control. [33489] [42591] Indapamide: (Moderate) The effects of indapamide may be additive when administered with other antihypertensive agents or diuretics. In some patients, this may be desirable, but orthostatic hypotension may occur. Angiotensin II receptor antagonists tend to reverse the potassium loss, but not the serum uric acid rise associated with thiazide diuretic monotherapy. [7737] Insulins: (Moderate) Monitor patients receiving angiotensin II receptor antagonists concomitantly with insulin for changes in glycemic control. Angiotensin II receptor antagonists may enhance the hypoglycemic effects of insulin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. [33489] [42591] [60172] Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. [30536] [30537] [30538] [30539] [30540] Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when isocarboxazid is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during concurrent therapy of isocarboxazid with angiotensin II receptor antagonists. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of isocarboxazid and an angiotensin II receptor antagonist. [27957] [29656] Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Coadministration may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and rifampin is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan. [29130] [39870] [60860] Isoniazid, INH; Rifampin: (Minor) Coadministration may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and rifampin is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan. [29130] [39870] [60860] Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents. [28004] Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. [28521] Lidocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. [56575] Linagliptin; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Lisdexamfetamine: (Minor) Lisdexamfetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. [33263] Lisinopril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Lisinopril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Lithium: (Moderate) Angiotensin II receptor antagonists (Angiotensin Receptor Blockers, or ARBs) should be used very cautiously, if at all, in patients already receiving lithium. The risk of lithium toxicity may be increased in patients receiving ARBs. ARBs decrease lithium clearance, possibly as a result of sodium depletion which leads to increased renal tubular reabsorption of lithium. Start with lower doses of lithium or reduce dosage, while frequently monitoring serum lithium concentrations and for signs/symptoms of lithium toxicity. [27991] [28654] [47399] Loop diuretics: (Moderate) Coadministration of furosemide and Angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists may result in severe hypotension and deterioration in renal function, including renal failure. Hyponatremia or hypovolemia predisposes patients to acute hypotensive episodes following initiation of ACE inhibitor therapy. While ACE inhibitors and loop diuretics are routinely administered together in the treatment of heart failure, if an ACE inhibitor is to be administered to a patient receiving furosemide, initial doses should be conservative. [28429] [48546] Lopinavir; Ritonavir: (Moderate) Concurrent use of lopinavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); lopinavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. [56579] [61510] [61511] [61513] (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. [44027] Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known. [42227] Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists. [41573] Meglitinides: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained. [805] Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Metformin; Repaglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Metformin; Rosiglitazone: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Metformin; Saxagliptin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Metformin; Sitagliptin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Methamphetamine: (Minor) Methamphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. [33363] Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension. [28277] Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents such as angiotensin II receptor antagonists. [28518] [66501] Miglitol: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response. [30865] Moexipril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Naproxen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Nateglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Nefazodone: (Minor) Although relatively infrequent, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with antihypertensive agents. Blood pressure monitoring is recommended. Dependent upon clinical response, dosage adjustments of either drug may be necessary. [5414] Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents. [29061] Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. [44027] Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. [44027] Nirmatrelvir; Ritonavir: (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary. [29386] [29551] Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure. [49213] Nonsteroidal antiinflammatory drugs: (Moderate) Nonsteroidal antiinflammatory drugs (NSAIDs) (including selective COX-2 inhibitors) may alter the response to Angiotensin II receptor blockers due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less. In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function who are being treated with NSAIDs, coadministration of angiotensin II receptor antagonists may result in further deterioration of renal function, including acute renal failure. These effects are usually reversible. [24233] [27388] [27991] [28608] [29130] [60860] Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to valsartan. Valsartan is a substrate of OATP1B1 and obeticholic acid inhibits OAT1B1 in vitro. Caution and close monitoring is advised if these drugs are used together. [29130] [60840] Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. [5517] Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. [5517] Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. [5517] Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. [29130] [34686] [58664] [60002] (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Oritavancin: (Moderate) Valsartan is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated valsartan plasma concentrations. If these drugs are administered concurrently, blood pressure should be monitored closely. [29130] [34686] [57741] Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. If these drugs are used together, closely monitor for changes in blood pressure. [26181] [61733] Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin II receptor antagonists who are susceptible to hypotension. [32936] [40936] Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced. [6316] Perindopril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Perindopril; Amlodipine: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Phenelzine: (Moderate) Additive hypotensive effects may be seen when phenelzine is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during concurrent therapy of phenelzine with angiotensin II receptor antagonists. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of phenelzine and angiotensin II receptor antagonists. [27957] [29656] Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Pioglitazone; Metformin: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of metformin by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. ARBs may rarely reduce renal function, a risk factor for reduced renal clearance of metformin. Patients receiving these drugs together should be monitored for changes in renal function and glycemic control. [28550] [33489] [42591] Polyethylene Glycol; Electrolytes: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists. [41573] Polyethylene Glycol; Electrolytes; Ascorbic Acid: (Moderate) Use caution when prescribing sulfate salt bowel preparation in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists. [41573] Potassium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations. [49592] Potassium Phosphate; Sodium Phosphate: (Major) Avoid coadministration of potassium phosphate and angiotensin II receptor antagonists as concurrent use may increase the risk of severe and potentially fatal hyperkalemia, particularly in high-risk patients (renal impairment, cardiac disease, adrenal insufficiency). If concomitant use is necessary, closely monitor serum potassium concentrations. [49592] Potassium: (Moderate) Monitor serum potassium concentrations closely if potassium supplements and angiotensin II receptor antagonists are used together. Concomitant use may increase the risk of hyperkalemia. [28608] [29130] [30272] [57713] Pramlintide: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of pramlintide by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with pramlintide should be monitored for changes in glycemic control. [33489] [42591] Prazosin: (Moderate) razosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. [6065] Prilocaine; Epinephrine: (Moderate) Antihypertensives, including angiotensin II receptor antagonists, antagonize the vasopressor effects of parenteral epinephrine. [56575] Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects. [4977] Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. [28996] [29080] Promethazine; Phenylephrine: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. [24172] [26181] [27369] Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Monitor heart rate and blood pressure. [26181] [29548] Quinapril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Quinapril; Hydrochlorothiazide, HCTZ: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension. [28249] Ramipril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Rasagiline: (Moderate) Additive hypotensive effects may be seen when rasagiline is combined with angiotensin II receptor antagonists. Careful monitoring of blood pressure is suggested during coadministration. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider. [27957] [29656] Repaglinide: (Moderate) Angiotensin II receptor antagonists (ARB) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Rifampin: (Minor) Coadministration may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and rifampin is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan. [29130] [39870] [60860] Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of angiotensin II receptor antagonists. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving angiotensin II receptor antagonists concomitantly. [28414] Ritonavir: (Minor) Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration. [28315] [29130] [36646] [39870] [60860] Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. [28325] SGLT2 Inhibitors: (Moderate) Patients receiving these drugs concomitantly should be monitored for changes in blood pressure, volume status, renal function, serum potassium and other electrolytes, and for glycemic control. When an SGLT2 inhibitor is initiated, mild diuresis and naturesis occurs, producing intravascular volume contraction. These effects may be additive to certain antihypertensive medications, such as the angiotensin II receptor antagonists (also known as angiotensin receptor blockers or ARBs). Patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2), low systolic blood pressure, or who are elderly may also be at a greater risk. Volume status should be assessed and corrected. In addition, some SGLT2 inhibitors, like canagliflozin, can increase serum potassium. Monitor serum potassium levels periodically and monitor for hyperkalemia. ARBs may also enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. [29403] [30585] [33489] [42591] [53972] [56603] [57718] [62718] Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents. [34483] Simeprevir: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness. [29130] [56471] Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) Concomitant use of medicines with potential to alter renal perfusion or function such as angiotensin II receptor antagonists, may increase the risk of acute phosphate nephropathy in patients taking sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous. [32159] [32160] Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that may affect renal function such as angiotensin II receptor antagonists. In addition, use caution in patients receiving drugs where hypokalemia is a particular risk. [51258] Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of valsartan, an Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3) substrate, may be increased when administered concurrently with voxilaprevir, an OATP1B1/1B3. Monitor patients for changes in blood pressure and increased side effects if these drugs are administered concurrently. [56579] [62131] Spironolactone: (Moderate) Monitor serum potassium concentrations closely if angiotensin II receptor antagonists and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [28608] [29016] [29134] [60860] Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if angiotensin II receptor antagonists and spironolactone are used together. Concomitant use may increase the risk of hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [28608] [29016] [29134] [60860] Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors. [43890] [55864] [67024] [67025] Sulfonylureas: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Telithromycin: (Minor) Valsartan is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1. Coadministration of valsartan with inhibitors of OATP, such as telithromycin may theoretically result in increased concentrations of valsartan. [28156] [29130] [39870] Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents. [28996] [29080] Thiazolidinediones: (Moderate) Angiotensin II receptor antagonists (ARBs) may enhance the hypoglycemic effects of antidiabetic agents by improving insulin sensitivity. In addition, angiotensin II receptor antagonists have been associated with a reduced incidence in the development of new-onset diabetes in patients with hypertension or other cardiac disease. Patients receiving an ARB in combination with antidiabetic agents should be monitored for changes in glycemic control. [33489] [42591] Thiopental: (Moderate) Concurrent use of thiopental and alpha-blockers or antihypertensive agents increases the risk of developing hypotension. [30143] Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible. [5732] [5750] [5888] [7932] [7933] [7934] Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy. [30150] Tolvaptan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. [35780] Trandolapril: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Trandolapril; Verapamil: (Contraindicated) Sacubitril; valsartan is contraindicated with the concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors) due to the increased risk of angioedema. Do not administer sacubitril; valsartan within 36 hours of switching to or from an ACE inhibitor. [59904] Tranylcypromine: (Contraindicated) The use of hypotensive agents and tranylcypromine is contraindicated by the manufacturer of tranylcypromine because the effects of hypotensive agents may be markedly potentiated. [29656] Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone. [28719] Triamterene: (Major) Potassium-sparing diuretics, such as triamterene, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [28608] [29160] [43532] [60860] Triamterene; Hydrochlorothiazide, HCTZ: (Major) Potassium-sparing diuretics, such as triamterene, should be used with caution in patients taking drugs that may increase serum potassium levels such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. [28608] [29160] [43532] [60860] Trimethoprim: (Moderate) Monitor for hyperkalemia if concomitant use of an angiotensin II receptor antagonist and trimethoprim is necessary. Avoid concomitant use and consider alternative antibiotic therapy in patients with additional risk factors for hyperkalemia, including patients older than 65 years, those with underlying disorders of potassium metabolism, renal insufficiency, or those requiring high doses of trimethoprim. Amongst patients older than 65 years, concomitant use has been associated with a 2- to 7-fold increased risk of significant hyperkalemia compared to other antibiotics. Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially in those with pre-existing risk factors. [43890] [55864] [67024] [67025] Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled blood pressure. [28863] [29542] Zafirlukast: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan. [28001] [28222] Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents. [28233]
      Revision Date: 05/18/2022, 02:29:00 AM

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      Monitoring Parameters

      • blood pressure
      • serum creatinine/BUN
      • serum potassium

      US Drug Names

      • Entresto
      ;