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Drug Interactions between losartan and spironolactone

This report displays the potential drug interactions for the following 2 drugs:

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Major

spironolactone losartan

Applies to: spironolactone and losartan

MONITOR CLOSELY: Concomitant use of angiotensin II receptor blockers (ARBs) and potassium-sparing diuretics may increase the risk of hyperkalemia. Inhibition of angiotensin II results in decreased aldosterone secretion, which can lead to increases in serum potassium that may be additive with that induced by potassium-sparing diuretics. Life-threatening and fatal hyperkalemia can occur, especially when the combination is used in patients with risk factors such as renal impairment, diabetes, advanced age, severe or worsening heart failure, dehydration, and concomitant use of other agents that block the renin-angiotensin-aldosterone system or otherwise increase serum potassium levels. Individually, both ARBs and potassium-sparing diuretics have been associated with hyperkalemia in patients with renal impairment. ARBs may also cause deterioration of renal function in patients with chronic heart failure, and the risk is increased if they are sodium-depleted or dehydrated secondary to excessive diuresis. In a meta-analysis of 20 randomized controlled studies evaluating serum potassium changes in individuals taking ARBs and/or angiotensin converting enzyme inhibitors (ACEIs) with spironolactone (n=570) versus controls on ARBs and/or ACEIs alone (n=547), mean serum potassium concentration was shown to increase by 0.19 mEq/L with the addition of spironolactone. However, a total of 27 patients from eleven studies were withdrawn from participation due to the occurrence of an acute hyperkalemic event (defined as serum potassium >= 5.5 mEq/L), and their data did not contribute to these findings, which could have led to an under-estimation of the result. A retrospective analysis of evaluating the incidence of hyperkalemia in the CHARM study (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) found that the addition of candesartan to standard medical therapy for heart failure was associated with a 2- to 3-fold increase in risk of hyperkalemia, which was further amplified by cotreatment with spironolactone or ACE inhibitors. In a case series conducted over approximately 4 years, 44 patients with congestive heart failure who were receiving spironolactone (mean dosage = 88 mg, range 25-200 mg daily) plus an ACEI or ARB experienced life threatening hyperkalemia, with death occurring in 2 patients. Additionally, authors identified several possible conditions (e.g., advanced age, a daily spironolactone dose of >25 mg, reduced renal function and diabetes mellitus type 2) that may lead to the development of severe hyperkalemia in patients with heart failure who are taking spironolactone with an ACE or ARB.

MANAGEMENT: Caution and close monitoring are advised if angiotensin II receptor blockers (ARBs) and potassium-sparing diuretics are used concurrently due to the risk of potentially life-threatening hyperkalemia. Some authorities advise against combining certain ARBs with potassium-sparing diuretics unless the anticipated benefits substantially outweigh the potential risks. Particular caution is advised in older patients and those with certain disease states (e.g., renal impairment, diabetes, severe or worsening heart failure, dehydration) or when additional agents that increase serum potassium (e.g., potassium-containing salt substitutes, nonsteroidal anti-inflammatory drugs, beta-blockers, cyclosporine, heparin, tacrolimus, trimethoprim) are prescribed. For patients with heart failure, local guidelines should be consulted for specific therapy recommendations, as these may differ from general product labeling. For instance, the AHA/ACC/HFSA Guideline for the Management of Heart Failure advise that individuals with heart failure and reduced ejection fraction (HFrEF) should be treated with a combination of an ACEI or an ARB, along with a potassium-sparing diuretic (also known as a mineralocorticoid receptor antagonist or MRA), as part of a combination therapy regimen. If after careful consideration and/or consultation with local treatment guidelines both an ARB and a potassium-sparing diuretic are deemed necessary, serum potassium and renal function should be checked prior to initiating therapy and at frequent intervals thereafter, including after any dosage increases. In addition, if spironolactone is coadministered with an ARB, some investigators recommend that its dosage not exceed 25 mg/day in high-risk patients (e.g., advanced age, reduced renal function and type 2 diabetes). Patients and their caregivers should be given counseling on the appropriate levels of potassium and fluid intake, and advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Individual product labeling should be consulted for further guidance.

References

  1. Walmsley RN, White GH, Cain M, McCarthy PJ, Booth J (1984) "Hyperkalemia in the elderly." Clin Chem, 30, p. 1409-12
  2. McNay JL, Oran E (1970) "Possible predisposition of diabetic patients to hyperkalemia following administration of potassium-retaining diuretic, amiloride (MK 870)." Metabolism, 19, p. 58-70
  3. Lawson DH, O'Connor PC, Jick H (1982) "Drug attributed alterations in potassium handling in congestive cardiac failure." Eur J Clin Pharmacol, 23, p. 21-5
  4. (2001) "Product Information. Midamor (amiloride)." Merck & Co., Inc
  5. (2001) "Product Information. Cozaar (losartan)." Merck & Co., Inc
  6. (2001) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals
  7. (2001) "Product Information. Atacand (candesartan)." Astra-Zeneca Pharmaceuticals
  8. Obialo CI, Ofili EO, Mirza T (2002) "Hyperkalemia in congestive heart failure patients aged 63 to 85 years with subclinical renal disease." Am J Cardiol, 90, p. 663-5
  9. Bozkurt B, Agoston I, Knowlton AA (2003) "Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines." J Am Coll Cardiol, 41, p. 211-4
  10. Wrenger E, Muller R, Moesenthin M, Welte T, Frolich JC, Neumann KH (2003) "Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases." BMJ, 327, p. 147-9
  11. Jarman PR, Mather HM (2003) "Diabetes may be independent risk factor for hyperkalaemia." BMJ, 327, p. 812
  12. Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D (2003) "Hyperkalaemia and impaired renal function in patients taking spironolactone for congestive heart failure: retrospective study." BMJ, 327, p. 1141-2
  13. (2004) "Spironolactone + ace inhibitor or sartan: risk of hyperkalaemia." Prescrire Int, 13, p. 58
  14. McMurray JJ, O'Meara E (2004) "Treatment of heart failure with spironolactone--trial and tribulations." N Engl J Med, 351, p. 526-8
  15. Tamirisa KP, Aaronson KD, Koelling TM (2004) "Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure." Am Heart J, 148, p. 971-8
  16. Masoudi FA, Gross CP, Wang Y, et al. (2005) "Adoption of spironolactone therapy for older patients with heart failure and left ventricular systolic dysfunction in the United States, 1998-2001." Circulation, 112, p. 39-47
  17. Marcy TR, Ripley TL (2006) "Aldosterone antagonists in the treatment of heart failure." Am J Health Syst Pharm, 63, p. 49-58
  18. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  19. Desai AS, Swedberg K, McMurray JJ, et al. (2007) "Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program." J Am Coll Cardiol, 50, p. 1959-66
  20. Perazella MA (2000) "Drug-induced hyperkalemia: old culprits and new offenders." Am J Med, 109, p. 307-14
  21. Fujii H, Nakahama H, Yoshihara F, Nakamura S, Inenaga T, Kawano Y (2005) "Life-threatening hyperkalemia during a combined therapy with the angiotensin receptor blocker candesartan and spironolactone." Kobe J Med Sci, 51, p. 1-6
  22. Jarman PR, Kehely AM, Mather HM (1995) "Hyperkalaemia in diabetes: prevalence and associations." Postgrad Med J, 71, p. 551-2
  23. Perazella MA, Mahnensmith RL (1997) "Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis." J Gen Intern Med, 12, p. 646-56
  24. Large DM, Carr PH, Laing I, Davies M (1984) "Hyperkalaemia in diabetes mellitus--potential hazards of coexisting hyporeninaemic hypoaldosteronism." Postgrad Med J, 60, p. 370-3
  25. (2021) "Product Information. Irbesartan (irbesartan)." Alembic Pharmaceuticals
  26. (2022) "Product Information. Avapro (irbesartan)." Sanofi-Aventis Canada Inc
  27. (2021) "Product Information. Aprovel (irbesartan)." Sanofi
  28. (2021) "Product Information. Valsartan (valsartan)." Alembic Pharmaceuticals
  29. (2023) "Product Information. Auro-Valsartan (valsartan)." Auro Pharma Inc
  30. (2023) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals UK Ltd
  31. (2020) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals Pty Ltd
  32. (2023) "Product Information. Telmisartan (telmisartan)." Alembic Pharmaceuticals
  33. (2023) "Product Information. Ach-Telmisartan (telmisartan)." Accord Healthcare Inc
  34. (2023) "Product Information. Micardis (telmisartan)." Boehringer Ingelheim Ltd
  35. (2022) "Product Information. Micardis (telmisartan)." Boehringer Ingelheim Pty Ltd
  36. (2022) "Product Information. Olmesartan Medoxomil (olmesartan)." ASCEND LABORATORIES S.P.A.
  37. (2022) "Product Information. Olmesartan Medoxomil (olmesartan)." Thornton & Ross Ltd
  38. (2022) "Product Information. IXIA (olmesartán)." MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG, S.A.
  39. (2024) "Product Information. Losartan Potassium (losartan)." Strides Pharma Inc.
  40. (2023) "Product Information. Auro-Losartan (losartan)." Auro Pharma Inc
  41. (2022) "Product Information. Cozaar (losartan)." Organon Pharma (UK) Ltd
  42. (2022) "Product Information. Eprosartan (eprosartan)." Amarox Ltd
  43. (2021) "Product Information. Candesartan Cilexetil (candesartan)." Alembic Pharmaceuticals
  44. (2022) "Product Information. Amias (candesartan)." Neon Healthcare Ltd
  45. (2022) "Product Information. Edarbi (azilsartan)." Takeda UK Ltd
  46. (2023) "Product Information. Stivarga (regorafenib)." Bayer Plc
  47. (2022) "Product Information. Adesan (candesartan)." Viatris AB
  48. (2022) "Product Information. Cozaar (losartan)." Organon Pharmaceuticals
  49. (2022) "Product Information. Teveten (eprosartan)." VIATRIS
  50. Villa-Zapata L, Carhart BS, Horn JR, Hansten PD, Subbian V, Gephart S, et al. (2024) Serum potassium changes due to concomitant ACEI/ARB and spironolactone therapy: A systematic review and meta-analysis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194784/
  51. Wrenger E, Muller R, Moesenthin M, Welte T, Frolich JC, Neumann KH (2024) Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1126510/
  52. (2020) "Product Information. DIOVAN (valsartán)." NOVARTIS FARMA S.P.A.
  53. (2008) "Product Information. MICARDIS (telmisartán)." BOEHRINGER INGELHEIM ESPAÑA, S.A.
  54. (2022) "Product Information. IXIA (olmesartán)." MENARINI,S.A.
  55. (2022) "Product Information. COZAAR (losartán)." Organon Pharmaceuticals
  56. (2021) "Product Information. IRBESARTAN CINFA (irbesartán)." CINFA S.A.
  57. (2022) "Product Information. FUTURAN (eprosartán)." VIATRIS
  58. (2021) "Product Information. CANDESARTAN CINFA (candesartán)." CINFA S.A.
  59. heidenreich pa, Bozkurt B, aguilar d, Byun JJ, Colvin MM, deswal a, et al. (2024) 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the american college of cardiology/american heart association joint committee on clinical practice guidelines https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063
View all 59 references

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Drug and food interactions

Moderate

losartan food

Applies to: losartan

GENERALLY AVOID: Moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using angiotensin II receptor blockers (ARBs). ARBs can promote hyperkalemia through inhibition of angiotensin II-induced aldosterone secretion. Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

MANAGEMENT: Patients should receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician. If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended. Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

MONITOR: Grapefruit juice may modestly decrease and delay the conversion of losartan to its active metabolite, E3174. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The clinical significance is unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Patients who regularly consume grapefruits and grapefruit juice should be monitored for altered efficacy of losartan. Grapefruits and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact.

References

  1. (2001) "Product Information. Cozaar (losartan)." Merck & Co., Inc
  2. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, Golik A, Scapa E (2001) "Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers." Ther Drug Monit, 23, p. 369-73
  3. Ray K, Dorman S, Watson R (1999) "Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially life threatening interaction." J Hum Hypertens, 13, p. 717-20

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Moderate

spironolactone food

Applies to: spironolactone

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

References

  1. Sternbach H (1991) "Fluoxetine-associated potentiation of calcium-channel blockers." J Clin Psychopharmacol, 11, p. 390-1
  2. Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lamas GA (1984) "Ethanol intoxication complicating intravenous nitroglycerin therapy." Ann Intern Med, 101, p. 498-9
  3. Feder R (1991) "Bradycardia and syncope induced by fluoxetine." J Clin Psychiatry, 52, p. 139
  4. Ellison JM, Milofsky JE, Ely E (1990) "Fluoxetine-induced bradycardia and syncope in two patients." J Clin Psychiatry, 51, p. 385-6
  5. Rodriguez de la Torre B, Dreher J, Malevany I, et al. (2001) "Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients." Ther Drug Monit, 23, p. 435-40
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Pacher P, Kecskemeti V (2004) "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des, 10, p. 2463-75
  8. Andrews C, Pinner G (1998) "Postural hypotension induced by paroxetine." BMJ, 316, p. 595
View all 8 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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