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Drug Interactions between amlodipine / valsartan and sirolimus protein-bound

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

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Interactions between your drugs

Major

amLODIPine sirolimus protein-bound

Applies to: amlodipine / valsartan and sirolimus protein-bound

ADJUST DOSE: Coadministration of protein-bound sirolimus intravenous suspension with moderate or weak inhibitors of CYP450 3A4 may increase the systemic exposure to sirolimus, which is primarily metabolized by the isoenzyme and also a substrate of the P-glycoprotein (P-gp) efflux transporter. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. However, significant increases in systemic exposure have been reported for oral sirolimus coadministered with moderate dual inhibitors of CYP450 3A4 and P-gp such as diltiazem, erythromycin and verapamil, all of which are also substrates of CYP450 3A4 and P-gp. When 10 mg of sirolimus oral solution was administered with 120 mg of diltiazem in 18 healthy volunteers, sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.4- and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites, desacetyldiltiazem and desmethyldiltiazem. When sirolimus oral solution 2 mg once a day was coadministered with erythromycin ethylsuccinate 800 mg every 8 hours to steady state in 24 healthy volunteers, sirolimus Cmax and AUC increased by 4.4- and 4.2-fold, respectively, while erythromycin Cmax and AUC increased by 1.6- and 1.7-fold, respectively. Likewise, when sirolimus oral solution 2 mg once a day was coadministered with verapamil 180 mg every 12 hours to steady state in 25 healthy volunteers, sirolimus Cmax and AUC increased by 2.3- and 2.2-fold, respectively, while Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil both increased by 1.5-fold. Increased exposures to sirolimus may increase the risk of adverse effects such stomatitis, nausea, diarrhea, vomiting, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, edema, rash, alopecia, and hemorrhage.

MANAGEMENT: When administered concomitantly with moderate or weak CYP450 3A4 inhibitors, the manufacturer recommends reducing the dosage of protein-bound sirolimus intravenous suspension to 56 mg/m2. Clinical response and toxicities should be closely monitored, and the dosage of protein-bound sirolimus further adjusted as necessary. In addition, patients may also require monitoring for potentially increased effects of concomitant CYP450 3A4 inhibitors, as many are also substrates of CYP450 3A4 and/or P-gp and may be impacted by sirolimus. The prescribing information for concomitant medications should be consulted.

References

  1. (2001) "Product Information. Rapamune (sirolimus)." Wyeth-Ayerst Laboratories
  2. Claesson K, Brattstrom C, Burke JT (2001) "Sirolimus and erythromycin interaction: two cases." Transplant Proc, 33, p. 2136
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Cerner Multum, Inc. "Australian Product Information."
  5. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.
View all 5 references

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Drug and food interactions

Moderate

valsartan food

Applies to: amlodipine / valsartan

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.

References

  1. (2001) "Product Information. Cozaar (losartan)." Merck & Co., Inc
  2. (2001) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals

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Moderate

sirolimus protein-bound food

Applies to: sirolimus protein-bound

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with grapefruit juice may increase the systemic exposure to sirolimus. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of sirolimus by certain compounds present in grapefruit. However, grapefruit juice primarily inhibits CYP450 3A4-mediated first-pass metabolism in the gut wall and may have limited effects on medications that are not administered orally. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

MANAGEMENT: The manufacturer recommends avoiding grapefruit and grapefruit juice during treatment with protein-bound sirolimus.

References

  1. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.

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Moderate

amLODIPine food

Applies to: amlodipine / valsartan

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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Moderate

amLODIPine food

Applies to: amlodipine / valsartan

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

References

  1. Henry M, Kay MM, Viccellio P (1985) "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med, 3, p. 334-6
  2. Moller IW (1987) "Cardiac arrest following intravenous verapamil combined with halothane anaesthesia." Br J Anaesth, 59, p. 522-6
  3. Oszko MA, Klutman NE (1987) "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm, 6, p. 448-9
  4. Schoen MD, Parker RB, Hoon TJ, et al. (1991) "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol, 67, p. 300-4
  5. O'Quinn SV, Wohns DH, Clarke S, Koch G, Patterson JH, Adams KF (1990) "Influence of calcium on the hemodynamic and anti-ischemic effects of nifedipine observed during treadmill exercise testing." Pharmacotherapy, 10, p. 247
  6. Woie L, Storstein L (1981) "Successful treatment of suicidal verapamil poisoning with calcium gluconate." Eur Heart J, 2, p. 239-42
  7. Morris DL, Goldschlager N (1983) "Calcium infusion for reversal of adverse effects of intravenous verapamil." JAMA, 249, p. 3212-3
  8. Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E (1987) "Treatment of severe left ventricular dysfunction with calcium chloride in patients receiving verapamil." J Clin Pharmacol, 27, p. 407-9
  9. Luscher TF, Noll G, Sturmer T, Huser B, Wenk M (1994) "Calcium gluconate in severe verapamil intoxication." N Engl J Med, 330, p. 718-20
  10. Bar-Or D, Gasiel Y (1981) "Calcium and calciferol antagonise effect of verapamil in atrial fibrillation." Br Med J (Clin Res Ed), 282, p. 1585-6
  11. Lipman J, Jardine I, Roos C, Dreosti L (1982) "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med, 8, p. 55-7
  12. McMillan R (1988) "Management of acute severe verapamil intoxication." J Emerg Med, 6, p. 193-6
  13. Perkins CM (1978) "Serious verapamil poisoning: treatment with intravenous calcium gluconate." Br Med J, 2, p. 1127
  14. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M (1980) "Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning." Clin Toxicol, 17, p. 395-400
View all 14 references

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Minor

amLODIPine food

Applies to: amlodipine / valsartan

The consumption of grapefruit juice may slightly increase plasma concentrations of amlodipine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Data have been conflicting and the clinical significance is unknown. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

References

  1. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  2. Josefsson M, Zackrisson AL, Ahlner J (1996) "Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers." Eur J Clin Pharmacol, 51, p. 189-93
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL (2000) "Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine." Br J Clin Pharmacol, 50, p. 455-63
  5. Josefsson M, Ahlner J (2002) "Amlodipine and grapefruit juice." Br J Clin Pharmacol, 53, 405; discussion 406
  6. Kane GC, Lipsky JJ (2000) "Drug-grapefruit juice interactions." Mayo Clin Proc, 75, p. 933-42
View all 6 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.

See also

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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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