Skip to main content

Drug Interactions between aliskiren / valsartan and cyclosporine

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

Edit list (add/remove drugs)

Interactions between your drugs

Major

cycloSPORINE aliskiren

Applies to: cyclosporine and aliskiren / valsartan

GENERALLY AVOID: Coadministration with cyclosporine may significantly increase the plasma concentrations of aliskiren. The proposed mechanism is cyclosporine inhibition of the intestinal efflux of aliskiren via P-glycoprotein. According to the product labeling, coadministration of 200 mg and 600 mg cyclosporine, a highly potent P-glycoprotein inhibitor, with 75 mg aliskiren resulted in an approximately 2.5-fold increase in aliskiren peak plasma concentration (Cmax) and a 5-fold increase in systemic exposure (AUC).

MANAGEMENT: Concomitant use of aliskiren with cyclosporine is not recommended.

References (1)
  1. (2007) "Product Information. Tekturna (aliskiren)." Novartis Pharmaceuticals
Major

valsartan aliskiren

Applies to: aliskiren / valsartan and aliskiren / valsartan

CONTRAINDICATED: In patients with type 2 diabetes and renal impairment, coadministration of aliskiren with ACE inhibitors or angiotensin receptor blockers (ARBs) has been associated with an increased risk of adverse events including renal complications, hyperkalemia, and hypotension. Interim review of data from the ALTITUDE study after 18 to 24 months revealed no additional benefit and a higher incidence of adverse events when aliskiren 300 mg daily, as opposed to placebo, was added to optimal cardiovascular treatment including an ACE inhibitor or ARB. Another preliminary finding was a slight excess of death or stroke in the aliskiren group; however, the relationship to aliskiren treatment has not been established. ALTITUDE was a multinational study in 8,606 patients from 36 countries evaluating the potential benefits of aliskiren to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes and renal impairment, who are known to be at high risk of cardiovascular and renal events. The trial was halted in December 2011 per recommendation of the independent data monitoring committee overseeing the study.

GENERALLY AVOID: In patients without diabetes, coadministration of aliskiren with ACE inhibitors or ARBs may also be associated with increased risk of symptomatic hypotension, hyperkalemia, and changes in renal function including acute renal failure. All drugs inhibiting the renin-angiotensin system (RAS) can have these effects, which may be additive during concomitant administration. The risk of symptomatic hypotension is increased in the presence of marked volume and/or salt depletion. Elevations in serum potassium levels to greater than 5.5 mEq/L were infrequent with aliskiren alone (0.9% compared to 0.6% with placebo), but increased to 5.5% when used in combination with an ACE inhibitor in a diabetic population. Patients whose renal function may depend in part on the activity of the RAS, including those with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion, may be at particular risk for developing acute renal failure with these drugs.

MANAGEMENT: The use of aliskiren with ACE inhibitors or ARBs is considered contraindicated in patients with diabetes and should be avoided in general, particularly in patients with moderate to severe renal impairment (i.e., creatinine clearance (CrCl) < 60 mL/min). Prescribers should not initiate aliskiren in diabetic patients who are taking an ACE inhibitor or an ARB, and should stop any aliskiren-containing treatment if these patients are already receiving the combination. Alternative antihypertensive treatment should be considered as necessary. Most patients do not obtain any additional benefit from combination therapy relative to monotherapy; therefore, the potential risks should be thoroughly assessed when aliskiren is prescribed with ACE inhibitors or ARBs for the treatment of essential hypertension in patients without diabetes. Volume or salt depletion should be corrected prior to initiation of treatment. Routine monitoring of blood pressure, electrolytes, and renal function are recommended, particularly in the elderly or patients with worsening heart failure or a risk for dehydration. Potassium supplementation should generally be avoided unless it is closely monitored, and patients should be advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as weakness, listlessness, confusion, tingling of the extremities, and irregular heartbeat.

References (6)
  1. (2007) "Product Information. Tekturna (aliskiren)." Novartis Pharmaceuticals
  2. Novartis International AG (2012) Novartis announces termination of ALTITUDE study with Rasilez Tekturna in high-risk patients with diabetes and renal impairment. http://cardiobrief.files.wordpress.com/2011/12/novartis-aliskiren-altitude-pr.pdf
  3. Chief Scientific Officer and Senior Vice-President Clinical and Regulatory Affairs, Health Canada, Leclerc JM (2012) Potential risks of cardiovascular and renal adverse events in patients with type 2 diabetes treated with aliskiren (RASILEZ) or aliskiren/hydrochlorothiazide (RASILEZ HCT). http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/advisories-avis/prof/2012/r
  4. National Kidney Foundation (2012) "KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update." Am J Kidney Dis, 60, p. 850-86
  5. EMA. European Medicines Agency (2014) PRAC recommends against combined use of medicines affecting the renin-angiotensin (RAS) system: recommendation will now be considered by CHMP for final opinion. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Renin-angiotensin_sys
  6. MHRA. Medicines and Healthcare Regulatory Agency (2014) Combination use of medicines from different classes of renin-angiotensin system blocking agents: risk of hyperkalaemia, hypotension, and impaired renal function--new warnings. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON426905
Moderate

cycloSPORINE valsartan

Applies to: cyclosporine and aliskiren / valsartan

MONITOR: Coadministration of cyclosporine with ACE inhibitors or angiotensin II receptor antagonists may increase the risk of hyperkalemia or precipitate acute renal failure. Cyclosporine causes afferent arteriolar vasoconstriction and decreased glomerular filtration. These effects may be significant when combined with ACE inhibitors or angiotensin II receptor antagonists, which block the mechanism that maintains glomerular filtration rate by constricting the efferent arterioles.

MONITOR: Coadministration with inhibitors of the hepatic uptake transporter OATP 1B1 such as cyclosporine may increase the systemic exposure to valsartan, which is a substrate of the transporter.

MANAGEMENT: Caution is advised if valsartan is used in combination with cyclosporine. Pharmacologic response and blood pressure should be monitored more closely following the addition, discontinuation, or change of dosage of cyclosporine, and the valsartan regimen adjusted as necessary. Serum potassium levels and renal function should also be checked regularly. Particular caution is warranted in patients with renal impairment, diabetes, old age, severe or worsening heart failure, or dehydration. Patients should be 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.

References (2)
  1. (2001) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals
  2. (2007) "Product Information. Exforge (amlodipine-valsartan)." Novartis Pharmaceuticals

Drug and food interactions

Moderate

cycloSPORINE food

Applies to: cyclosporine

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

References (13)
  1. Honcharik N, Yatscoff RW, Jeffery JR, Rush DN (1991) "The effect of meal composition on cyclosporine absorption." Transplantation, 52, p. 1087-9
  2. Ducharme MP, Provenzano R, Dehoornesmith M, Edwards DJ (1993) "Trough concentrations of cyclosporine in blood following administration with grapefruit juice." Br J Clin Pharmacol, 36, p. 457-9
  3. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  4. Hollander AAMJ, Vanrooij J, Lentjes EGWM, Arbouw F, Vanbree JB, Schoemaker RC, Vanes LA, Vanderwoude FJ, Cohen AF (1995) "The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients." Clin Pharmacol Ther, 57, p. 318-24
  5. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  6. Tan KKC, Trull AK, Uttridge JA, Metcalfe S, Heyes CS, Facey S, Evans DB (1995) "Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in kidney transplant recipients." Clin Pharmacol Ther, 57, p. 425-33
  7. Yee GC, Stanley DL, Pessa LJ, et al. (1995) "Effect of grrapefruit juice on blood cyclosporin concentration." Lancet, 345, p. 955-6
  8. Ducharme MP, Warbasse LH, Edwards DJ (1995) "Disposition of intravenous and oral cyclosporine after administration with grapefruit juice." Clin Pharmacol Ther, 57, p. 485-91
  9. Ioannidesdemos LL, Christophidis N, Ryan P, Angelis P, Liolios L, Mclean AJ (1997) "Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases." J Rheumatol, 24, p. 49-54
  10. Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG (1996) "Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients." Transplantation, 62, p. 123-5
  11. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  12. Tsunoda SM, Harris RZ, Christians U, et al. (2001) "Red wine decreases cyclosporine bioavailability." Clin Pharmacol Ther, 70, p. 462-7
  13. Oliveira-Freitas VL, Dalla Costa T, Manfro RC, Cruz LB, Schwartsmann G (2010) "Influence of purple grape juice in cyclosporine availability." J Ren Nutr, 20, p. 309-13
Moderate

valsartan food

Applies to: aliskiren / 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 (2)
  1. (2001) "Product Information. Cozaar (losartan)." Merck & Co., Inc
  2. (2001) "Product Information. Diovan (valsartan)." Novartis Pharmaceuticals
Moderate

aliskiren food

Applies to: aliskiren / valsartan

GENERALLY AVOID: Coadministration with orange, apple, or grapefruit juice may significantly decrease the oral bioavailability and renin-inhibiting effect of aliskiren. The exact mechanism of interaction is unknown, but may include inhibition of OATP2B1-mediated influx of aliskiren in the small intestine, formation of insoluble complexes between fruit juice constituents and aliskiren, and/or increased ionization of aliskiren due to reduced intestinal pH. In 12 healthy volunteers, 200 mL of either orange juice or apple juice administered three times daily for 5 days in combination with a single 150 mg oral dose of aliskiren on day 3 reduced the mean aliskiren peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 80% and 60%, respectively, compared to water. Plasma renin activity was 87% and 67% higher at 24 hours postdose when aliskiren was administered with orange juice and apple juice, respectively, compared to water. No significant differences were observed in the blood pressure or heart rate between treatments. However, this may be due to the delayed onset of aliskiren's blood pressure-lowering effect, which would not be apparent following a single dose. A similar pharmacokinetic interaction has been reported with grapefruit juice. In 11 healthy volunteers, 200 mL of normal strength grapefruit juice administered three times daily for 5 days in combination with a single 150 mg oral dose of aliskiren on day 3 reduced the mean aliskiren Cmax and AUC by 81% and 61%, respectively, but there was no change in plasma renin activity compared to water. A high degree of interpatient variability was observed with all three interactions.

MONITOR: High-fat meals can substantially reduce the gastrointestinal absorption of aliskiren. According to the product labeling, administration of aliskiren with a high-fat meal decreased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) by 85% and 71%, respectively. In clinical trials, however, aliskiren was administered without a fixed requirement in relation to meals.

MANAGEMENT: To ensure steady systemic drug levels and therapeutic effects, patients should establish a routine pattern for administration of aliskiren with regard to meals. Coadministration with orange, apple, or grapefruit juice should be avoided, especially if these juices are to be consumed on a regular basis or shortly before or after aliskiren dosing.

References (4)
  1. (2007) "Product Information. Tekturna (aliskiren)." Novartis Pharmaceuticals
  2. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP (2008) "Clinical pharmacokinetics and pharmacodynamics of aliskiren." Clin Pharmacokinet, 47, p. 515-31
  3. Tapaninen T, Neuvonen PJ, Niemi M (2010) "Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren." Clin Pharmacol Ther, 88, p. 339-42
  4. Tapaninen T, Neuvonen PJ, Niemi M (2010) "Orange and apple juices greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren." Br J Clin Pharmacol, 71, p. 718-26

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.


Report options

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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.