Back To Search Results

Aliskiren

Editor: Jamie M. Terrell Updated: 2/12/2024 1:42:06 AM

Indications

FDA-Approved Indications

Hypertension

Aliskiren is FDA-approved to treat hypertension in adults and children 6 years and older. Aliskiren may be used as monotherapy or in combination with other antihypertensive agents.[1] Aliskiren is currently available in combination products with hydrochlorothiazide or amlodipine, as well as with both amlodipine and hydrochlorothiazide.

Aliskiren received approval in 2007 after demonstrating its antihypertensive effects in 6 randomized, double-blind, placebo-controlled trials. All patients included had mild to moderate hypertension. Most patients demonstrated a blood pressure-lowering effect within 2 weeks of treatment. These study results revealed a mean reduction in systolic blood pressure of 2.9 to 10 mm Hg and a mean decrease in diastolic blood pressure of 3.3 to 8.6 mm Hg.[2][3][4]

In November 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated treatment guidelines for patients with high blood pressure. According to the 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, most patients will have a blood pressure goal of less than 130/80 mm Hg. This guideline is a significant change from the 2014 JNC 8 Guidelines (Evidence-based guideline for managing high blood pressure in adults: a report from panel members appointed to the Eighth Joint National Committee JNC8). The JNC 8 guidelines recommended a blood pressure goal of 140/90 mm Hg for most patients and an even higher reading for older patients. For patients older than 60, the JNC 8 guideline recommended a blood pressure goal of less than 150/90 mm Hg.

Off-Label Uses 

In addition to the new lower blood pressure goals, the ACC/AHA guidelines strongly focus on decreasing the risk of cardiovascular disease. Their current recommendation is that patients with elevated blood pressure should receive treatment with medication to reduce cardiovascular risk by lowering blood pressure. However, aliskiren does not currently have outcome data demonstrating cardiovascular disease (CVD) risk reduction with its use. The ACC/AHA guidelines emphasize the importance of blood pressure-lowering over drug selection, but initial recommendations for most patients currently include calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEI), and angiotensin-receptor blockers (ARB) because of their evidence of CVD risk reduction.

There is also no outcome data for using aliskiren in patients with diabetes mellitus and nephropathy, patients with coronary artery disease, or post-MI patients. The ATMOSPHERE study found aliskiren not to be inferior to enalapril in congestive heart failure patients in the primary composite endpoint of cardiovascular death or heart failure hospitalization.[5][6] Aliskiren is not indicated for these conditions and would probably not be a substitute for ACEIs or ARBs for these patients.

At this time, aliskiren remains a medication that would be most appropriate for use as an add-on therapy for patients already managed with one or more medications that have demonstrated the ability to decrease cardiovascular risk.[7][8]

Savoia C. et al conducted a clinical trial on 16 patients with mild essential hypertension and type 2 diabetes.[9] The researchers compared the vasorelaxant effects of aliskiren (N = 9) and ramipril (N = 7) from small artery biopsies. The doses used on the patients were 150 mg once daily for aliskiren and 5 mg once daily for ramipril. A micromyograph evaluated the endothelium-mediated vasorelaxant effects of acetylcholine plus or minus N omega-nitro-L-arginine methyl ester HCL in norepinephrine-pretreated vessels. Both aliskiren and ramipril reduced blood pressure. Aliskiren demonstrated statistically improved endothelium-mediated relaxation, increasing the formation of endothelial p1177 nitric oxide synthase. Savoia C. et al concluded that aliskiren caused quicker peripheral vasodilation in mild hypertensive type 2 diabetes patients.

Bokuda K. et al conducted a study on 39 patients with hypertension and chronic kidney disease.[10] The patients received one-time aliskiren or amlodipine treatment. The renin-angiotensin system's vascular, renal, and elements were evaluated before treatment at 12 weeks and again at 24 weeks. The aliskiren cohort significantly reduced the cardio-ankle vascular index, protein excretion, and urinary albumin. These researchers concluded that aliskiren demonstrated additional renal and vascular protection in addition to its blood pressure-lowering effects.

Mechanism of Action

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Mechanism of Action

Aliskiren is active in the renin-angiotensin-aldosterone system (RAAS).[11] Renin secretion occurs by specialized cells found in the juxtaglomerular apparatus within the kidney based on changes in blood volume and renal perfusion as sensed by the macula densa in the distal tubule of the nephron. Renin is responsible for converting angiotensinogen to angiotensin I. Angiotensin I is then converted to angiotensin II by the angiotensin-converting enzyme (ACE), which is present in the lungs' capillaries and endothelial cells in the kidneys. Angiotensin II is believed to be the first active mediator in the RAAS system and exerts its effects by binding to the AT1 receptor and works as a vasoconstrictor, causing the release of catecholamines and promoting aldosterone secretion and sodium reabsorption. These effects together act to increase blood pressure. Angiotensin II also can inhibit renin release, causing negative feedback to the renin-angiotensin-aldosterone system. 

Aliskiren acts as a renin inhibitor, which blocks the conversion of angiotensinogen to angiotensin I. This effect subsequently decreases the formation of angiotensin II. Angiotensin II acts on the AT1 receptor, responsible for vasoconstriction, aldosterone secretion, and catecholamine release. Hence, blood pressure decreases by decreasing the amount of angiotensin II that reaches the AT1 receptor, thereby causing a decrease in vasoconstriction, aldosterone secretion, and catecholamine release. Any agent that works to inhibit the RAAS can suppress the negative feedback loop.

O'Rawe et al conducted a phase I clinical trial to determine the safety and tolerability of several drugs that target the renin-angiotensin system in patients with glioblastoma.[12] The glioblastoma stem cells contain elements of the renin-angiotensin system. Thus, inhibiting the renin-angiotensin system in glioblastoma stem cells might have anticancer effects. Patients who relapsed from standard treatment, eg, surgery, radiation, and temozolomide, and met inclusion criteria received oral doses of aliskiren, aspirin, celecoxib, cilazapril, curcumin/piperine, metformin, and propranolol. Ten patients out of 17 completed the pharmacotherapy regimen. Two patients reported mild adverse effects. The median survival was 19.9 months compared with 14.6 months for standard therapy. O'Rawe et al state that this difference is not statistically significant. However, the trend of greater survival time for relapsed patients receiving drugs that target the renin-angiotensin system is a promising lead.

Pharmacokinetics

Absorption

Aliskiren is poorly absorbed in the gastrointestinal tract, with a bioavailability between 2.0 and 2.5%. The drug achieves peak plasma concentrations between 1 and 3 hours following administration, and steady-state concentrations are achieved within 7 to 8 days of starting regular administration.[13][14]

Distribution

Eighty percent of aliskiren in the plasma is unchanged drug, and its volume of distribution at steady-state is approximately 135 L.[14][15] The drug's average protein binding is 49.5%.

Metabolism

Aliskiren's major metabolic pathwayis O-demethylation at the phenyl-proxy side chain or the 3-methoxypropoxy group, with further oxidation to the carboxylic acid derivative. Aliskiren is also minimally metabolized by CYP3A4 enzymes, but it is not an inhibitor or inducer of the cytochrome P450 hepatic enzyme system. Aliskiren's half-life averages 24 hours, making it suitable for once-daily dosing.

Excretion

Aliskiren is partially cleared by the kidneys and excreted in the urine, 25% as an unchanged drug.

Administration

Dosage Forms and Strengths

Aliskiren is available as 150 mg or 300 mg tablets. Patients usually initiate therapy on 150 mg daily, which may be increased to 300 mg daily if necessary. Doses over 300 mg daily did not demonstrate any additional blood pressure lowering but did show an increased rate of diarrhea. Aliskiren is also available as oral pellets for patients who cannot swallow tablets. The pellets are available as a 37.5 mg capsule. Aliskiren is also available in combination with hydrochlorothiazide in multiple strengths: 150-12.5 mg, 150-25 mg, 300-12.5 mg, and 300-25 mg, respectively. The drug is also marketed with amlodipine and hydrochlorothiazide: 150-5-12.5 mg, 300-5-12.5 mg, 300-5-25 mg, 300-10-12.5 mg, and 300-10-25 mg, respectively. A combination formulation with aliskiren and amlodipine was discontinued.[16]

Aliskiren administration is via the oral route; it should be taken daily at the same time. Patients may take aliskiren with or without a meal, but the recommendation is for consistent administration with meals. High-fat meals can decrease the absorption of aliskiren.

Adult Dosing

For hypertension: 150 to 300  mg orally once daily. Maximum dose is 300 mg daily.

Pediatric Dosing

For hypertension in children 6 or older:

  • 20 to 50 kg: 75 to 150 mg orally daily. The maximum dose is 150 mg daily.
  • >50 kg: 150 to 300 mg orally once daily. The maximum dose is 300 mg daily.

Special Patient Populations

Hepatic Impairment

No dose adjustment is necessary.

Renal Impairment

For a CrCl >30, there are no dose adjustments. Patients on hemodialysis require no dose adjustment and no supplement. Peritoneal dialysis dosing remains undefined at present.

Pregnant Women

Avoid using aliskiren during pregnancy. If the drug is necessary, monitor amniotic fluid and fetus closely; there is no known risk of teratogenicity, but animal data points towards possible low birth weight.[17]

Breastfeeding Women

No human data exists to assess infant harm or impact on milk production; clinicians should weigh the risks vs benefits.

Pediatric Patients

See pediatric dosing above.

Older Patients

Study results have revealed no problems specific to older patients that would limit the use of aliskiren in this population. However, older patients are more sensitive to the effects of aliskiren.

Adverse Effects

According to the package insert, the primary adverse effect of aliskiren is diarrhea, with 2.3% of patients experiencing it. Other common adverse effects include a cough, rash, headaches, and dizziness.

Clinical lab findings observed in clinical trials include increased blood urea nitrogen or serum creatinine, small decreases in hemoglobin and hematocrit, increases in serum potassium, increased serum uric acid, and increased creatine kinase.[18] Serious adverse reactions reported in clinical trials include fetal toxicity, anaphylactic reactions, head and neck angioedema, and hypotension.[19][20]

Drug-Drug Interactions

Aliskiren is contraindicated with ACE inhibitors and angiotensin receptor blockers in diabetic patients due to additive effects. Other drugs to avoid include amikacin, aripirazole, cyclosporine, itraconazole, potassium chloride, ritonavir, and tacrolimus. As always, a thorough medication reconciliation is necessary before any drug regimen changes.

Contraindications

According to the manufacturer, aliskiren is contraindicated in patients with a known hypersensitivity to any component, in pediatric patients younger than 2, and in patients with diabetes who take an ACE inhibitor or an angiotensin receptor blocker. Patients should not use aliskiren in pregnancy or if they are taking an ARB or ACEI. Caution is necessary for patients with volume depletion.

Box Warning

Aliskiren carries an FDA Box Warning for fetal toxicity. If pregnancy is detected, aliskiren must be stopped immediately, as drugs that act directly on the renin-angiotensin system can result in fetal injury and death.

Monitoring

Medical staff should observe patients taking aliskiren for hyperkalemia and impaired renal function. Serum potassium requires periodic monitoring. Patients at risk include those with renal insufficiency, diabetes mellitus, combination use with ARBs or ACEs, and patients using potassium supplements or potassium-sparing diuretics. Renal function also should be monitored periodically. Individual patients will be at higher risk of developing acute renal failure while taking aliskiren. These patients include those taking ARBs, ACEIs, non-steroidal anti-inflammatory drugs (NSAIDs), and patients with renal artery stenosis, severe heart failure, post-myocardial infarction, or volume depletion.[21][22]

Toxicity

There is limited data regarding overdose in humans. Patients would most likely present with hypotension. If this occurs, supportive treatment would be appropriate.

Enhancing Healthcare Team Outcomes

Healthcare workers, including nurse practitioners who prescribe aliskiren for hypertension in adults, should know the contraindications and precautions. Patients taking aliskiren require monitoring for hyperkalemia and impaired renal function. Serum potassium also requires periodic observation. Patients at risk include those with renal insufficiency, diabetes mellitus, combination use with ARBs or ACEs, and patients using potassium supplements or potassium-sparing diuretics. Renal function is also something clinicians should watch. Individual patients will be at higher risk of developing acute renal failure while taking aliskiren. These patients include those taking ARBs, ACEIs, non-steroidal anti-inflammatory drugs (NSAIDs), and patients with renal artery stenosis, severe heart failure, post-myocardial infarction, or volume depletion.

As part of a patient's overall hypertensive control regimen, aliskiren therapy requires an interprofessional healthcare team that includes physicians, advanced practice practitioners, nursing staff, and pharmacists. When initiating aliskiren, the clinician should consult a pharmacist, who can review the entire medication regimen and assist with deciding the appropriateness of adding aliskiren and what other changes might be necessary for the patient's regimen. Nursing staff can provide administration counseling, monitor the patient, and assess pharmacotherapy adherence. If the nurse or pharmacist notes any issues, they should be able to communicate these to the prescriber promptly, giving their clinical opinion regarding the patient's condition. With interprofessional team coordination, aliskiren therapy can achieve optimal outcomes with minimal adverse events. 

References


[1]

Zhao Q, Shen J, Lu J, Jiang Q, Wang Y. Clinical efficacy, safety and tolerability of Aliskiren Monotherapy (AM): an umbrella review of systematic reviews. BMC cardiovascular disorders. 2020 Apr 17:20(1):179. doi: 10.1186/s12872-020-01442-z. Epub 2020 Apr 17     [PubMed PMID: 32303191]

Level 1 (high-level) evidence

[2]

Łukawski K, Raszewski G, Czuczwar SJ. Effect of aliskiren, a direct renin inhibitor, on the protective action of antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice. Fundamental & clinical pharmacology. 2019 Apr:33(2):191-198. doi: 10.1111/fcp.12421. Epub 2018 Nov 21     [PubMed PMID: 30312501]


[3]

Yamashita S, Biswas KB, Nabi AHMN, Nakagawa T, Suzuki F, Ebihara A. Aliskiren reduces the release of soluble (pro)renin receptor from human umbilical vein endothelial cells. Biomedical reports. 2018 Sep:9(3):247-252. doi: 10.3892/br.2018.1124. Epub 2018 Jul 5     [PubMed PMID: 30271601]


[4]

Nakano D, Nishiyama A. A novel role of renin inhibitor in the complement cascade. Kidney international. 2018 Oct:94(4):650-652. doi: 10.1016/j.kint.2018.05.025. Epub     [PubMed PMID: 30243307]


[5]

Bjerre HL, Christensen JB, Buus NH, Simonsen U, Su J. The role of aliskiren in the management of hypertension and major cardiovascular outcomes: a systematic review and meta-analysis. Journal of human hypertension. 2019 Nov:33(11):795-806. doi: 10.1038/s41371-018-0149-8. Epub 2019 Jan 10     [PubMed PMID: 30631130]

Level 1 (high-level) evidence

[6]

Vaduganathan M, Cheema B, Cleveland E, Sankar K, Subacius H, Fonarow GC, Solomon SD, Lewis EF, Greene SJ, Maggioni AP, Böhm M, Zannad F, Butler J, Gheorghiade M. Plasma renin activity, response to aliskiren, and clinical outcomes in patients hospitalized for heart failure: the ASTRONAUT trial. European journal of heart failure. 2018 Apr:20(4):677-686. doi: 10.1002/ejhf.973. Epub 2017 Nov 16     [PubMed PMID: 29143416]

Level 2 (mid-level) evidence

[7]

Yandrapalli S, Jolly G, Biswas M, Rochlani Y, Harikrishnan P, Aronow WS, Lanier GM. Newer hormonal pharmacotherapies for heart failure. Expert review of endocrinology & metabolism. 2018 Jan:13(1):35-49. doi: 10.1080/17446651.2018.1406799. Epub 2017 Nov 22     [PubMed PMID: 30063443]


[8]

Simeoni M, Nicotera R, Pelagi E, Libri E, Comi N, Fuiano G. Successful Use of Aliskiren in a Case of IgA- Mesangial Glomerulonephritis Unresponsive to Conventional Therapies. Reviews on recent clinical trials. 2019:14(1):72-76. doi: 10.2174/1574887113666180726103648. Epub     [PubMed PMID: 30047335]

Level 3 (low-level) evidence

[9]

Savoia C, De Ciuceis C, Paini A, Carletti R, Arrabito E, Nicoletti C, Mercantini P, Di Gioia C, Battistoni A, Ucci S, Filippini A, Agabiti Rosei E, Volpe M, Muiesan ML, Rizzoni D, Salvetti M. Effect of direct renin inhibition on vascular function after long-term treatment with aliskiren in hypertensive and diabetic patients. Journal of hypertension. 2021 Jan:39(1):169-180. doi: 10.1097/HJH.0000000000002595. Epub     [PubMed PMID: 32740409]


[10]

Bokuda K, Morimoto S, Seki Y, Yatabe M, Watanabe D, Yatabe J, Ando T, Shimizu S, Itoh H, Ichihara A. Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level. Hypertension research : official journal of the Japanese Society of Hypertension. 2018 Jun:41(6):435-443. doi: 10.1038/s41440-018-0037-1. Epub 2018 Apr 4     [PubMed PMID: 29618841]


[11]

Pantzaris ND, Karanikolas E, Tsiotsios K, Velissaris D. Renin Inhibition with Aliskiren: A Decade of Clinical Experience. Journal of clinical medicine. 2017 Jun 9:6(6):. doi: 10.3390/jcm6060061. Epub 2017 Jun 9     [PubMed PMID: 28598381]


[12]

O'Rawe M, Wickremesekera AC, Pandey R, Young D, Sim D, FitzJohn T, Burgess C, Kaye AH, Tan ST. Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2022 Jan:95():48-54. doi: 10.1016/j.jocn.2021.11.023. Epub 2021 Dec 4     [PubMed PMID: 34929651]

Level 1 (high-level) evidence

[13]

Buczko W, Hermanowicz JM. Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacological reports : PR. 2008 Sep-Oct:60(5):623-31     [PubMed PMID: 19066408]


[14]

Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clinical pharmacokinetics. 2008:47(8):515-31     [PubMed PMID: 18611061]


[15]

Waldmeier F, Glaenzel U, Wirz B, Oberer L, Schmid D, Seiberling M, Valencia J, Riviere GJ, End P, Vaidyanathan S. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug metabolism and disposition: the biological fate of chemicals. 2007 Aug:35(8):1418-28     [PubMed PMID: 17510248]


[16]

. Aliskiren/amlodipine (Tekamlo): another combination tablet for hypertension. The Medical letter on drugs and therapeutics. 2010 Nov 29:52(1352):94-5     [PubMed PMID: 21116232]

Level 3 (low-level) evidence

[17]

. Drugs for hypertension. The Medical letter on drugs and therapeutics. 2020 May 18:62(1598):73-80     [PubMed PMID: 32555118]

Level 3 (low-level) evidence

[18]

Zheng SL, Roddick AJ, Ayis S. Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: A systematic review and meta-analysis of 13,395 patients. Diabetes & vascular disease research. 2017 Sep:14(5):400-406. doi: 10.1177/1479164117715854. Epub 2017 Aug 27     [PubMed PMID: 28844155]

Level 1 (high-level) evidence

[19]

Schlienger RG, Korn JR, Wehler E, Lopez Leon S, Yeaw J. Angioedema Among Hypertensive Patients Treated with Aliskiren or Other Antihypertensive Medications in the United States. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2017 Dec:17(6):465-474. doi: 10.1007/s40256-017-0242-3. Epub     [PubMed PMID: 28779444]


[20]

Okamura K, Takamiya Y, Mori K, Shirai K, Urata H. Add-on aliskiren treatment can decrease blood pressure but requires attention to risks of renal impairment and hyperkalemia Chikushi Anti-Hypertension Trial-Rasilez® (CHAT-Ras). Clinical and experimental hypertension (New York, N.Y. : 1993). 2020 Aug 17:42(6):545-552. doi: 10.1080/10641963.2020.1723618. Epub 2020 Feb 8     [PubMed PMID: 32037898]


[21]

Békássy ZD, Kristoffersson AC, Rebetz J, Tati R, Olin AI, Karpman D. Aliskiren inhibits renin-mediated complement activation. Kidney international. 2018 Oct:94(4):689-700. doi: 10.1016/j.kint.2018.04.004. Epub 2018 Jun 5     [PubMed PMID: 29884545]


[22]

Pawloski PL, Moreira CG, Horinouchi CDS, Fernandes D, Olchanheski LR Júnior, Machado W, Cabrini DA, Dietrich M, Paludo K, Otuki MF. Aliskiren: Preclinical evidence for the treatment of hyperproliferative skin disorders. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018 Aug:104():151-157. doi: 10.1016/j.biopha.2018.03.157. Epub 2018 May 14     [PubMed PMID: 29772435]