Brand name: Tekturna
Drug class: Renin Inhibitors
Chemical name: (2S,4S,5S,7S)-N-(2-Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate
Molecular formula: C₃₀H₅₃N₃O₆•0.5 C₄H₄O₄
CAS number: 173334-57-1

Medically reviewed by Drugs.com on Nov 22, 2023. Written by ASHP.

Introduction

Nonpeptide renin inhibitor.

Uses for Aliskiren

Hypertension in Adults

Management of hypertension in adults (alone or in combination with other antihypertensive agents); may be used in fixed combination with hydrochlorothiazide when such combined therapy is indicated.

Not considered a preferred agent for initial management of hypertension in adults according to current evidence-based hypertension guidelines.

Most experience with aliskiren combination therapy in adults to date has been with diuretics, an angiotensin II receptor antagonist (valsartan), or a calcium-channel blocking agent (amlodipine); concomitant use of aliskiren with any of these drugs at maximum recommended dosages produces a greater BP response than does use of each drug alone. Triple combination of aliskiren, amlodipine, and hydrochlorothiazide produces greater BP reductions compared with dual combinations of these drugs.

Use in combination with an ACE inhibitor or angiotensin II receptor antagonist is contraindicated in diabetic patients; such concomitant use generally not recommended, particularly in patients with moderate or severe renal impairment (Cl_cr <60 mL/minute). (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Previous hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potentials harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommends initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommends initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Hypertension in Pediatric Patients

Management of hypertension in children and adolescents ≥6 years of age.

Reductions in SBP and DBP from baseline with aliskiren or enalapril were similar at the end of a 52-week randomized, extension study in children and adolescents in which antihypertensive drug dosage was titrated to achieve desired BP (i.e., mean sitting SBP <90th percentile for age, gender, and height).

Do not use in patients <6 years of age or in those weighing <20 kg. (See Contraindications and also see Pediatric Use under Cautions.)

Aliskiren Dosage and Administration

General

BP Monitoring and Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic). Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.

Administration

Oral Administration

Manufacturer recommends that patients establish a routine pattern for taking the drug with regard to meals; administration with a high-fat meal substantially decreases absorption of the drug.

Dosage

Available as aliskiren hemifumarate; dosage expressed in terms of the base.

Pediatric Patients

Hypertension

Aliskiren Therapy

Oral

Children or adolescents 6–17 years of age who weigh 20 to up to 50 kg: Initially, 75 mg once daily; may titrate dosage up to maximum of 150 mg once daily.

Children or adolescents 6–17 years of age weighing ≥50 kg: Same daily dosage as in adults.

Adults

Hypertension

Aliskiren Therapy

Oral

Initially, 150 mg once daily, alone or in combination with other antihypertensive agents. May increase dosage to 300 mg once daily if BP not adequately controlled; 85–90% of antihypertensive effect at a given dosage is attained within 2 weeks.

Dosages >300 mg daily do not appear to further increase BP response, but are associated with an increased frequency of diarrhea.

Aliskiren/Hydrochlorothiazide Fixed-combination Therapy

Oral

In patients who do not respond adequately to monotherapy with aliskiren or hydrochlorothiazide: Initially, 150 mg of aliskiren and 12.5 mg of hydrochlorothiazide once daily as the fixed combination. May titrate dosage after 2–4 weeks, up to maximum of 300 mg of aliskiren and 25 mg of hydrochlorothiazide once daily.

Initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents: Initially, 150 mg of aliskiren and 12.5 mg of hydrochlorothiazide once daily as the fixed combination. May titrate dosage after 2–4 weeks, up to maximum of 300 mg of aliskiren and 25 mg of hydrochlorothiazide once daily.

Patients whose BP is well controlled with hydrochlorothiazide monotherapy but are experiencing hypokalemia: May switch to fixed combination of aliskiren and hydrochlorothiazide.

Patients who experience dose-limiting adverse effects of aliskiren or hydrochlorothiazide: May switch to the fixed-combination preparation containing a lower dose of that component.

May also use the fixed combination as a substitute for the individually titrated drugs.

Estimated probability of achieving an SBP <140 mm Hg with placebo, aliskiren 300 mg daily, hydrochlorothiazide 25 mg daily, or aliskiren 300 mg and hydrochlorothiazide 25 mg daily was 34, 62, 54, or 77%, respectively; estimated probability of achieving a DBP <90 mm Hg with these same regimens was 37, 61, 49, or 74%, respectively.

Prescribing Limits

Pediatric Patients

Hypertension

Aliskiren Therapy

Oral

Children or adolescents 6–17 years of age who weigh 20 to up to 50 kg: Maximum 150 mg once daily.

Adults

Hypertension

Aliskiren Therapy

Oral

Maximum 300 mg once daily.

Aliskiren/Hydrochlorothiazide Fixed-combination Therapy

Oral

Maximum 300 mg of aliskiren and 25 mg of hydrochlorothiazide once daily.

Special Populations

Hepatic Impairment

No initial dosage adjustment required in patients with mild to severe hepatic impairment. (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No initial dosage adjustment required in patients with renal impairment. No dosage adjustment required in patients undergoing hemodialysis. (See Absorption: Special Populationsand also Elimination: Special Populations, under Pharmacokinetics.) However, manufacturer states safety and efficacy not established in patients with severe renal impairment (Cl_cr <30 mL/minute). (See Renal Impairment and also Other Warnings/Precautions under Cautions.)

Geriatric Patients

No initial dosage adjustment required. (See Geriatric Use under Cautions and see Absorption: Special Populations, under Pharmacokinetics.)

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiating therapy or initiate therapy under close medical supervision.

Cautions for Aliskiren

Contraindications

• Use in combination with ACE inhibitors or angiotensin II receptor antagonists in patients with diabetes mellitus. (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

• Known hypersensitivity to aliskiren or any ingredient in the formulation.

• Use in pediatric patients <2 years of age. (See Pediatric Use under Cautions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act on renin-angiotensin system (e.g., aliskiren) reduce fetal renal function and can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. Most epidemiologic studies assessing fetal abnormalities following exposure to antihypertensive agents during the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Discontinue as soon as possible when pregnancy is detected. (See Boxed Warning.)

Other Warnings/Precautions

Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists

Use in combination with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes mellitus and renal disease (either albuminuria or GFR 30 to <60 mL/minute per 1.73 m² with microalbuminuria) associated with increased risk of hypotension, hyperkalemia, and renal impairment. Incidence of stroke and death also slightly increased, but causal relationship not established.

Use in combination with ACE inhibitors or angiotensin II receptor antagonists is contraindicated in patients with diabetes mellitus; in general, avoid combined use of these drugs, particularly in patients with moderate or severe renal impairment (Cl_cr <60 mL/minute).

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider cautions, precautions, contraindications, and interactions associated with hydrochlorothiazide. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.

Sensitivity Reactions

Anaphylactic reactions and angioedema of face, extremities, lips, tongue, glottis, and/or larynx reported; has resulted in hospitalization and intubation. May occur at any time during treatment. Has occurred in patients with or without history of angioedema associated with ACE inhibitors or angiotensin II receptor antagonists.

Angioedema involving the throat, tongue, glottis, or larynx or occurring in patients with a history of upper respiratory tract surgery may result in airway obstruction and death. Patients with manifestations of angioedema of the head or neck, even in the absence of respiratory distress, require prolonged observation since antihistamines and corticosteroids may not prevent respiratory involvement. Prompt medical intervention (e.g., epinephrine, measures to maintain an adequate airway) may be necessary.

Discontinue aliskiren immediately and permanently if an anaphylactic reaction (e.g., difficulty breathing or swallowing, tightness of the chest, urticaria, general rash, swelling, itching, dizziness, vomiting, abdominal pain) or angioedema occurs.

Hypotension

Symptomatic hypotension may occur following initiation of therapy in patients with an activated renin-angiotensin system, including volume- and/or salt-depleted patients (e.g., those receiving high dosages of diuretics). (See Volume- and/or Salt-Depleted Patients under Dosage and Administration.)

Transient hypotension is not a contraindication to further treatment, which usually may be continued without difficulty once BP is stabilized.

Increased risk of hypotension in patients with diabetes mellitus and renal disease who receive aliskiren in combination with an ACE inhibitor or angiotensin II receptor antagonist. (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Renal Effects

Can cause renal impairment, including acute renal failure. Patients whose renal function depends in part on activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-MI, or volume depletion) and patients receiving concomitant therapy with ACE inhibitors, angiotensin II receptor antagonists, or NSAIAs may be at particular risk for developing acute renal failure.

Monitor renal function periodically. Consider withholding or discontinuing therapy if clinically important deterioration of renal function occurs.

Increased risk of renal impairment in patients with diabetes mellitus and renal disease who receive aliskiren in combination with an ACE inhibitor or angiotensin II receptor antagonist. (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and in those receiving concomitant therapy with ACE inhibitors, angiotensin II receptor antagonists, NSAIAs, or drugs that can increase serum potassium concentration (e.g., potassium supplements, potassium-sparing diuretics). (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Monitor serum potassium concentrations periodically.

Cyclosporine or Itraconazole Interaction

Substantial increase in plasma aliskiren concentrations with concomitant cyclosporine or itraconazole; avoid concomitant use. (See Interactions.)

Specific Populations

Pregnancy

Can cause fetal harm when administered to a pregnant woman. (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Breast-feeding not recommended during treatment with aliskiren.

Pediatric Use

Safety of aliskiren therapy evaluated in pediatric patients 6–17 years of age receiving the drug for up to 52 weeks. (See Uses: Hypertension in Pediatric Patients.) In these studies, no unanticipated adverse effects observed; adverse effects in pediatric patients ≥6 years of age expected to be similar to those observed in adults.

Manufacturer states that aliskiren is contraindicated in children <2 years of age and should not be used in children 2 to <6 years of age or in children who weigh <20 kg.

Support BP and renal function if oliguria or hypotension occurs in neonates with a history of in utero exposure to aliskiren; exchange transfusions or dialysis may be required. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Geriatric Use

No overall differences in efficacy or safety compared with younger adults, but increased sensitivity cannot be ruled out. (See Geriatric Patients under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Safety and efficacy not established in patients with severe renal impairment (Cl_cr <30 mL/minute); patients with GFR <30 mL/minute excluded from clinical trials of aliskiren. (See Renal Impairment under Dosage and Administration and see Renal Effects and also Hyperkalemia under Cautions.)

Avoid use in combination with ACE inhibitors or angiotensin II receptor antagonists in patients with Cl_cr <60 mL/minute. (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Common Adverse Effects

Diarrhea, headache, dizziness, fatigue, cough, back pain, flu-like symptoms, rash, hyperkalemia, small increases in BUN or S_cr, increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.

Drug Interactions

Does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A or induce CYP isoenzyme 3A4.

Metabolized by CYP3A4 in vitro; however, appears to undergo minimal hepatic metabolism. (See Elimination under Pharmacokinetics.)

Substrate but not inhibitor of P-glycoprotein (P-gp). Preclinical studies indicate P-gp is the major efflux system involved in absorption and disposition of aliskiren. Potential for P-gp-related interactions likely depends on degree of P-gp inhibition.

Substrate of organic anion transport protein (OATP) 2B1.

Specific Drugs

Aliskiren Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed; oral bioavailability is about 2.5%.

Peak plasma concentrations usually attained within 1–3 hours following oral administration. Steady-state concentrations of aliskiren achieved in about 7–8 days.

Onset

Substantial proportion (85–90%) of antihypertensive effect attained within 2 weeks of initiation of therapy.

Food

High-fat meal decreases mean AUC and peak plasma concentration by 71 and 85%, respectively; however, in clinical studies the drug was administered without requiring a fixed relation of administration to meals.

Special Populations

In geriatric patients AUC may be increased. (See Geriatric Patients under Dosage and Administration and see Geriatric Use under Cautions.)

In patients with varying degrees of renal impairment, peak plasma concentration and AUC were increased; however, changes in exposure did not consistently correlate with severity of renal impairment. (See Renal Impairment under Dosage and Administration.)

In patients with mild to severe hepatic impairment, pharmacokinetics of drug not substantially altered.

Distribution

Extent

Crosses the placenta and is distributed into the amniotic fluid and fetus in animals.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Approximately 47–51%.

Elimination

Metabolism

In vitro studies suggest CYP3A4 is the main enzyme responsible for metabolism. However, amount of absorbed dose that undergoes metabolism not established; drug appears to undergo minimal hepatic metabolism. Also a substrate for P-glycoprotein and OATP 2B1.

Elimination Route

Unabsorbed drug excreted principally in feces as unchanged drug, and absorbed drug eliminated principally in feces via hepatobiliary clearance as unchanged drug and minimally in urine; approximately 25% of an absorbed oral dose is eliminated in urine as unchanged drug.

Half-life

Accumulation half-life is approximately 24 hours.

Terminal half-life is approximately 24–40 hours; wide interpatient variability observed.

Special Populations

Poorly removed by hemodialysis.

Stability

Storage

Oral

Tablets

Aliskiren: Original container at 25°C (may be exposed to 15–30°C); protect from moisture.

Fixed combination of aliskiren and hydrochlorothiazide: Original container at 25ºC (may be exposed to 15–30ºC); protect from moisture.

Actions

• Binds with high affinity to plasma renin.

• Inhibits conversion of angiotensinogen to angiotensin I and reduces plasma renin activity (PRA) and concentrations of angiotensin I, angiotensin II, and aldosterone.

• May suppress feedback inhibition of renin secretion leading to a compensatory increase in plasma renin concentrations; however, PRA does not appear to increase, unlike therapy with ACE inhibitors or angiotensin II receptor antagonists.

• Not known whether aliskiren affects other renin-angiotensin-aldosterone (RAA) system components (e.g., ACE, non-ACE pathways).

Advice to Patients

• Importance of reading the manufacturer's patient information before initiating therapy and each time the prescription is refilled.

• When aliskiren is used in fixed combination with hydrochlorothiazide, advise patients of important precautionary information about the concomitant agent(s).

• Advise patients to take the drug once daily at same time every day, establishing a routine pattern with regard to food. Advise patients that high-fat meals substantially decrease oral absorption of the drug.

• Importance of advising patient that if a dose of aliskiren is missed to take it as soon as it is remembered. If it is almost time for the next dose, omit the missed dose and administer the next dose at the regularly scheduled time.

• Risk of angioedema, including laryngeal edema, and of anaphylactic reaction; importance of discontinuing the drug and immediately reporting suggestive manifestations of angioedema (e.g., edema of face, extremities, eyes, lips, or tongue; swallowing or breathing with difficulty) or a severe allergic reaction (e.g., difficulty breathing or swallowing, chest tightness, urticaria, general rash, swelling, itching, dizziness, vomiting, abdominal pain) to a clinician.

• Risk of fetal and neonatal morbidity and death when administered to pregnant women.

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed. Advise women to discontinue aliskiren if they become pregnant and that breast-feeding is not recommended during treatment with the drug.

• Risk of hypotension, lightheadedness, or syncope, especially during initial therapy or with volume depletion secondary to inadequate fluid intake, excessive perspiration, diarrhea, or vomiting. Importance of informing clinician if lightheadedness occurs. If syncope occurs, importance of discontinuing therapy until clinician has been consulted.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. Importance of not using potassium supplements or potassium-containing salt substitutes without consulting clinician.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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