AHFS Class:

• Renin Inhibitors 24:32.40

Generic Name(s):

• Aliskiren Hemifumarate

• Aliskiren Hemifumarate and Hydrochlorothiazide

Chemical Name:

• (2 S ,4 S ,5 S ,7 S )- 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

Aliskiren is a nonpeptide renin inhibitor.1,2,3,4,5,6,7,8,9,10

Hypertension in Adults

Aliskiren hemifumarate is used alone or in combination with other antihypertensive agents in the management of hypertension.1,3,4,5,6,7,8,9,11,41 However, current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics) because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes) with drugs in those classes.501,502,503,504,1200

Most experience with aliskiren in combination therapy for the management of hypertension 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 blood pressure response than does use of each drug alone.1,34,35 However, data indicate that simultaneous administration of renin-angiotensin inhibitors (i.e., ACE inhibitor with angiotensin II receptor antagonist; ACE inhibitor or angiotensin II receptor antagonist with aliskiren, a renin inhibitor) increases cardiovascular and renal risk.1200 Aliskiren should not be used in combination with an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus because of the increased risk of renal impairment, hyperkalemia, and hypotension in such patients.1 (See Cautions: Contraindications.) In general, such concomitant therapy should be avoided, particularly in patients with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute).1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

For information on overall principles for the management of hypertension in adults and overall expert recommendations for the disease, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Safety and efficacy of aliskiren as monotherapy in the management of hypertension in adults were established in 6 randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with mild to moderate hypertension.1,3,4,5,6,8,9 In these studies, patients received aliskiren (75-600 mg daily) or placebo.1,3,4,5,6,8 Usual dosages of aliskiren (150 or 300 mg administered once daily) decreased placebo-corrected seated trough systolic blood pressure by about 2.1-11.2 mm Hg and diastolic blood pressure by about 1.7-7.5 mm Hg.1,3,4,5,6,8 Administration of aliskiren at a dosage of 600 mg daily did not appear to further increase blood pressure response.1,3,6 Clinical studies have shown that the antihypertensive effect of aliskiren in patients with mild to moderate hypertension is greater than that of placebo1,3,4,5,6,8 and that the drug is at least as effective as irbesartan, losartan, or valsartan.3,4,12 There was no evidence of rebound hypertension following abrupt withdrawal of aliskiren.1,6 Although aliskiren lowered blood pressure in all demographic subgroups, a smaller reduction in blood pressure was observed in black patients than in Caucasian or Asian patients, as has been observed with ACE inhibitors and angiotensin II receptor antagonists.1,6

The current indication for use of aliskiren in combination with other antihypertensive agents in the management of hypertension is based principally on the results of several randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with hypertension.1,5,41 Combined therapy with aliskiren and hydrochlorothiazide, aliskiren and valsartan, or aliskiren and amlodipine resulted in greater reductions in blood pressure compared with each drug alone.1,5,41 In another randomized, double-blind study, the addition of aliskiren 150 mg daily to a regimen of amlodipine 5 mg daily resulted in further blood pressure reduction, which was numerically but not statistically superior to that achieved by increasing the amlodipine dosage to 10 mg daily.1,7 In patients with moderate or severe hypertension, combined therapy with aliskiren, amlodipine, and hydrochlorothiazide resulted in greater reductions in blood pressure compared with dual combinations of these drugs.35

Hypertension in Pediatric Patients

Safety and efficacy of aliskiren as monotherapy in the management of hypertension in children and adolescents were established in a randomized, double-blind, placebo-controlled trial of 8 weeks' duration and a 52-week extension study in pediatric patients 6-17 years of age with hypertension.1,42 Most patients (82%) in the 8-week trial had primary hypertension; 59% had a body mass index (BMI) in the 95th percentile or higher, 20% had an estimated glomerular filtration rate (GFR) of 60-90 mL/minute per 1.73 m², and less than 2% had an estimated GFR of less than 60 mL/minute per 1.73 m².1 The mean age of patients in this trial was 11.8 years and 74% were Caucasian.1 In the initial 4-week, dose-response phase of the trial, patients were allocated to low- , medium- , and high-dose groups based on body weight.1 (See Table 1.)

At the end of this phase, patients were re-randomized within each weight category to continue the same dose of aliskiren or take placebo for 4 weeks.1 During the initial dose-response phase, aliskiren reduced mean sitting systolic and diastolic blood pressure in a weight-based, dose-dependent manner.1,42 Sitting systolic blood pressure, the primary end point of the trial, was reduced by 4.8, 5.6, and 8.7 mm Hg from baseline in the low- , medium- , and high-dose groups, respectively.1

Following the 8-week trial, 208 patients were enrolled in a 52-week, randomized extension study in which they received either aliskiren or enalapril (regardless of whether they received aliskiren or placebo at the end of the 8-week initial study).1 The extension study included 3 dosages based on weight; optional upward titration of dosage to control blood pressure was allowed during the study.1 (See Table 2.) By week 42, more than 50% of the patients within each weight group had been titrated to a higher daily dosage in an effort to achieve the desired blood pressure (i.e., mean sitting systolic blood pressure less than the 90th percentile for age, gender, and height).42 Approximately 9 or 10% of patients in the aliskiren or enalapril arm of the study, respectively, required add-on medication for blood pressure reduction.42 At the end of 52 weeks, reductions in systolic and diastolic blood pressure from baseline were similar in patients receiving aliskiren (7.6/3.9 mm Hg) or enalapril (7.9/4.9 mm Hg).1,42

Aliskiren should not be used in patients younger than 6 years of age or in those weighing less than 20 kg.1 (See Cautions: Contraindications and also see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

General

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension in Adults.) In patients who develop unacceptable adverse effects with aliskiren, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Administration

Aliskiren is administered orally.1 The manufacturer recommends that patients establish a routine pattern for taking aliskiren with regard to meals; administration with a high-fat meal substantially decreases absorption of the drug.1,9,41

Dosage

Dosage of aliskiren hemifumarate is expressed in terms of aliskiren.1

Hypertension in Pediatric Patients

Aliskiren Therapy

The usual initial dosage of aliskiren for the management of hypertension in children or adolescents 6-17 years of age who weigh 20-50 kg is 75 mg once daily; the maximum recommended dosage of aliskiren in such patients is 150 mg once daily.1 In children or adolescents 6-17 years of age who weigh 50 kg or more, the usual daily dosage of aliskiren is the same as in adults.1 (See Aliskiren Therapy under Dosage: Hypertension in Adults, in Dosage and Administration.)

For more information on overall management of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Hypertension in Adults

Aliskiren Therapy

The usual initial dosage of aliskiren for the management of hypertension in adults is 150 mg once daily, alone or in combination with other antihypertensive agents.1,9,11 Dosage may be increased to 300 mg once daily if blood pressure is not adequately controlled.1,9 Dosages exceeding 300 mg daily do not appear to further increase blood pressure response1,2,3,6 but have been associated with an increased frequency of diarrhea.1,6 Most (85-90%) of the antihypertensive effect of a given dosage is attained within 2 weeks.1

Aliskiren/Hydrochlorothiazide Fixed-combination Therapy

In adults who do not respond adequately to monotherapy with aliskiren or hydrochlorothiazide, the usual recommended initial dosage of the fixed combination is 150 mg of aliskiren and 12.5 mg of hydrochlorothiazide daily.41

Commercially available preparations containing aliskiren and hydrochlorothiazide in fixed combination may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control.41 In such patients, the fixed-combination preparation should be initiated at a dosage of 150 mg of aliskiren and 12.5 mg of hydrochlorothiazide once daily.41 The fixed-combination preparation is not recommended for initial therapy in patients with intravascular volume depletion.41

If needed, dosage of the fixed-combination preparation may be increased to a maximum dosage of 300 mg of aliskiren and 25 mg of hydrochlorothiazide given once daily.41 Because most of the antihypertensive effect of a given dosage is achieved within 1 week (maximum effect seen at 4 weeks), dosage may be adjusted after 2-4 weeks if needed to attain desired blood pressure control.41

Patients whose blood pressure is well controlled with hydrochlorothiazide monotherapy but who experience hypokalemia also may be switched to the fixed combination of aliskiren and hydrochlorothiazide.41 In addition, patients who experience dose-limiting adverse effects with aliskiren or hydrochlorothiazide monotherapy may be switched to a lower dosage of that drug given as the fixed combination to achieve similar blood pressure reductions.41 Aliskiren and hydrochlorothiazide in fixed combination also can be used as a substitute for the individually titrated drugs.41

In an 8-week, randomized, placebo-controlled, 15-arm factorial study in patients whose mean baseline blood pressure was 154/99 mm Hg, combination therapy with aliskiren and hydrochlorothiazide resulted in greater reductions in blood pressure than with the individual drugs alone.41 In this study, the estimated probability of achieving a systolic blood pressure less than 140 mm Hg with placebo, aliskiren 300 mg daily, hydrochlorothiazide 25 mg daily, or the combination of aliskiren 300 mg and hydrochlorothiazide 25 mg daily was 34, 62, 54, or 77%, respectively; the estimated probability of achieving a diastolic blood pressure less than 90 mm Hg with these same regimens was 37, 61, 49, or 74%, respectively.41

Special Populations

Volume and/or salt depletion should be corrected prior to initiation of therapy with aliskiren or, alternatively, therapy should be initiated under close medical supervision.1

No initial dosage adjustment of aliskiren is required in patients with mild to severe hepatic impairment.1,2,18

No consistent correlation has been established between severity of renal impairment and systemic exposure to aliskiren, and initial dosage adjustment is not required in patients with renal impairment.1,16 Aliskiren is poorly removed by hemodialysis, and dosage adjustment is not required in patients undergoing hemodialysis.1 However, because patients with a creatinine clearance of less than 30 mL/minute were excluded from clinical trials of the drug, the manufacturer states that safety and efficacy of aliskiren in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) have not been established.1 (See Other Warnings/Precautions under Cautions: Warnings/Precautions.)

The safety and efficacy of the fixed-combination preparation of aliskiren and hydrochlorothiazide have not been established in patients with severe renal impairment.41

Dosage of aliskiren in pediatric patients is based on age and weight.1 (See Hypertension in Pediatric Patients, under Dosage and Administration: Dosage.)

No initial dosage adjustment of aliskiren is required in geriatric patients.1,17 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Concomitant use of aliskiren and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus.1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Known hypersensitivity to aliskiren or any ingredient in the formulation.1

Use in pediatric patients younger than 2 years of age.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act on the renin-angiotensin system reduce fetal renal function and can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1 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.1 Aliskiren should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving.1 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.1,33 For additional information on the risk during pregnancy of drugs that act on the renin-angiotensin system, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and Enalaprilat/Enalapril 24:32.04.

Other Warnings/Precautions

Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists

Use of aliskiren in combination with an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus and renal disease has been associated with an increased risk of hypotension, hyperkalemia, and renal impairment.1,23 In a randomized, double-blind, placebo-controlled trial (ALTITUDE trial), safety and efficacy of aliskiren (300 mg once daily) when added to ACE inhibitor or angiotensin II receptor antagonist therapy were evaluated in patients with type 2 diabetes mellitus and renal disease (presence of albuminuria or presence of reduced glomerular filtration rate [GFR of 30 to less than 60 mL/minute per 1.73 m²] and microalbuminuria) to determine whether combined therapy resulted in greater cardiovascular and renal risk reduction than conventional ACE inhibitor or angiotensin II receptor antagonist therapy.1,22 The primary efficacy end point was time to first cardiovascular or renal event (i.e., cardiovascular death, resuscitated sudden death, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease, renal death, sustained [1 month or longer] doubling of serum creatinine concentration from baseline).1,22 After a median follow-up of about 32 months, the trial was terminated early because of lack of efficacy and because the incidences of renal impairment (14.5 versus 12.4%), hypotension (19.9 versus 16.3%), and hyperkalemia (38.9 versus 28.8%) were increased in patients receiving aliskiren compared with those receiving placebo in combination with an ACE inhibitor or angiotensin II receptor antagonist.1 The incidences of stroke (3.4 versus 2.7%) and death (8.4 versus 8%) also were slightly higher in patients receiving aliskiren compared with those receiving placebo in combination with an ACE inhibitor or angiotensin II receptor antagonist;1 however, a causal relationship between use of these drugs and the occurrence of stroke or death has not been established.23

Use of aliskiren in combination with ACE inhibitors or angiotensin II receptor antagonists is contraindicated in patients with diabetes mellitus.1 In general, such concomitant therapy should be avoided, particularly in those with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute).1,23

Use of Fixed Combinations

When aliskiren is used in fixed combination with hydrochlorothiazide, the cautions, precautions, contraindications, and interactions associated with hydrochlorothiazide should be considered.41 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 also should be considered.41

Sensitivity Reactions

Hypersensitivity reactions (e.g., anaphylactic reactions or angioedema of the face, extremities, lips, tongue, glottis, larynx) have been reported in patients receiving aliskiren and have resulted in hospitalization and intubation.1 Angioedema may occur at any time during treatment and has occurred in patients with or without a history of angioedema associated with ACE inhibitors or angiotensin II receptor antagonists.1 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.1 Patients with manifestations of angioedema of the head or neck, even in the absence of respiratory distress, require prolonged observation since treatment with antihistamines and corticosteroids may not prevent respiratory involvement.1 Prompt medical intervention (e.g., epinephrine, measures to maintain an adequate airway) may be necessary.1 Aliskiren should be discontinued immediately and should not be readministered in patients who develop symptoms of an anaphylactic reaction (e.g., difficulty breathing or swallowing, tightness of the chest, urticaria, general rash, swelling, itching, dizziness, vomiting, abdominal pain) or angioedema.1

Hypotension

Symptomatic hypotension may occur following initiation of aliskiren therapy in patients with an activated renin-angiotensin system, including volume- and/or salt-depleted patients (e.g., those receiving high dosages of diuretics).1 (See Dosage and Administration: Special Populations.) Transient hypotension is not a contraindication to further treatment, which usually may be continued without difficulty once blood pressure is stabilized.1

In patients with diabetes mellitus and renal disease, an increased risk of hypotension was reported in patients receiving aliskiren in combination with an ACE inhibitor or angiotensin II receptor antagonist.1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Renal Effects

Renal function should be monitored periodically in patients receiving aliskiren, since drugs that inhibit the renin-angiotensin system can cause renal impairment, including acute renal failure.1 Patients whose renal function depends in part on activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, postmyocardial infarction, or volume depletion) and patients receiving concomitant therapy with ACE inhibitors, angiotensin II receptor antagonists, or nonsteroidal anti-inflammatory agents (NSAIAs) may be at particular risk for developing acute renal failure while receiving aliskiren.1 Consideration should be given to withholding or discontinuing therapy in patients who experience clinically important deterioration of renal function.1

In patients with diabetes mellitus and renal disease, an increased risk of renal impairment was reported in patients receiving aliskiren in combination with an ACE inhibitor or angiotensin II receptor antagonist.1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Hyperkalemia

Serum potassium concentrations should be monitored periodically in patients receiving aliskiren, since drugs that affect the renin-angiotensin system can cause 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).1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Cyclosporine or Itraconazole Interaction

Concomitant use of cyclosporine or itraconazole should be avoided in patients taking aliskiren because of a substantial increase in aliskiren plasma concentrations.1 (See Cyclosporine and also see Antifungal Agents: Itraconazole, under Drug Interactions.)

Specific Populations

Pregnancy

Aliskiren can cause fetal harm when administered to a pregnant woman.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Aliskiren is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 Breast-feeding is not recommended during treatment with aliskiren.1

Pediatric Use

Safety of aliskiren therapy has been evaluated in pediatric patients 6-17 years of age receiving the drug for up to 52 weeks.1 (See Uses: Hypertension in Pediatric Patients.) In these studies, no unanticipated adverse effects were observed; adverse effects in pediatric patients 6 years of age or older are expected to be similar to those observed in adults.1 Preclinical studies in rats indicate a potential for a substantial increase in exposure to aliskiren in pediatric patients.1 The manufacturer states that aliskiren is contraindicated in children younger than 2 years of age and should not be used in children 2 to younger than 6 years of age or in children who weigh less than 20 kg.1

If oliguria or hypotension occurs in neonates with a history of in utero exposure to aliskiren, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

When the total number of patients studied in clinical trials of aliskiren is considered, 19% were 65 years of age or older, while 3.4% were 75 years of age or older.1 In clinical trials of aliskiren in fixed combination with hydrochlorothiazide, 19.6% of patients were 65 years of age or older and 3.2% were 75 years of age and older.41 Although no overall differences in efficacy or safety were observed between geriatric and younger patients and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1,41

Renal Impairment

Safety and efficacy of aliskiren in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) have not been established.1 Use of aliskiren in combination with ACE inhibitors or angiotensin II receptor antagonists should be avoided in patients with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute).1 (See Dosage and Administration: Special Populations and also see Other Warnings/Precautions under Cautions: Warnings/Precautions.)

Common Adverse Effects

Common adverse effects reported in hypertensive patients receiving aliskiren include diarrhea,1 headache,1 dizziness,1 fatigue,1 cough,1 back pain,1 flu-like symptoms,1 rash,1 hyperkalemia,1 small increases in BUN or serum creatinine concentration,1 and increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Aliskiren does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A or induce CYP isoenzyme 3A4.1,2 Aliskiren is metabolized by the CYP3A4 isoenzyme in vitro.1,11 The amount of an absorbed dose that is metabolized has not been established;1 however, aliskiren appears to undergo minimal hepatic metabolism.2,9,11,13,16

Drugs Affecting Transport Systems

Aliskiren is a substrate1,11,13,16,17,27 but not an inhibitor27 of P-glycoprotein (P-gp, multidrug resistance transporter 1 [MDR1; Mdr1a/Mdr1b]). In preclinical studies, P-gp was found to be the major efflux system involved in absorption and disposition of aliskiren.1,27 The potential for drug interactions involving the P-gp transport system likely depends on the degree of inhibition of this transporter.1

Aliskiren also is a substrate of organic anion transport protein (OATP) 2B1.24,25,26,27,30,32

Drugs that Increase Serum Potassium Concentration

Concomitant use of aliskiren with drugs that increase the serum potassium concentration (e.g., potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes) may increase the risk of hyperkalemia.1

Drugs that Block the Renin-Angiotensin System

There is an increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (e.g., acute renal failure) with concomitant use of aliskiren and other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists); when aliskiren is used concomitantly with such drugs, blood pressure, renal function, and serum electrolyte concentrations should be monitored.1 Most patients do not obtain any additional benefit from receiving 2 drugs that inhibit the renin-angiotensin system compared with monotherapy.1 In general, such concomitant therapy should be avoided, particularly in patients with renal impairment (creatinine clearance less than 60 mL/minute).1 Concomitant use of aliskiren and an ACE inhibitor or angiotensin II receptor antagonist is contraindicated in patients with diabetes mellitus.1 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Irbesartan

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and irbesartan (300 mg once daily) in healthy individuals or individuals with renal impairment did not substantially alter plasma concentrations or area under the plasma concentration-time curve (AUC) of aliskiren.1,16

Ramipril

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and ramipril (10 mg once daily) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug.1,20

Valsartan

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and valsartan (320 mg once daily) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug.1,20

Antidiabetic Agents

Metformin

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and metformin hydrochloride (1 g once daily) in healthy individuals did not result in clinically important changes in the peak plasma concentration or AUC of either drug.1,29 No dosage adjustment is required.1,29

Pioglitazone

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and pioglitazone (45 mg once daily) in healthy individuals did not substantially alter the peak plasma concentration or AUC of either drug.29 No dosage adjustment is required.29

Antifungal Agents

Itraconazole

In a placebo-controlled crossover study in healthy individuals, multiple doses of itraconazole (a potent inhibitor of P-gp and CYP3A4; initial dose of 200 mg followed by 100 mg twice daily) increased the peak plasma concentration and AUC of aliskiren (administered as a single 150-mg dose) by 5.8- and 6.5-fold, respectively; the elimination half-life of aliskiren was not altered substantially.1,24 Plasma renin activity measured 24 hours after aliskiren administration was 68% lower during the itraconazole phase than during the placebo phase of this crossover study.24 Concomitant use of aliskiren and itraconazole should be avoided.1,24

Ketoconazole

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and ketoconazole (an inhibitor of P-gp and CYP3A4; 200 mg twice daily) in healthy individuals increased plasma concentrations and AUC of aliskiren by about 80%.1,11,17,27 However, no dosage adjustment is required.1,27 Larger increases in aliskiren exposure might be expected following administration of ketoconazole 400 mg once daily.1

Antilipemic Agents

Atorvastatin

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and atorvastatin (80 mg once daily) in healthy individuals increased the peak plasma concentration and AUC of aliskiren by about 50%1,11,27 but did not result in clinically important changes in the pharmacokinetics of atorvastatin.1,27 No dosage adjustment is required.1,27

Fenofibrate

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and fenofibrate (200 mg once daily) in healthy individuals did not substantially alter the peak plasma concentration or AUC of either drug.29 No dosage adjustment is required.29

Lovastatin

Concomitant administration of single doses of aliskiren (150 mg) and lovastatin (40 mg) in healthy individuals did not substantially alter the pharmacokinetics of either drug.1,21 No dosage adjustment is required.1

Atenolol

Concomitant administration of single doses of aliskiren (150 mg) and atenolol (100 mg) in healthy individuals did not substantially alter the pharmacokinetics of either drug.1,21 No dosage adjustment is required.1

Calcium-channel Blocking Agents

Amlodipine

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and amlodipine (10 mg once daily) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug.1,20 No dosage adjustment is required.1,20

Verapamil

In healthy individuals, multiple doses of verapamil hydrochloride (a moderate inhibitor of P-gp and a weak inhibitor of CYP3A4; 240 mg once daily) increased the peak plasma concentration and AUC of aliskiren (administered as a single 300-mg dose) by about twofold;1,26 concomitant administration did not result in clinically important changes in the peak plasma concentration or AUC of verapamil or norverapamil.26 No dosage adjustment is required.1,26

Cimetidine

Multiple doses of cimetidine (800 mg once daily) did not result in clinically important changes in the pharmacokinetics of aliskiren (administered as a single 150-mg dose) in healthy individuals.1,21 No dosage adjustment is required.1

Cyclosporine

In healthy individuals, a single 200- or 600-mg dose of cyclosporine (a potent inhibitor of P-gp and OATP and a weak inhibitor of CYP3A4) increased the peak plasma concentration of aliskiren (administered as a single 75-mg dose) by 2.5-fold and increased the AUC of aliskiren by fourfold to fivefold;1,25 the half-life of aliskiren was increased from 25 hours (without cyclosporine) to 45-46 hours (with concomitant administration of cyclosporine 200 or 600 mg).25 Concomitant use of aliskiren and cyclosporine should be avoided.1,25

Digoxin

Concomitant multiple-dose administration of digoxin (0.25 mg once daily) and aliskiren (300 mg once daily) in healthy individuals did not substantially alter the pharmacokinetics of either drug.1,27 No dosage adjustment is required.1,27

Diuretics

Furosemide

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and furosemide (60 mg orally once daily) in patients with heart failure reduced the peak plasma concentration and AUC of furosemide by 27 and 17%, respectively, and reduced 24-hour urinary furosemide excretion by 29%.1 Effects of furosemide may be reduced following initiation of aliskiren therapy; diuretic effects of furosemide should be monitored.1 However, no initial dosage adjustment is required.1

Hydrochlorothiazide

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and hydrochlorothiazide (25 mg once daily) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug.1,20 Dizziness occurred more frequently when the drugs were administered concomitantly than when either drug was administered alone.20 However, no initial dosage adjustment is required.1,20

Fruit Juices

Fruit (grapefruit, orange, apple) juices may reduce systemic exposure to aliskiren.30,31 In 2 similarly designed studies in healthy individuals, regular ingestion of grapefruit, orange, or apple juice (200 mL 3 times daily) decreased the peak plasma concentration and AUC of aliskiren (administered as a single 150-mg dose) by 80-84 and 61-63%, respectively.30,31 Both studies also evaluated the effects of juice (versus water) on aliskiren pharmacodynamics, as measured by plasma renin activity following the aliskiren dose.30,31 At 24 hours after aliskiren administration, plasma renin activity was 87% higher following ingestion of orange juice instead of water and 67% higher following ingestion of apple juice instead of water, but was not substantially increased following ingestion of grapefruit juice instead of water.30,31 Concomitant ingestion of grapefruit, orange, or apple juice with aliskiren is best avoided.30,31

Isosorbide Mononitrate

Concomitant multiple-dose administration of aliskiren (300 mg once daily) and isosorbide mononitrate (40 mg once daily as an extended-release preparation) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug.28 However, dizziness and low blood pressure (systolic or diastolic blood pressure below 90 or 50 mm Hg, respectively) occurred more frequently when the drugs were administered concomitantly than when either drug was administered alone.28

Nonsteroidal Anti-inflammatory Agents

The antihypertensive effect of aliskiren may be attenuated by nonsteroidal anti-inflammatory agents (NSAIAs).1

Concomitant use of aliskiren with NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, in geriatric patients and patients who are volume depleted or have compromised renal function may result in deterioration of renal function, including possible acute renal failure.1 These effects usually are reversible.1 Renal function should be monitored periodically in patients receiving aliskiren concomitantly with an NSAIA.1

Celecoxib

Concomitant administration of single doses of aliskiren (150 mg) and celecoxib (200 mg) in healthy individuals did not substantially alter the pharmacokinetics of either drug.1,21 No dosage adjustment is required.1

Rifampin

In a placebo-controlled crossover study in healthy individuals, multiple doses of rifampin (600 mg once daily) decreased the peak plasma concentration and AUC of aliskiren (administered as a single 150-mg dose) by 39 and 56%, respectively.32 Plasma renin activity measured 24 hours after aliskiren administration was 61% higher during the rifampin phase than during the placebo phase of this crossover study.32 Blood pressure and heart rate in healthy individuals were not substantially affected by concomitant rifampin administration.32

Warfarin

Multiple doses of aliskiren (150 mg once daily) did not substantially alter the pharmacokinetics or pharmacodynamics of warfarin sodium (single 25-mg dose) in healthy individuals.19 A single dose of warfarin sodium (25 mg) did not substantially alter the pharmacokinetics of aliskiren.1 No dosage adjustment is required.1

Pharmacokinetics

Absorption

Bioavailability

Aliskiren is poorly absorbed following oral administration; oral bioavailability is about 2.5%.1,2,9,10,16

Peak plasma concentrations usually are attained within 1-3 hours following oral administration.1,2,9,13 Steady-state concentrations of aliskiren are achieved in about 7-8 days.1

Onset

A substantial proportion (85-90%) of the antihypertensive effect of aliskiren is attained within 2 weeks of initiation of therapy.1,6,9

Food

A high-fat meal decreases mean area under the concentration-time curve (AUC) and peak plasma concentration by 71 and 85%, respectively; however, in clinical studies, aliskiren was administered without requiring a fixed relation of administration to meals.1,2

Special Populations

In geriatric patients, systemic exposure to aliskiren (as measured by AUC) may be increased.1,17 (See Dosage and Administration: Special Populations and see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

In patients with varying degrees of renal impairment, rate and extent of systemic exposure (peak plasma concentration and AUC) to the drug were increased; however, changes in exposure did not consistently correlate to severity of renal impairment.1,16 (See Dosage and Administration: Special Populations.)

In patients with mild to severe hepatic impairment, pharmacokinetics of the drug were not substantially altered.1,18

Distribution

Extent

Aliskiren crosses the placenta and is distributed into the amniotic fluid and fetus in animals.1

Aliskiren is distributed into milk in rats; it is not known whether aliskiren is distributed into human milk.1

Plasma Protein Binding

Aliskiren is approximately 47-51% bound to plasma proteins.2,16,20

Elimination

Metabolism

The amount of an absorbed dose that undergoes metabolism has not been established;1 however, aliskiren appears to undergo minimal hepatic metabolism.2,9,11,13,16 CYP isoenzyme 3A4 appears to be main enzyme responsible for metabolism of the drug based on in vitro studies.1,9,11 Aliskiren also is a substrate for P-glycoprotein11,13,16,17 and organic anion transport protein (OATP) 2B1.24,25,26,27,30,32

Elimination Route

Unabsorbed drug is excreted principally in feces as unchanged drug, and absorbed drug is eliminated principally in feces via hepatobiliary clearance as unchanged drug and minimally in urine;1,2,9,10,11,13,16,17,20 approximately 25% of an absorbed oral dose is eliminated in urine as unchanged drug.1,9

Half-life

Accumulation half-life of aliskiren is approximately 24 hours.1,11

Terminal half-life is approximately 24-40 hours; 2,9,10,11,13,14,16,17 wide interpatient variability has been observed.11

Special Populations

Aliskiren is poorly removed by hemodialysis.1

Description

Aliskiren is a nonpeptide renin inhibitor.1,2,3,4,5,6,7,8,9,10 Renin catalyzes the conversion of angiotensinogen to angiotensin I, the initial and rate-limiting enzymatic reaction of the renin-angiotensin-aldosterone (RAA) system; angiotensin I is subsequently cleaved to angiotensin II by angiotensin-converting enzyme (ACE).1,2,3,4,8,9,10 Angiotensin II has vasoconstrictor and aldosterone-secreting effects,1,2,8,10 which increase blood pressure.1,3,8 All drugs that inhibit the RAA system, including renin inhibitors, suppress feedback inhibition of renin secretion, leading to a compensatory increase in plasma renin concentrations.1,9,10 When this increase occurs during therapy with ACE inhibitors or angiotensin II receptor antagonists, the result is increased plasma renin activity (PRA).1,9 Because aliskiren binds with high affinity to plasma renin, aliskiren inhibits effects of increased renin concentrations and conversion of angiotensinogen to angiotensin I, resulting in reduced PRA and reduced concentrations of angiotensin I, angiotensin II, and aldosterone;1,2,3,4,6,8,9,10 whether aliskiren affects other RAA system components (e.g., ACE, non-ACE pathways) is not known.1

Oral bioavailability of aliskiren is low (about 2.5%).1,2,10 Based on in vitro studies, aliskiren appears to be metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1,9 The amount of the absorbed dose that is metabolized has not been established;1 however, aliskiren appears to undergo minimal hepatic metabolism.2,9,11,13,16 In addition, aliskiren is a substrate for P-glycoprotein11,13,16,17 and organic anion transport protein (OATP) 2B1.24,25,26,27,30,32 Unabsorbed aliskiren is excreted principally in feces as unchanged drug, and absorbed drug is eliminated principally in feces via hepatobiliary clearance as unchanged drug and minimally in urine;1,2,9,10,11,13,16,17,20 approximately 25% of an absorbed oral dose of aliskiren is eliminated in urine as unchanged drug.1,9,10

Advice to Patients

Importance of reading the manufacturer's patient information before initiating therapy and each time the prescription is refilled.1

When aliskiren is used in fixed combination with hydrochlorothiazide, advise patients of important precautionary information about the concomitant agent.41

Advise patients to take the drug once daily at the same time every day, establishing a routine pattern with regard to food.1,11,41 Advise patients that high-fat meals substantially decrease oral absorption of the drug.1

Importance of advising patient that if a dose of aliskiren is missed, the dose should be taken as soon as it is remembered.1 If it is close to the time for the next dose, the missed dose should be omitted and the next dose should be taken at the regularly scheduled time.1

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.1

Importance of advising women of the risk of fetal and neonatal morbidity and death when the drug is administered to pregnant women.1

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise women to discontinue aliskiren if they become pregnant and that breast-feeding is not recommended during treatment with the drug.1

Risk of hypotension, lightheadedness, or syncope, especially during initial therapy or with volume depletion secondary to inadequate fluid intake, excessive perspiration, diarrhea, or vomiting.1 Importance of informing clinician if lightheadedness occurs.1 If syncope occurs, importance of discontinuing therapy until clinician has been consulted.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 Importance of not using potassium supplements or potassium-containing salt substitutes without first consulting the prescribing clinician.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Noden Pharma. Tekturna^® (aliskiren) tablets prescribing information. Boston, MA; 2017 Nov.

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3. Gradman AH, Schmieder RE, Lins RL et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation . 2005; 111:1012-8. [PubMed 15723979]

4. Pool JL, Schmieder RE, Azizi M et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens . 2007; 20:11-20. [PubMed 17198906]

5. Villamil A, Chrysant SG, Calhoun D et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens . 2007; 25:217-26. [PubMed 17143194]

6. Oh BH, Mitchell J, Herron JR et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol . 2007; 49:1157-63. [PubMed 17367658]

7. Munger MA, Drummond W, Essop MR et al. Aliskiren as add-on to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose. Eur Heart J . 2006; 25(Suppl):P784. Abstract.

8. Kushiro T, Itakura H, Abo Y et al. Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens Res . 2006; 29:997-1005. [PubMed 17378372]

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11. Novartis, East Hanover, NJ: Personal communication.

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27. Vaidyanathan S, Camenisch G, Schuetz H et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren. J Clin Pharmacol . 2008; 48:1323-38. [PubMed 18784280]

28. Vaidyanathan S, Bartlett M, Dieterich HA et al. Pharmacokinetic interaction of the direct renin inhibitor aliskiren with furosemide and extended-release isosorbide-5-mononitrate in healthy subjects. Cardiovasc Ther . 2008; 26:238-46. [PubMed 19035874]

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30. Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther . 2010; 88:339-42. [PubMed 20664534]

31. Tapaninen T, Neuvonen PJ, Niemi M. Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol . 2011; 71:718-26. [PubMedCentral][PubMed 21204914]

32. Tapaninen T, Neuvonen PJ, Niemi M. Rifampicin reduces the plasma concentrations and the renin-inhibiting effect of aliskiren. Eur J Clin Pharmacol . 2010; 66:497-502. [PubMed 20179914]

33. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull . 1992; 22:2.

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35. Novartis Pharmaceuticals Corporation. Amturnide^® (aliskiren, amlodipine and hydrochlorothiazide) tablets prescribing information. East Hanover, NJ; 2015 Mar.

41. Noden Pharma. Tekturna^® HCT (aliskiren and hydrochlorothiazide) tablets prescribing information. Boston, MA; 2016 Nov.

42. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 0210709: Clinical and clinical pharmacology review. From FDA website.

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