Generic Name: Aliskiren Hemifumarate
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

Introduction

Nonpeptide renin inhibitor.^{1 2 3 4 5 6 7 8 9 10}

Uses for Tekturna

Hypertension

Management of hypertension (alone or in combination with other antihypertensive agents).^{1 3 4 5 6 7 8 9 11 15}

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Most experience with combination therapy 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.¹

Not known whether effects of aliskiren and ACE inhibitors or aliskiren and β-adrenergic blocking agents are additive.¹ Whether aliskiren further improves BP control in patients receiving maximum dosages of an ACE inhibitor not established.¹

Use in combination with an ACE inhibitor or angiotensin II receptor antagonist is contraindicated in diabetic patients and is not recommended in patients with moderate or severe renal impairment (GFR <60 mL/minute).¹ (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Tekturna Dosage and Administration

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.^{1 9}

Dosage

Available as aliskiren hemifumarate; dosage expressed in terms of the base.¹

Adults

Hypertension

Oral

Initially, 150 mg once daily, alone or in combination with other antihypertensive agents.^{1 9 11} May increase dosage to 300 mg once daily if BP not adequately controlled;^{1 9} 85–90% of antihypertensive effect at a given dosage is attained within 2 weeks.¹

Dosages >300 mg daily do not appear to further increase BP response,^{1 2 3 6} but are associated with an increased frequency of diarrhea.^{1 6}

Special Populations

Hepatic Impairment

No initial dosage adjustment required in patients with mild to severe hepatic impairment.^{1 2 18} (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No initial dosage adjustment required in patients with renal impairment.^{1 16} No dosage adjustment required in patients undergoing hemodialysis.¹ (See Absorption: Special Populationsand also Elimination: Special Populations, under Pharmacokinetics.) However, manufacturer states safety and efficacy not established in patients with severe renal impairment.¹ (See Renal Impairment and also Other Warnings/Precautions under Cautions.)

Geriatric Patients

No initial dosage adjustment required.^{1 17} (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.¹

Cautions for Tekturna

Contraindications

• Use in combination with ACE inhibitors or angiotensin II receptor antagonists in patients with diabetes mellitus.¹ (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists 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.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

Discontinue as soon as possible when pregnancy is detected.¹

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.^{1 22 23} Incidence of stroke and death also slightly increased,^{1 23} but causal relationship not established.²³

Use in combination with ACE inhibitors or angiotensin II receptor antagonists is contraindicated in patients with diabetes mellitus; avoid combined use of these drugs in patients with moderate or severe renal impairment (GFR <60 mL/minute).^{1 23}

Sensitivity Reactions

Angioedema of face, extremities, lips, tongue, glottis, and/or larynx reported; has resulted in hospitalization and intubation.¹ May occur at any time during treatment.¹ Has occurred in patients with or without 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 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

Discontinue aliskiren immediately and permanently if angioedema occurs.¹

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).¹ (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.¹

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.¹ (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Renal Effects

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, 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.¹

Monitor renal function periodically.¹ Consider withholding or discontinuing therapy if clinically important deterioration of renal function occurs.¹

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.¹ (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).¹ (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Monitor serum potassium concentrations periodically.¹

Specific Populations

Pregnancy

Category D.¹ (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.¹ Discontinue nursing or the drug.^{1 11}

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

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.¹ (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.^{1 17} (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.¹ (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 GFR <60 mL/minute.¹ (See Use in Combination with ACE Inhibitors or Angiotensin II Receptor Antagonists under Cautions.)

Common Adverse Effects

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 S_cr,¹ increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.¹

Interactions for Tekturna

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

Metabolized by CYP3A4 in vitro;^{1 11} however, appears to undergo minimal hepatic metabolism.^{2 9 11 13 16} (See Elimination under Pharmacokinetics.)

Substrate^{1 11 13 16 17 27} but not inhibitor²⁷ of P-glycoprotein (P-gp). Preclinical studies indicate P-gp is the major efflux system involved in absorption and disposition of aliskiren.^{1 27} Potential for P-gp-related interactions likely depends on degree of P-gp inhibition.¹

Substrate of organic anion transport protein (OATP) 2B1.^{24 25 26 27 30 32}

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Increased risk of renal impairment, hyperkalemia, and hypotension in diabetic patients with renal disease1 23	Contraindicated in diabetic patients1 23 Avoid concomitant use if GFR <60 mL/minute1 23
Amlodipine	Clinically important pharmacokinetic interactions unlikely1 20	No dosage adjustment required1 20
Angiotensin II receptor antagonists	Increased risk of renal impairment, hyperkalemia, and hypotension in diabetic patients with renal disease1 23	Contraindicated in diabetic patients1 23 Avoid concomitant use if GFR <60 mL/minute1 23
Atenolol	Pharmacokinetic interactions unlikely1 21	No dosage adjustment required1
Atorvastatin	Increased peak plasma concentration and AUC of aliskiren by about 50%1 11 27 Clinically important changes in pharmacokinetics of atorvastatin unlikely1 27	No dosage adjustment required1 27
Celecoxib	Pharmacokinetic interactions unlikely1 21	No dosage adjustment required1
Cimetidine	Clinically important pharmacokinetic interactions unlikely1 21	No dosage adjustment required1
Cyclosporine	Increased aliskiren peak plasma concentration (by 2.5-fold), AUC (by fourfold to fivefold), and half-life (from 25 to 45–46 hours)1 25	Avoid concomitant use1 25
Digoxin	Pharmacokinetic interactions unlikely1 27	No dosage adjustment required1 27
Diuretics, potassium-sparing	May increase risk of hyperkalemia1
Fenofibrate	Pharmacokinetic interactions unlikely29	No dosage adjustment required29
Fruit juice (grapefruit, orange, apple)	Decreased peak plasma concentration and AUC of aliskiren by 80–84 and 61–63%, respectively; may reduce aliskiren's inhibitory effect on plasma renin activity (PRA)30 31	Generally avoid concomitant use30 31
Furosemide	No clinically important increases in systemic exposure to aliskiren1 28 Decreased peak plasma concentration and AUC of furosemide by 49 and 28%, respectively1 11 28	Effects of furosemide may be reduced following initiation of aliskiren therapy; however, no initial dosage adjustment required1
Hydrochlorothiazide	Clinically important pharmacokinetic interactions unlikely1 20 Dizziness more likely with combined therapy20	No initial dosage adjustment required1 20
Irbesartan	No substantial effect on plasma concentrations or AUC of aliskiren1 16	No dosage adjustment required1
Isosorbide mononitrate	Clinically important pharmacokinetic interactions unlikely28 Dizziness and low BP more likely with combined therapy28
Itraconazole	Increased peak plasma concentration and AUC of aliskiren by 5.8- and 6.5-fold, respectively; enhanced aliskiren's inhibitory effect on PRA1 24	Avoid concomitant use1 24
Ketoconazole	Ketoconazole 200 mg twice daily increased plasma concentrations and AUC of aliskiren by about 80%1 11 17 27	No dosage adjustment required1 27 Ketoconazole 400 mg once daily may have larger effect on exposure of aliskiren1
Lovastatin	Pharmacokinetic interactions unlikely1 21	No dosage adjustment required1
Metformin	Clinically important pharmacokinetic interactions unlikely1 29	No dosage adjustment required1 29
NSAIAs	May attenuate antihypertensive effect of aliskiren1 Possible deterioration of renal function, including acute renal failure, in geriatric patients and patients with volume depletion or compromised renal function; usually reversible1	Monitor renal function during concomitant therapy1
Pioglitazone	Pharmacokinetic interactions unlikely29	No dosage adjustment required29
Potassium supplements and potassium-containing salt substitutes	May increase risk of hyperkalemia1
Ramipril	Clinically important pharmacokinetic interactions unlikely1 20	No dosage adjustment required1 20
Rifampin	Decreased peak plasma concentration and AUC of aliskiren by 39 and 56%, respectively; reduced aliskiren's inhibitory effect on PRA32
Valsartan	Clinically important pharmacokinetic interactions unlikely1 20	No dosage adjustment required20
Verapamil	Increased peak plasma concentration and AUC of aliskiren by about twofold1 26 Clinically important changes in verapamil pharmacokinetics unlikely26	No dosage adjustment required1 26
Warfarin	Pharmacokinetic interactions unlikely;1 19 effect on warfarin pharmacodynamics unlikely19	No dosage adjustment required1

Tekturna Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed; oral bioavailability is about 2.5%.^{1 2 9 10 16}

Peak plasma concentrations usually attained within 1–3 hours following oral administration.^{1 2 9 13}

Onset

Substantial proportion (85–90%) of antihypertensive effect attained within 2 weeks of initiation of therapy.^{1 6 9}

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.^{1 2}

Special Populations

In geriatric patients AUC may be increased.^{1 17} (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.^{1 16} (See Renal Impairment under Dosage and Administration.)

In patients with mild to severe hepatic impairment, pharmacokinetics of drug not substantially altered.^{1 18}

Distribution

Extent

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

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Approximately 47–51%.^{2 16 20}

Elimination

Metabolism

In vitro studies suggest CYP3A4 is the main enzyme responsible for metabolism.^{1 9 11} However, amount of absorbed dose that undergoes metabolism not established;¹ drug appears to undergo minimal hepatic metabolism.^{2 9 11 13 16} Also a substrate for P-glycoprotein^{11 13 16 17} and OATP 2B1.^{24 25 26 27 30 32}

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;^{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 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 observed.¹¹

Special Populations

Poorly removed by hemodialysis.¹

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed to 15–30°C); protect from moisture.¹

Actions

• Binds with high affinity to plasma renin.⁹

• Inhibits conversion of angiotensinogen to angiotensin I and reduces plasma renin activity (PRA) and concentrations of angiotensin I, angiotensin II, and aldosterone.^{1 2 3 4 6 8 9 10}

• 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.^{1 9 10}

• Not known whether aliskiren affects other renin-angiotensin-aldosterone (RAA) system components (e.g., ACE, non-ACE pathways).¹

Advice to Patients

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

• Advise patients to take the drug once daily at same time every day, establishing a routine pattern with regard to food.^{1 11} 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 to take it as soon as it is remembered.¹ If it is almost time for the next dose, omit the missed dose and administer the next dose at the regularly scheduled time.¹

• Risk of angioedema, including laryngeal edema; importance of discontinuing the drug and immediately reporting suggestive manifestations (e.g., edema of face, extremities, eyes, lips, or tongue; swallowing or breathing with difficulty) to a clinician.¹

• Risk of fetal and neonatal morbidity and death when 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.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 consulting clinician.¹

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

Preparations

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

Aliskiren Hemifumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	150 mg (of aliskiren)	Tekturna	Novartis
		300 mg (of aliskiren)	Tekturna	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Amturnide 300-10-25MG Tablets (NOVARTIS): 30/$109.99 or 90/$305.96

Tekamlo 300-10MG Tablets (NOVARTIS): 30/$119.99 or 90/$339.98

Tekturna 150MG Tablets (NOVARTIS): 30/$97.92 or 90/$277.43

Tekturna 300MG Tablets (NOVARTIS): 30/$123.00 or 90/$349.96

Tekturna HCT 300-25MG Tablets (NOVARTIS): 30/$123.41 or 90/$341.66

Valturna 150-160MG Tablets (NOVARTIS): 30/$95.99 or 90/$270.97