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
Brands: Tekturna

• 
  

  May cause fetal and neonatal morbidity and mortality if used during pregnancy.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  If pregnancy is detected, discontinue aliskiren as soon as possible.¹

  
  

Introduction

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

Uses for Aliskiren Hemifumarate

Hypertension

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

Most experience with combination therapy to date has been with diuretics or an angiotensin II receptor antagonist (valsartan); concomitant use of aliskiren with either 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

Aliskiren Hemifumarate Dosage and Administration

Administration

Oral Administration

Manufacturer recommends that patients establish a routine pattern for taking 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}

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 Special Populations under Pharmacokinetics.)

Renal Impairment

No initial dosage adjustment required in patients with mild to severe renal impairment; however, select dosage with caution in patients with severe renal impairment (S_cr >1.7 mg/dL [women] or S_cr >2 mg/dL [men], and/or GFR <30 mL/minute) as clinical experience is limited.^{1 2 11 16} (See Special Populations under Pharmacokinetics and see Renal Effects under Cautions.)

Geriatric Patients

No initial dosage adjustment required.^{1 17} (See Geriatric Use under Cautions and see 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 Aliskiren Hemifumarate

Contraindications

Manufacturer states that there are no contraindications to use of aliskiren.^{1 11}

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.¹ (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.¹

Retrospective data indicate that ACE inhibitors, a class of drugs acting on the renin-angiotensin-aldosterone (RAA) system, have been associated with an increased risk of major congenital malformations when administered during the first trimester of pregnancy.¹

Discontinue as soon as possible when pregnancy is detected.¹

Hypotension

Excessive hypotension reported rarely in patients with uncomplicated hypertension receiving the drug alone and infrequently during combination therapy with other antihypertensive agents.^{1 11}

Possible symptomatic hypotension, particularly in 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.)

If excessive hypotension occurs, place patient in supine position and, if necessary, administer IV infusion of 0.9% sodium chloride injection.¹ Transient hypotension is not a contraindication to further treatment, which usually may be continued without difficulty once BP is stabilized.¹

Sensitivity Reactions

Angioedema of face, extremities, lips, tongue, glottis and/or larynx reported; angioedema associated with laryngeal or tongue edema may be fatal.¹ Angioedema associated with respiratory symptoms, periorbital edema without respiratory symptoms, and edema involving the face, hands, or whole body reported rarely.¹

If angioedema occurs, promptly discontinue drug and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms.¹ Provide immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.¹ Antihistamines and corticosteroids may not prevent respiratory involvement; prolonged observation may be necessary.¹

General Precautions

Renal Effects

Use with caution in patients with severe renal impairment (S_cr >1.7 mg/dL [women] or S_cr >2.0 mg/dL [men], and/or GFR <30 mL/minute) or history of peritoneal or hemodialysis, nephrotic syndrome, or renovascular hypertension; safety not established and potential risk of increased S_cr or BUN associated with other drugs acting on the RAA system.^{1 11}

Minor increases in BUN or S_cr observed in patients with essential hypertension receiving the drug alone.¹

Hyperkalemia

Increases in serum potassium >5.5 mEq/L reported infrequently in patients receiving the drug alone.¹

Increased serum potassium reported more frequently during combination therapy with ACE inhibitors in diabetic patients; routinely monitor electrolytes and renal function.^{1 11}

Specific Populations

Pregnancy

Category C (first trimester); Category D (second and third trimesters).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

Geriatric Use

BP response and adverse reactions similar to those in younger adults.^{1 17} (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Renal Impairment

Use with caution in patients with severe renal impairment.^{1 11} (See Renal Effects under Cautions.)

Select dosage with caution in patients with severe renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,¹ headache,¹ dizziness,¹ fatigue,¹ upper respiratory tract infection,¹ nasopharyngitis,¹ cough,¹ back pain.¹

Interactions for Aliskiren Hemifumarate

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} (See Metabolism under Pharmacokinetics.)

Specific Drugs

Drug	Interaction	Comments
Amlodipine	Clinically important pharmacokinetic interactions unlikely1 20	No initial dosage adjustment of aliskiren required20
Atenolol	Clinically important pharmacokinetic interactions unlikely1 21	Further study of long-term concomitant administration may be required21
Atorvastatin	Increased peak plasma concentration and AUC of aliskiren by about 50% following multiple dosing1 11 Pharmacokinetics of atorvastatin not substantially affected by aliskiren1
Celecoxib	Clinically important pharmacokinetic interactions unlikely1 21	Further study of long-term concomitant administration may be required21
Cimetidine	Clinically important pharmacokinetic interactions unlikely21	Further study of long-term concomitant administration may be required21
Digoxin	Pharmacokinetic interactions unlikely1
Furosemide	Concomitant administration does not appear to result in clinically important increases in systemic exposure to aliskiren1 Decreased peak plasma concentration and AUC of furosemide with concomitant administration1 11	Effects of furosemide may be reduced following initiation of aliskiren therapy1
Hydrochlorothiazide	Clinically important pharmacokinetic interactions unlikely1 20	No initial dosage adjustment of aliskiren required20
Irbesartan	May decrease peak plasma concentration of aliskiren by up to 50% following multiple dosing1 11 16
Ketoconazole	Increased plasma concentrations of aliskiren by about 80%1 11 17
Lovastatin	Clinically important pharmacokinetic interactions unlikely1 21	Further study of long-term concomitant administration may be required21
Metformin	Pharmacokinetic interactions unlikely1
Ramipril	Clinically important pharmacokinetic interactions unlikely1 20	No initial dosage adjustment of aliskiren required20
Valsartan	Clinically important pharmacokinetic interactions unlikely1 20	No initial dosage adjustment of aliskiren required20
Warfarin	Concomitant administration does not appear to result in clinically important increases in systemic exposure to aliskiren1 Effects of aliskiren on warfarin pharmacokinetics not established in a well-controlled clinical study1 19

Aliskiren Hemifumarate 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, systemic exposure to drug (measured by 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, rate and extent of systemic exposure (peak plasma concentration and AUC) to drug were increased; however, changes in exposure did not consistently correlate with severity of renal impairment.^{1 16} (See Renal Impairment under Dosage and Administration and see Renal Effects under Cautions.)

In patients with mild to severe hepatic impairment, pharmacokinetics of drug not substantially altered.^{1 18} (See Hepatic Impairment under Dosage and Administration.)

Distribution

Extent

Crosses the placenta and is distributed in 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

Amount of absorbed dose that undergoes metabolism not established;¹ however, drug appears to undergo minimal hepatic metabolism.^{2 9 11 13 16} CYP3A4 appears to be main enzyme responsible for metabolism of drug based on in vitro studies.^{1 9 11} Also a substrate for p-glycoprotein.^{11 13 16 17}

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

Stability

Storage

Oral

Tablets

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

ActionsActions

• 
  

  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 RAA system components (e.g., ACE, non-ACE pathways).¹

  
  

Advice to Patients

• 
  

  Advise patients to take the drug once daily, at same time every day establishing a routine pattern with regard to food.^{1 11}

  
  


• 
  

  Importance of advising patient that if a dose of aliskiren is missed to take it as soon as 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 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

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.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 (with povidone)	Novartis
		300 mg (of aliskiren)	Tekturna (with povidone)	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tekturna 150MG Tablets (NOVARTIS): 30/$96.99 or 90/$271.96

Tekturna 300MG Tablets (NOVARTIS): 30/$119.99 or 90/$342.96

Tekturna HCT 300-25MG Tablets (NOVARTIS): 30/$120.99 or 90/$334.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis. Tekturna (aliskiren) tablets prescribing information. East Hanover, NJ; 2007 Apr.

2. Van Tassell BW, Munger MA. Aliskiren for renin inhibition: a new class of antihypertensives. Ann Pharmacother. 2007; 41:456-64. [PubMed 17341529]

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]

9. Anon. Aliskiren (Tekturna) for hypertension. Med Lett Drugs Ther. 2007; 49:29-31. [PubMed 17415282]

10. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet. 2006; 368:1449-56. [PubMed 17055947]

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

12. Stanton A, Jensen C, Nussberger J et al. Blood pressure lowerirng in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42:1137-43. [PubMed 14597641]

13. Waldmeier F, Glaenzel U, Wirz B et al. Absorption, distribution, metabolism, and elimination of the direct Renin inhibitor aliskiren in healthy volunteers. Drug Metab Dispos. 2007; 35:1418-28. [PubMed 17510248]

14. Nussberger J, Wuerzner G, Jensen C et al. Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100): comparison with enalapril. Hypertension. 2002; 39:E1-8. [PubMed 11799102]

15. Oparil S, Yarows SA, Patel S et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007; 370:221-9. [PubMed 17658393]

16. Vaidyanathan S, Bigler H, Yeh CM et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet. 2007; 46:661-75. [PubMed 17655373]

17. Vaidyanathan S, Reynolds C, Yeh CM et al. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. J Clin Pharmacol. 2007; 47:453-60. [PubMed 17389554]

18. Vaidyanathan S, Warren V, Yeh CM et al. Pharmacokinetics, safety, and tolerability of the oral renin inhibitor aliskiren in patients with hepatic impairment. J Clin Pharmacol. 2007; 47:192-200. [PubMed 17244770]

19. Dieterle W, Corynen S, Mann J. Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects. Br J Clin Pharmacol. 2004; 58:433-6. [PubMed 15373937]

20. Vaidyanathan S, Valencia J, Kemp C et al. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. Int J Clin Pract. 2006; 60:1343-56. [PubMed 17073832]

21. Dieterle W, Corynen S, Vaidyanathan S et al. Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine. Int J Clin Pharmacol Ther. 2005; 43:527-35. [PubMed 16300168]

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