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Aliskiren Hemifumarate

Pronunciation

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

Warning(s)

  • May cause fetal 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

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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.)

Aliskiren Hemifumarate 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 Aliskiren Hemifumarate

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 (Clcr <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 Scr,1 increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations.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 however, appears to undergo minimal hepatic metabolism.2 9 11 13 16 (See Elimination under Pharmacokinetics.)

Substrate1 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

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 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-glycoprotein11 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 02/2014. 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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis. Tekturna (aliskiren) tablets prescribing information. East Hanover, NJ; 2012 Mar.

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]

22. Parving HH, Brenner BM, McMurray JJ et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant. 2009; 24:1663-71. [PubMed 19145003]

23. US Food and Drug Administration. FDA drug safety communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). Rockville, MD; 2012 Apr 20. From FDA website.

24. Tapaninen T, Backman JT, Kurkinen KJ et al. Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. J Clin Pharmacol. 2011; 51:359-67. [PubMed 20400651]

25. Rebello S, Compain S, Feng A et al. Effect of cyclosporine on the pharmacokinetics of aliskiren in healthy subjects. J Clin Pharmacol. 2011; 51:1549-60. [PubMed 21406600]

26. Rebello S, Leon S, Hariry S et al. Effect of verapamil on the pharmacokinetics of aliskiren in healthy participants. J Clin Pharmacol. 2011; 51:218-28. [PubMed 20413453]

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]

29. Vaidyanathan S, Maboudian M, Warren V et al. A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects. Curr Med Res Opin. 2008; 24:2313-26. [PubMed 18786303]

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. [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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