Aliskiren Hemifumarate

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 34 35

Dosage

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

Adults

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

Fixed-combination aliskiren/amlodipine tablets may be used for initial treatment of hypertension in patients likely to require combination therapy with multiple antihypertensive agents to control BP.34

If the patient's baseline BP is 157/100 mm Hg, the estimated probability of achieving SBP control (SBP <140 mm Hg) is 49, 62, or 74% and of achieving DBP control (DBP <90 mm Hg) is 50, 69, or 83% with aliskiren (300 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with aliskiren (same dosages), respectively.34

Can use the fixed combination as a substitute for the individually administered drugs.34 Can switch to the fixed-combination preparation containing the corresponding individual doses of aliskiren and amlodipine; alternatively, can increase the dosage of one or both components for additional antihypertensive effects.34

If BP is not adequately controlled by monotherapy with aliskiren or amlodipine (or another dihydropyridine-derivative calcium-channel blocker), can switch to aliskiren/amlodipine fixed combination.34

If dose-limiting adverse effects have developed during monotherapy with aliskiren or amlodipine, can switch to an aliskiren/amlodipine fixed-combination preparation containing a lower dose of that drug to achieve similar BP control.34

When used for initial therapy of hypertension in patients likely to require combination therapy with multiple antihypertensive agents, recommended initial dosage is aliskiren 150 mg and amlodipine 5 mg once daily.34

May adjust dosage after 2–4 weeks at current dosage, up to maximum of 300 mg of aliskiren and 10 mg of amlodipine once daily; most of the antihypertensive effect of a given dosage is achieved within 1–2 weeks after a change in dosage.34

Manufacturer states fixed-combination preparation should not be used for initial treatment of hypertension.35

Can switch to fixed-combination aliskiren/amlodipine/hydrochlorothiazide tablets if BP is not adequately controlled by combined therapy with any 2 of the following: aliskiren, dihydropyridine-derivative calcium-channel blockers, or thiazide diuretics.35

In patients who experience dose-limiting adverse effects of aliskiren, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs, may switch to the triple fixed-combination preparation containing a lower dose of that component.35

Can use the fixed combination as a substitute for the individually titrated drugs.35

May increase dosage of the fixed combination after 2 weeks if additional BP control is needed (up to maximum of aliskiren 300 mg, amlodipine 10 mg, and hydrochlorothiazide 25 mg once daily).35

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.)

Fixed-combination preparations containing aliskiren and amlodipine (with or without hydrochlorothiazide) exceed recommended initial amlodipine dosage (2.5 mg daily) for patients with hepatic impairment.34 35 36

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.)

Fixed-combination preparations containing aliskiren and amlodipine (with or without hydrochlorothiazide) exceed recommended initial amlodipine dosage (2.5 mg daily) for geriatric patients.34 35 36

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiating therapy or initiate therapy under close medical supervision.1

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

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 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

When used in fixed combination with amlodipine with or without hydrochlorothiazide, consider cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).34 35 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.34 35

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

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.)

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.)

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

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1 11

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.)

No overall differences in efficacy or safety compared with younger adults, but increased sensitivity cannot be ruled out.1 17 34 35 (See Geriatric Patients under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

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

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

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

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

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