Aliskiren

MEDICATION SAFETY ISSUES
International issues:
Aliskiren may be confused with Aliseum which is a brand name for diazepam in Italy

U.S. BRAND NAMES — Tekturna®

PHARMACOLOGIC CATEGORY
Renin Inhibitor

DOSING: ADULTS — Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment initiation.

DOSING: PEDIATRIC — Children <18 years: Dosage not established.

DOSING: ELDERLY — Refer to adult dosing. No initial dosage adjustment required.

DOSING: RENAL IMPAIRMENT
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required

Severe impairment [GFR<30>1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment

DOSING: HEPATIC IMPAIRMENT — No dosage adjustment required.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
Tekturna®: 150 mg, 300 mg

DOSAGE FORMS: CONCISE
Tablet:
Tekturna®: 150 mg, 300 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.

USE — Treatment of hypertension, alone or in combination with other antihypertensive agents

USE - UNLABELED / INVESTIGATIONAL — Treatment of persistent proteinuria in patients with type 2 diabetes mellitus, hypertension, and nephropathy despite administration of optimized recommended renoprotective therapy (eg, angiotensin II receptor blocker)

ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (2%)
Dermatologic: Rash (1%)
Endocrine & metabolic: Hyperkalemia (monotherapy ≤ 1%; concurrent with ACE inhibitor in patients with diabetes 6%)
Gastrointestinal: Diarrhea (1% to 2%)
Hematologic: Creatine kinase increased (>300%: 1%)
Renal: BUN increased (≤ 7%), serum creatinine increased (≤ 7%)
Respiratory: Cough (1%)

<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, hypotension (severe), myositis, renal stone formation, rhabdomyolysis, seizure, uric acid increased

CONTRAINDICATIONS
U.S. labeling: There are no contraindications listed in manufacturer's labeling.

Canada labeling: Hypersensitivity to aliskiren or any component of the formulation

WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.

Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Hyperkalemia: May occur (rarely) during monotherapy; risk may increase in patients with predisposing factors (eg, renal dysfunction, diabetes mellitus or concomitant use with ACE inhibitors, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts). Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in patients with an activated renin-angiotensin system (ie, volume or salt-depleted patients)

Disease-related concerns: Renal impairment: Use with caution in patients with severe renal impairment; not studied in patients with severe renal impairment [GFR <30>1.7 mg/dL (women); Scr >2 mg/dL (men)], history of dialysis, nephrotic syndrome, or renovascular hypertension. Use with caution or avoid in patients with deteriorating renal function or renal artery stenosis (bilateral or unilateral).

Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine).

Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (minor)

DRUG INTERACTIONS
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy

CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy

MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decrease absorption.

PREGNANCY RISK FACTOR — C (show table) (1st trimester); D (2nd and 3rd trimesters)

PREGNANCY IMPLICATIONS — Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.

LACTATION — Excretion in breast milk unknown/not recommended

DIETARY CONSIDERATIONS — May be taken with or without food; however, a high-fat meal reduces absorption

PRICING — (data from drugstore.com)
Tablets (Tekturna)
150 mg (30): $82.38
300 mg (30): $101.80

MONITORING PARAMETERS — Blood pressure; serum potassium, BUN, serum creatinine

CANADIAN BRAND NAMES — Rasilez®

INTERNATIONAL BRAND NAMES — Enviage (EE); Rasilez (BE, CH, CZ, DE, DK, EE, GB, ID, IE, IL, NO, PE, PH, SE); Tekturna (EE)

MECHANISM OF ACTION — Aliskerin is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Ang II also functions within the Renin-Angiotensin-Aldosterone System (RAAS) as a negative inhibitory feedback mediator within the renal parenchyma to suppress the further release of renin. Thus, reductions in Ang II levels suppress this feedback loop, leading to further increased plasma renin concentrations (PRC) and subsequent activity (PRA). This disinhibition effect can be potentially problematic for ACE inhibitor and ARB therapy, as increased PRA could partially overcome the pharmacologic inhibition of the RAAS. As aliskiren is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous. The effect of aliskiren on bradykinin levels is unknown.

PHARMACODYNAMICS / KINETICS
Onset of action: Maximum antihypertensive effect: Within 2 weeks

Absorption: Poor; absorption decreased by high-fat meal. Aliskiren is a substrate of P-glycoprotein; concurrent use of P-glycoprotein inhibitors may increase absorption.

Metabolism: Extent of metabolism unknown; in vitro studies indicate metabolism via CYP3A4

Bioavailability: ~3%

Half-life elimination: ~24 hours (range: 16-32 hours)

Time to peak, plasma: 1-3 hours

Excretion: Urine (~25% of absorbed dose excreted unchanged in urine); feces (unchanged via biliary excretion)