Aliskiren

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
ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Central nervous system: Dizziness (2%) Dermatologic: Rash (1%) Endocrine and metabolic: Hyperkalemia (monotherapy 1%; concurrent with ACE inhibitor in diabetic patients 6%) Gastrointestinal: Diarrhea (1% to 2%) Hematologic: Creatine kinase increased (>300%: 1%) Renal: BUN increased (7%), serum creatinine increased (7%) Respiratory: Cough (1% to 5%)
<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, myositis, renal stone formation, rhabdomyolysis, seizure, severe hypotension, uric acid increased
CONTRAINDICATIONS — Hypersensitivity to aliskiren or any component of the formulation; history of idiopathic or hereditary angioedema; history of ACE inhibitor- or ARB-related angioedema; bilateral renal artery stenosis; pregnancy
WARNINGS / PRECAUTIONS Box warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: At any time during treatment (especially following first dose) angioedema can occur; it may involve head and neck (potentially affecting the airway) or the extremities. Prolonged 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. Discontinue immediately following any signs and symptoms of angioedema. 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).
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.
DRUG INTERACTIONS — Substrate of CYP3A4 (minor)
Atorvastatin: May increase the level/effect of aliskiren; monitor blood pressure.
Furosemide: Aliskiren may decrease the level/effect of furosemide.
Ketoconazole: May increase the level/effect of aliskerin; monitor blood pressure.
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decreases 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 2nd and 3rd trimesters. There are no adequate and well-controlled studies in pregnant women. Discontinue aliskiren as soon as possible after 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
MONITORING PARAMETERS — Serum potassium, BUN, serum creatinine
TOXICOLOGY / OVERDOSE COMPREHENSIVE — Limited experience with overdosage. Treatment is symptom-directed and supportive.
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 aliskerin is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous.
PHARMACODYNAMICS / KINETICS Onset of action: Maximum antihypertensive effect: Within 2 weeks
Absorption: Poor; absorption decreased by high-fat meal
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)