Dosing & Uses
Dosage Forms & Strengths
May switch to aliskiren/amlodipine if patient inadequately controlled with aliskiren alone or amlodipine alone (or another dihydropyridine calcium channel blocker); may use as replacement therapy for patients currently maintained on aliskiren and amlodipine
Initial: 150 mg/5 mg PO qDay
If blood pressure remains uncontrolled after 2-4 weeks, may titrate upward as needed, not to exceed 300 mg/10 mg daily
<30 mL/min: Dose adjustment not necessary; use caution (monitor for hyperkalemia or renal dysfunction)
>30 mL/min: Dose adjustment not necessary
Use caution; consider lower initial dose; titrate slowly
High fat meals decrease bioavailability substantially
Safety and efficacy not established
In the short-term controlled clinical trials, 17% of patients treated were ≥65 yr; no overall differences in safety or effectiveness were observed between these subjects and younger subjects
Aliskiren AUC and Cmax increased by 57% and 28% respectively; no significant effect on clinical efficacy or safety
Amlodipine AUC increased by 40-60% in elderly patients ≥ 65 years and older; consider starting with lowest available dose of amlodipine (5 mg)
Serious - Use Alternative
Significant - Monitor Closely
Adverse reactions reported with combination product and individual agents
- Peripheral edema (2-15%)
Peripheral edema (6.2-8.9%)
- Diarrhea (2.3%)
- Cough (1.1%)
- Increased creatinine kinase (1%)
- Increased BUN (≤ 7%)
- Hyperkalemia (≤1%)
- Rash (1%)
- Flushing (1-5%)
- Palpitation (1-5%)
- Dizziness (1-3%)
- Fatigue (5%)
- Somnolence (1-2%)
- Rash (1-2%)
- Pruritus (1-2%)
- Male sexual dysfunction (1-2%)
- Nausea (3%)
- Dyspepsia (1-2%)
- Abdominal pain (1-2%)
- Muscle cramps (1-2%)
- Dyspnea (1-2%)
- Weakness (1-2%)
- Gastroesophageal reflux
- Periorbital edema
- Toxic epiderma necrolysis
- Increased uric acid
- Severe hypotension
- Stevens Johnson syndrome
- Abnormal vision
- Chest pain
- Abnormal dreams
- Increased apetite
- Acute interstitial nephritis
Black Box Warnings
Discontinue as soon as possible when pregnancy is detected; affects renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death
Pregnancy (2nd and 3rd trimesters; significant risk of fetal and neonatal morbidity/mortality; see Black Box Warnings)
Concomitant use with ACEIs or ARBs in patients with diabetes mellitus
Symptomatic hypotension may occur after initiation of treatment in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin‐ aldosterone system (RAAS); volume or salt depletion should be corrected prior to administration of therapy, or treatment should start under close medical supervision; a transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once blood pressure has stabilized
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation; treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement; prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary; discontinue therapy immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister
Increased angina or myocardial infarction with calcium channel blockers may occur upon dosage initiation or increased
Renal impairment: Decrease in renal function may be anticipated with susceptible individuals
Titrate slowly in patients with hepatic impairment or heart failure
Cyclosporine or itraconazole increase aliskiren levels; avoid concomitant use
Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients
Patients whose renal function may depend in part on activity of renin-angiotensin‐ aldosterone system (RAAS; e.g., patients with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion) or patients receiving ARB, ACE inhibitors or nonsteroidal anti-inflammatory drug (NSAID), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), therapy may be at particular risk of developing acute renal failure; monitor renal function periodically; consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function
Coadministration with ACE inhibitors or ARBs
- When aliskiren was prescribed with ACE inhibitors or angiotensin receptor blockers (ARBs) in the ALTITUDE study, an increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension was observed after 18-24 months
- The ALTITUDE trial included patients with hypertension plus type 2 diabetes and renal impairment who were at high risk of cardiovascular and renal events
- Coadministration of aliskiren with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with diabetes or kidney (renal) impairment; their use is contraindicated in patients with diabetes
- Avoid coadministration of aliskiren with ARBs or ACEIs in moderate to severe renal impairment (ie, GFR <60 mL/min)
- Hyperkalemia: Increases in serum potassium >5.5 mEq/L were infrequent with aliskiren (0.9% compared to 0.6% with placebo); however, when used in combination with an ACE inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%)
Pregnancy & Lactation
Hypertension in pregnancy increases maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage); hypertension increases fetal risk for intrauterine growth restriction and intrauterine death; pregnant women with hypertension should be carefully monitored and managed accordingly
Use of drugs that act on renin-angiotensin system in second and third trimesters of pregnancy can result in reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death
In patients taking the combination drug during pregnancy, perform serial ultrasound examinations to assess intra-amniotic environment; fetal testing may be appropriate, based on the week of gestation; patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury; closely observe infants with histories of in utero exposure to the drug combination for hypotension, oliguria, and hyperkalemia; if oliguria or hypotension occur in neonates with a history of in utero exposure to the drug combination, support blood pressure and renal perfusion; exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function
There is no information regarding the presence in human milk, the effects on the breastfed infant, or the effects on milk production; limited published studies report that amlodipine is present in human milk; however, there is insufficient information to determine effects of amlodipine on the breastfed infant; there is no available information on effects of amlodipine on milk production; because of potential for serious adverse reactions, including hypotension, hyperkalemia and renal impairment in nursing infants, advise a nursing woman that breastfeeding is not recommended during treatment
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Aliskiren: Renin inhibitor; blocks effect of increased renin levels, thereby decreasing feedback loop and reducing plasma renin activity, angiotensin I, and angiotensin II
Amlodipine: Calcium channel blocker; inhibits extracellular Ca ions across the membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction; this action causes dilation of the main coronary and systemic arteries
- Onset: Within 2 weeks
- Bioavailability: 3%
- Peak Plasma Time: 1-3 hr
- Metabolism: Metabolized by CYP3A4
- Half-Life: 24 hr
- Excretion: Urine (25% as parent compound in urine)
- Duration: 24 hr (antihypertensive effects)
- Vd: 21 L/kg
- Bioavailability: 64-90%
- Half-life: 30-50 hr
- Metabolism: Liver (>90%)
- Protein binding: 93-98%
- Peak plasma time: 6-12 hr
- Excretion: Urine (70%)
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