aliskiren/amlodipine/hydrochlorothiazide (Rx)

Adverse reactions reported with combination product and individual agents

1-10%

Peripheral edema (7.1%)

Dizziness (3.6%)

Headache (3.6%)

Nasopharyngitis (2.6%)

Amlodipine

• Palpitation (1-5%)
• Dizziness (1-3%)
• Flushing (1-5%)
• Somnolence (1-2%)
• Rash (1-2%)
• Fatigue (5%)
• Pruritus (1-2%)
• Male sexual dysfunction (1-2%)
• Nausea (3%)
• Dyspepsia (1-2%)
• Dyspnea (1-2%)
• Weakness (1-2%)

Aliskiren

• Diarrhea (2.3%)
• Cough (1.1%)
• Increased creatinine kinase (1%)
• Increased BUN (≤ 7%)
• Hyperkalemia (≤1%)
• Rash (1%)

<1%

Angioedema

Increased BUN

Increased creatinine

Hyperkalemia

Hypotension

Aliskiren

• Gastroesophageal reflux
• Periorbital edema
• Toxic epiderma necrolysis
• Increased uric acid
• Severe hypotension
• Stevens Johnson syndrome

Amlodipine

• Abnormal vision
• Arthralgia
• Chest pain
• Abnormal dreamsIncreased apetite
• Acute interstitial nephritis
• Alopecia
• Conjunctivitis
• Cough
• Depression
• Dysphagia
• Flatulence

Frequency Not Defined

Hydrochlorothiazide

• Anorexia
• Epigastric distress
• Hypotension
• Orthostatic hypotension
• Photosensitivity
• Anaphylaxis
• Anemia
• Confusion
• Erythema multiforme
• Stevens-Johnson syndrome
• Exfoliative dermatitis including toxic epidermal necrolysis
• Dizziness
• Hypokalemia and/or hypomagnesemia
• Hyperuricemia
• Headache

Postmarketing Reports

Aliskiren: Nausea/vomiting, hyponatremia

Contraindications

Hypersensitivity to aliskiren, amlodipine, hydrochlorothiazide, sulfonamide-derived drugs, or components of the formulation

Anuria

Pregnancy (2nd and 3rd trimesters): significant risk of fetal and neonatal morbidity/mortality

Concomitant use with ACEIs or ARBs in patients with diabetes

Cautions

Avoid use of aliskiren with ARBs or ACEIs in moderate to severe renal impairment (ie, GFR <60 mL/min); contraindicated in patients with diabetes

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

Increased angina or myocardial infarction may occur on dosage initiation or increase on amlodipine

Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with aliskiren and has necessitated hospitalization and intubation; this may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACEIs or angiotensin receptor antagonists; patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures; 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

Hydrochlorothiazide may exacerbate or activate systemic lupus erythematosus

Acute transient myopia and acute angle-closure glaucoma has been reported, particularly with history of sulfonamide or penicillin allergy (hydrochlorothiazide is a sulfonamide)

Gradual titration is necessary in patients with hepatic impairment

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

Serum potassium levels: Hydrochlorothiazide can cause hypokalemia and hyponatremia, whereas aliskiren may cause hyperkalemia; monitor serum electrolytes periodically

Hydrochlorothiazide may alter glucose tolerance and increase serum cholesterol and triglycerides

Cyclosporine or itraconazole increase aliskiren levels; avoid concomitant use

Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients

Coadministration with NSAIDs increase risk for renal impairment; monitor renal function periodically

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
• 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: Can cause fetal harm when administered to a pregnant woman; use of drugs that act on renin-angiotensin system during second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death; when pregnancy is detected discontinue therapy as soon as possible

Hypertension in pregnancy increases the 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

Aliskiren: If oliguria or hypotension occur in neonates with a history of in utero exposure to therapy, 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

Lactation: There is no information regarding therapy in human milk, effects on the breastfed infant, or the effects on milk production; amlodipine and hydrochlorothiazide reported by some studies to be present in human milk; there is insufficient information to determine effects of amlodipine and hydrochlorothiazide on breastfed infant and effects of hydrochlorothiazide on milk production; there is no available information on effects of amlodipine on milk production; because of potential for serious adverse reactions, including hypotension, electrolyte imbalances and renal impairment, in nursing infants, advise a nursing woman that breastfeeding is not recommended during therapy

Pregnancy Categories

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

Hydrochlorothiazide: Thiazide diuretic; affects the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride; diuretic action reduces plasma volume, increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium

Pharmacokinetics

Aliskiren

• 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)

Amlodipine

• 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%)

Hydrochlorothiazide

• Half-Life: 6-15 hr
• Bioavailability: 70%
• Onset: 2 hr (diuresis); 4-6 hr (peak effect)
• Duration: 6-12 hr (diuresis); 1 wk (HTN)
• Vd: 3.6-7.8 L/kg
• Peak Plasma:1.5-2.5 hr
• Protein Bound: 68%
• Metabolism: Minimally metabolized
• Clearance: 335 mL/min
• Excretion: Urine 50-70%
• Dialyzable: No