aliskiren/amlodipine/hydrochlorothiazide (Amturnide)

Dosing and uses of Amturnide (aliskiren/amlodipine/hydrochlorothiazide)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

aliskiren/amlodipine/hydrochlorothiazide

tablet

• 150mg/5mg/12.5mg
• 300mg/5mg/12.5mg
• 300mg/5mg/25mg
• 300mg/10mg/12.5mg
• 300mg/10mg/25mg

 

Hypertension

May use to substitute for individual components in patients currently maintained on all three agents separately; not for initial therapy

Initial: Dose once daily

May increase dose after 2 weeks; maximum recommended dose is 300mg/10mg/25mg

 

Administration

High fat meals decrease bioavailability substantially

May use for patients not adequately controlled with any two of the following: aliskiren, dihydropyridine calcium channel blockers, and thiazide diuretics

May switch a patient who experiences dose-limiting adverse reactions attributed to an individual component—while on any dual combination of the components of Amturnide—to Amturnide at a lower dose of that component to achieve similar blood pressure reductions

May use as replacement therapy for patients currently maintained on aliskiren, amlodipine and hydrochlorothiazide from separate tablets; substitute using the same component doses

 

Renal Impairment

CrCl <30 mL/min: Use caution; hydrochlorothiazide usually ineffective when CrCl <30 mL/min and contraindicated in anuric patients; hyperkalemia and progressive renal dysfunction may occur with aliskiren

CrCl ≥30 mL/min: Dose adjustment not necessary

 

Hepatic Impairment

Use caution; amlodipine elimination prolonged (consider lower initial dose titrate slowly)

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Geriatric dosage forms and strengths

In the short-term controlled clinical trial, 19% of patients treated were ≥ 65 yr; no overall differences in safety or effectiveness were observed between these subjects and younger subjects

Elderly patients have decreased clearance of amlodipine, with a resulting increase in AUC of approximately 40% - 60% in elderly patients ≥ 65 years; consider starting with lowest available dose of amlodipine (5 mg)

 

Amturnide (aliskiren/amlodipine/hydrochlorothiazide) adverse (side) effects

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

 

Warnings

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

 

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 and lactation

Pregnancy category: D (see Boxed Warning)

Lactation: excretion in milk unknown; breastfeeding not recommended while taking aliskiren/amlodipine/hydrochlorothiazide

 

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.

 

Pharmacology of Amturnide (aliskiren/amlodipine/hydrochlorothiazide)

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