Dosing and uses of Exforge HCT (valsartan-amlodipine-hydrochlorothiazide)
Adult dosage forms and strengths
valsartan/amlodipine/hydrochlorothiazide
tablet
- 5mg/160mg/12.5mg
- 5mg/160mg/25mg
- 10mg/160mg/12.5mg
- 10mg/160mg/25mg
- 10mg/320mg/25mg
Hypertension
5-10 mg amlodipine/160-320 mg valsartan/12.5-25 mg hydrochlorothiazide qDay; may titrate dose after 2 weeks
Use in patients not adequately controlled with monotherapy; may use as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals
Indicated for patients not adequately controlled on any 2 of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics, Or
Indicated for substitution for the individually titrated drug components
May increase dose after 2 weeks if needed
Not to exceed 10 mg/320 mg/25 mg PO once-daily
Renal & Hepatic Impairment
Renal impairment
- Mild or moderate (CrCl ≥30 mL/min): No dose adjustment necessary
- Severe (CrCl <30 mL/min): Safety and effectiveness not established
Hepatic impairment
- Not recommended for initial therapy; amlodipine 2.5 mg is not an available strength with available dosage forms for this drug combination
- Amlodipine: Extensively metabolized by liver and half-life increased (56 hr) with impaired hepatic function
- Valsartan: No dose adjustment necessary with mild-to-severe hepatic impairment
- Hydrochlorothiazide: Minor alterations of fluid and electrolyte balance may cause hepatic coma in patients with impaired hepatic function
Pediatric dosage forms and strengths
Safety/efficacy not established
Geriatric dosage forms and strengths
Hypertension
Not recommended for initial therapy; amlodipine 2.5 mg is not an available strength with available dosage forms for this drug combination
Initiate with 2.5 mg PO qDay; may titrate dose after 2 weeks
Indicated for patients not adequately controlled on any 2 of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics, Or
Indicated for substitution for the individually titrated drug components
May increase dose after 2 weeks if needed
Not to exceed 10 mg/320 mg/25 mg PO once-daily
Exforge HCT (valsartan-amlodipine-hydrochlorothiazide) adverse (side) effects
>10%
Amlodipine
- Edema (1.8-10.8%)
1-10%
Amlodipine
- Headache (7.3%)
- Fatigue (4.5%)
- Palpitation (0.7-4.5%)
- Dizziness (1.1-3.4%)
- Flushing (0.7-2.6%)
- Nausea (2.9%)
- Abdominal pain (1.6%)
- Somnolence (1.4%)
Valsartan
- Hyperkalemia (4-10%)
- Dizziness (2-8%)
- Hypotension (1-7%)
- Fatigue (3%)
Hydrochlorothiazide
- Anorexia
- Epigastric distress
- Hypokalemia
- Hypotension
- Phototoxicity
<1%
Hydrochlorothiazide
- Anaphylaxis
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Disorder of hematopoietic structure
- Hepatotoxicity
- Pancreatitis
Frequency not defined
Valsartan
- Headache
- Cough (rare, esp compared to ACE inhibitors)
Hydrochlorothiazide
- Confusion
- Hypomagnesemia
- Metabolic acidosis
- Dizziness
- Fatigue
- Headach
- Hypercalcemia
- Hyperuricemia, Hyperglycemia, Hyperlipidemia, Hypercholesterolemia, Muscle weakness or cramps, Nausea, Purpura, Rash, Vertigo, Vomiting
Postmarketing Reports
Valsartan
- Hypersensitivity: Angioedema (rare)
- Digestive: Elevated liver enzymes, hepatitis (rare)
- Renal: Impaired renal function, renal failure
- Clinical laboratory tests: Hyperkalemia
- Dermatologic: Alopecia, bullous dermatitis
- Blood and lymphatic: Thrombocytopenia (rare)
- Vascular: Vasculitis
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 valsartan, amlodipine, sulfonamide drugs, or other ingredients
Pregnancy (2nd and 3rd trimesters): Significant risk of fetal/neonatal morbidity and mortality
Anuria
Coadministration with aliskiren in patients with diabetes
Cautions
Avoid with severe hepatic impairment or renal impairment (ie, CrCl <30 mL/min)
Excessive hypotension may occur (rare); caution if volume/salt depleted, initiate cautiously in patients with heart failure, recent MI, or those undergoing surgery or dialysis
Worsening angina and acute MI may occur after starting or increasing amlodipine dose, particularly with severe obstructive CAd
Patients whose renal function may depend in part on the activity of the renin angiotensin system (eg, patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion); correct volume depletion prior to initiation
Dual blockade of the renin angiotensin system with ARBs, ACE inhibitors, or aliskiren associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy; closely monitor blood pressure
Acute transient myopia and acute angle-closure glaucoma has been reported, particularly with history of sulfonamide or penicillin allergy (hydrochlorothiazide is a sulfonamide)
Hydrochlorothiazide may exacerbate SLe
Hydrochlorothiazide may alter glucose tolerance and raise serum calcium, cholesterol, and triglycerides
Pregnancy and lactation
Pregnancy category: C (1st trimester); D (2nd & 3rd trimesters)
Lactation: Discontinue drug or do not nurse
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 Exforge HCT (valsartan-amlodipine-hydrochlorothiazide)
Mechanism of action
Amlodipine: Calcium channer blocker; blocks contractile effects of calcium on cardiac and vascular smooth muscle cells; results in peripheral arterial vasidilation, decreased peripheral vascular resistance, and blood pressure reduction
Valsartan: Angiotensin receptor blocker; blocks vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal, and renal cells
Hydrochlorothiazide: Thiazide diuretic; directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume
Pharmacokinetics
Bioavailability
- Amlodipine: 64-90%
- Valsartan: 10-35%
- Hydrochlorothiazide: 50-80%
Peak Concentration Time
- Amlodipine: 6 hr
- Valsartan: 3 hr
- Hydrochlorothiazide: 2 hr
Half-Life
- Amlodipine: 30-50 hr (terminal elimination half-life)
- Valsartan: 6 hr
- Hydrochlorothiazide: 5.8-18.9 hr
Vd
- Amlodipine: 21 L/kg
- Valsartan: 17 L/kg
- Hydrochlorothiazide: 3.6-7.8 L/kg
Protein Bound
- Amlodipine: 93%
- Valsartan: 95%
- Hydrochlorothiazide: 68%
Metabolism
- Amlodipine: 90% converted to inactive metabolites via hepatic metabolism
- Valsartan: 20% metabolized via CYP2C9
- Hydrochlorothiazide: Not metabolized
Excretion
- Amlodipine: 10% parent compound and 60% metabolites excreted in urine
- Valsartan: 83% (feces); 13% (urine)
- Hydrochlorothiazide: 61% excreted unchanged in urine
