Valsartan - Drug Monograph

Introduction

Valsartan is an angiotensin II receptor blocker (ARB) used primarily in the management of hypertension, heart failure, and post-myocardial infarction. As a selective antagonist of the angiotensin II type 1 (AT1) receptor, it represents a cornerstone therapy in cardiovascular medicine with proven efficacy in improving clinical outcomes across multiple cardiovascular conditions.

Mechanism of Action

Valsartan selectively blocks the binding of angiotensin II to the AT1 receptor found in vascular smooth muscle, adrenal glands, and other tissues. By inhibiting angiotensin II-mediated vasoconstriction, aldosterone secretion, and sympathetic nervous system activation, valsartan produces:

• Arterial and venous vasodilation
• Reduced systemic vascular resistance
• Decreased blood pressure
• Attenuation of cardiac remodeling in heart failure
• Reduction of afterload in left ventricular dysfunction

Unlike ACE inhibitors, valsartan does not inhibit kininase II, thereby avoiding bradykinin-mediated side effects such as cough and angioedema.

Indications

• Hypertension (monotherapy or combination therapy)
• Heart failure (NYHA Class II-IV) to reduce hospitalization
• Post-myocardial infarction in clinically stable patients with left ventricular dysfunction or heart failure

• Diabetic nephropathy (often used off-label)
• Migraine prophylaxis (off-label)

Dosage and Administration

• Initial dose: 80-160 mg once daily
• Maintenance dose: 80-320 mg daily
• Maximum dose: 320 mg daily

• Initial dose: 40 mg twice daily
• Target dose: 160 mg twice daily

• Initial dose: 20 mg twice daily
• Titration to target dose: 160 mg twice daily

• Renal impairment: No initial dosage adjustment required, but monitor closely
• Hepatic impairment: Use caution in moderate to severe impairment (start with 40 mg daily)
• Elderly: No dosage adjustment required
• Pediatric: 6-16 years: 1.3 mg/kg once daily (max 40 mg daily)

• Can be taken with or without food
• Consistent timing recommended
• Tablets should be swallowed whole

Pharmacokinetics

• Rapidly absorbed after oral administration
• Bioavailability: ~25%
• Time to peak concentration: 2-4 hours
• Food decreases AUC by approximately 40% and Cmax by approximately 50%

• Volume of distribution: ~17 liters
• Protein binding: ~95% (primarily albumin)
• Crosses placenta and enters breast milk

• Minimal hepatic metabolism via CYP2C9 (less than 20%)
• No active metabolites

• Primarily excreted unchanged in feces (~83%) and urine (~13%)
• Elimination half-life: ~6 hours
• Not significantly removed by hemodialysis

Contraindications

• Hypersensitivity to valsartan or any component of the formulation
• Concomitant use with aliskiren in patients with diabetes
• Pregnancy (second and third trimesters)
• Severe hepatic impairment, cirrhosis, or biliary obstruction

Warnings and Precautions

• FDA Pregnancy Category D (second and third trimesters)
• Can cause fetal injury and death
• Discontinue immediately when pregnancy is detected

• Monitor renal function in patients with renal artery stenosis
• May cause acute renal failure in susceptible patients

• Risk increased in patients with renal impairment, diabetes, or those taking potassium-sparing diuretics
• Monitor serum potassium regularly

• May occur in volume-depleted patients
• Correct volume depletion prior to administration

• Use with caution in patients with biliary obstruction
• Monitor liver function tests

Drug Interactions

• ACE inhibitors: Increased risk of hyperkalemia, hypotension, and renal impairment
• Aliskiren: Contraindicated in diabetic patients due to increased risk of renal impairment, hyperkalemia, and hypotension
• Lithium: Increased lithium concentrations and toxicity
• NSAIDs: May reduce antihypertensive effect and increase risk of renal impairment
• Potassium-sparing diuretics/potassium supplements: Increased risk of hyperkalemia

• Digoxin: May increase digoxin levels
• Warfarin: No significant interaction, but monitor INR

Adverse Effects

• Dizziness (9%)
• Fatigue (4%)
• Hypotension (4%)
• Headache (3%)
• Diarrhea (3%)
• Upper respiratory infection (3%)
• Arthralgia (3%)
• Back pain (3%)

• Angioedema (0.1%)
• Hepatotoxicity
• Acute renal failure
• Hyperkalemia
• Neutropenia
• Rhabdomyolysis
• Severe hypotension

Monitoring Parameters

• Blood pressure
• Renal function (BUN, creatinine, eGFR)
• Electrolytes (especially potassium)
• Liver function tests
• Pregnancy test in women of childbearing potential

• Blood pressure at 2-4 weeks after initiation or dose change
• Renal function and electrolytes within 2-4 weeks after initiation and periodically thereafter
• Monitor for signs of angioedema
• Assess for symptomatic hypotension
• Pregnancy testing as appropriate

• Blood pressure <130/80 mmHg in most hypertensive patients
• Improved functional status in heart failure patients
• Reduced cardiovascular events post-MI

Patient Education

• Take medication at the same time each day
• Do not stop taking suddenly without medical advice
• Report any signs of pregnancy immediately
• Watch for symptoms of low blood pressure (dizziness, lightheadedness)
• Monitor for swelling of face, lips, or tongue (angioedema)
• Regular blood pressure monitoring is important
• Maintain consistent salt intake unless otherwise directed
• Avoid potassium supplements unless prescribed
• Report persistent dry cough, although less common than with ACE inhibitors
• Inform all healthcare providers about all medications being taken
• Do not use salt substitutes containing potassium without medical advice

• Regular physical activity
• Weight management
• Dietary sodium restriction
• Limited alcohol consumption
• Smoking cessation

References

1. FDA Prescribing Information: Diovan (valsartan). 2022 2. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104 3. Yancy CW, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803 4. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-1675 5. Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893-1906 6. McInnes GT. Valsartan: an overview of the pharmacology and pharmacokinetics. Eur Heart J Suppl. 1999;1(Suppl L):L6-L11 7. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001;103(6):904-912 8. Sica DA. Pharmacokinetics and pharmacodynamics of angiotensin II receptor antagonists. Am J Hypertens. 2002;15(5):475-481