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Valsartan

Pronunciation

Pronunciation

(val SAR tan)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Diovan: 40 mg [DSC]

Diovan: 40 mg [scored]

Diovan: 80 mg, 160 mg, 320 mg

Generic: 40 mg, 80 mg, 160 mg, 320 mg

Brand Names: U.S.

  • Diovan

Pharmacologic Category

  • Angiotensin II Receptor Blocker
  • Antihypertensive

Pharmacology

Valsartan produces direct antagonism of the angiotensin II (AT2) receptors, unlike the ACE inhibitors. It displaces angiotensin II from the AT1 receptor and produces its blood pressure-lowering effects by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. This action results in more efficient blockade of the cardiovascular effects of angiotensin II and fewer side effects than the ACE inhibitors.

Distribution

Vd: Adults: 17 L

Metabolism

To inactive metabolite (valeryl 4-hydroxy valsartan)

Excretion

Feces (83%) and urine (13%) as unchanged drug

Clearance: Found to be similar per kg bodyweight in children vs adults receiving a single dose of the suspension (Blumer 2009)

Onset of Action

~2 hours

Time to Peak

Serum: Children and Adolescents 1 to 16 years: Oral suspension: 2 hours (Blumer 2009); Adults: 2 to 4 hours

Duration of Action

24 hours

Half-Life Elimination

Children 1 to 5 years: ~4 hours (Blumer 2009)

Children and Adolescents 6 to 16 years: ~5 hours (Blumer 2009)

Adults: ~6 hours; ~35% longer in elderly patients

Protein Binding

95%, primarily albumin

Special Populations: Hepatic Function Impairment

Patients with mild-to-moderate chronic liver disease have about twice the AUC value.

Special Populations: Elderly

AUC is about 70% higher and the half-life is 35% longer in elderly patients.

Use: Labeled Indications

Heart failure: Treatment of heart failure (NYHA Class II to IV).

Hypertension: Management of hypertension (monotherapy or in combination with other antihypertensives).

Left ventricular dysfunction or failure after MI: Reduction of cardiovascular mortality in patients with left ventricular dysfunction or failure postmyocardial infarction.

Guideline recommendations:

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8; James 2013]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:

• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age with SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD), including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD), including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Coronary artery disease and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with coronary artery disease (CAD) recommends the use of an ARB (or ACE inhibitor) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

Heart failure: The ACCF/AHA 2013 heart failure guidelines recommend the use of ARBs (ie, candesartan, losartan, and valsartan) in patients with HF with reduced ejection fraction who cannot tolerate ACE inhibitors (due to cough) to reduce morbidity and mortality. They also suggest that ARBs are reasonable first-line alternatives to ACE inhibitors in patients already maintained on an ARB for other indications (ACCF/AHA [Yancy 2013]).

Contraindications

Hypersensitivity to valsartan or any component of the formulation; concomitant use with aliskiren in patients with diabetes mellitus

Documentation of allergenic cross-reactivity for angiotensin II receptor blockers is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren in patients with moderate-to-severe renal impairment (GFR <60 mL/minute/1.73 m2); pregnancy; breast-feeding

Dosing: Adult

Hypertension: Initial: 80 mg or 160 mg once daily (in patients who are not volume depleted); dose may be increased to achieve desired effect; usual dosage range (ASH/ISH [Weber 2014]): 80 to 320 mg once daily; target dose (JNC8 [James, 2013]): 160 to 320 mg once daily; maximum dose: 320 mg/day.

Heart failure: Initial: 40 mg twice daily; titrate dose to 80 mg, and then to 160 mg twice daily, as tolerated; maximum dose: 320 mg/day. The ACCF/AHA 2013 heart failure guidelines suggest initial dose of 20 to 40 mg twice daily and a target dose of 160 mg twice daily (Yancy 2013).

Left ventricular dysfunction or failure after MI: Initial: 20 mg twice daily; may increase within 7 days to 40 mg twice daily; titrate dose to target of 160 mg twice daily as tolerated; may initiate ≥12 hours following MI.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Due to increased bioavailability of extemporaneously prepared oral suspension (not commercially available), patients may require a higher dose when converting from oral suspension to tablet dosage form.

Hypertension: Oral:

Children and Adolescents 6 to 16 years: Initial: 1.3 mg/kg once daily (maximum initial dose: 40 mg/day); dose may be increased to achieve desired effect; doses >2.7 mg/kg (up to 160 mg) once daily have not been studied.

Dosing: Renal Impairment

Children and Adolescents 6 to 16 years of age:

Glomerular filtration rate (GFR) ≥30 mL/minute/1.73m2: No dosage adjustment necessary.

GFR <30 mL/minute/1.73m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dialysis: Has not been studied.

Adults:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Dialysis: Not significantly removed.

Dosing: Hepatic Impairment

Mild-to-moderate impairment: No dosage adjustment necessary; use with caution.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Extemporaneously Prepared

A 4 mg/mL oral suspension may be made from tablets, Ora-Plus, and Ora-Sweet SF. Add 80 mL of Ora-Plus to an 8-ounce amber glass bottle containing eight valsartan 80 mg tablets. Shake well for ≥2 minutes. Allow the suspension to stand for a minimum of 1 hour, then shake for ≥1 minute. Add 80 mL of Ora-Sweet SF to the bottle and shake for ≥10 seconds. Store in amber glass prescription bottles; label "shake well". Stable for 30 days at room temperature or 75 days refrigerated.

Diovan prescribing information, Novartis Pharmaceuticals Corp, East Hanover, NJ, 2015.

Administration

Administer with or without food.

Dietary Considerations

Avoid salt substitutes which contain potassium.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Valsartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the valsartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Ciprofloxacin (Systemic): Angiotensin II Receptor Blockers may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

CycloSPORINE (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Drospirenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HydroCHLOROthiazide: May enhance the hypotensive effect of Valsartan. Valsartan may increase the serum concentration of HydroCHLOROthiazide. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Dizziness (heart failure trials 17%)

Renal: Increased blood urea nitrogen (>50% increase; heart failure trials 17%)

1% to 10%:

Cardiovascular: Hypotension (heart failure trials 7%; MI trial 1%), orthostatic hypotension (heart failure trials 2%), syncope (up to >1%)

Central nervous system: Dizziness (hypertension trial 2% to 8%), fatigue (heart failure trials 3%; hypertension trial 2%), orthostatic dizziness (heart failure trials 2%), headache (heart failure trials >1%), vertigo (up to >1%)

Endocrine & metabolic: Increased serum potassium (>20% increase; 4% to 10%), hyperkalemia (heart failure trials 2%)

Gastrointestinal: Diarrhea (heart failure trials 5%), abdominal pain (2%), nausea (heart failure trials >1%), upper abdominal pain (heart failure trials >1%)

Hematologic & oncologic: Neutropenia (2%)

Infection: Viral infection (3%)

Neuromuscular & skeletal: Arthralgia (heart failure trials 3%), back pain (≤3%)

Ophthalmic: Blurred vision (heart failure trials >1%)

Renal: Increased serum creatinine (doubled: MI trial 4%; >50% increase: heart failure trials 4%), renal insufficiency (>1%)

Respiratory: Cough (1% to 3%)

All indications: <1% (Limited to important or life-threatening): Alopecia, anaphylaxis, anemia, angioedema, anorexia, bullous dermatitis, decreased hematocrit, decreased hemoglobin, dyspepsia, flatulence, hepatitis (rare), hypersensitivity reaction, impotence, insomnia, liver function tests increased, microcytic anemia, myalgia, palpitation, paresthesia, photosensitivity, pruritus, renal failure, rhabdomyolysis, skin rash, taste disorder, thrombocytopenia (very rare), vasculitis, xerostomia

ALERT: U.S. Boxed Warning

Fetal toxicity:

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue valsartan as soon as possible.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported rarely with some angiotensin II receptor antagonists (ARBs) and may occur at any time during treatment (especially following first dose). It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. Intramuscular (IM) administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.

• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use with caution with these agents; monitor potassium closely.

• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with valsartan.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy, because of valsartan-induced hypotension. Careful monitoring of blood urea nitrogen (BUN), serum creatinine, and potassium is necessary especially if pre-existing renal disease exists.

• Hepatic impairment: Use with caution in patients with hepatic impairment (exposure to valsartan is increased).

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in patients with preexisting renal insufficiency and severe renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).

Monitoring Parameters

Baseline and periodic blood pressure, electrolyte panels, renal function; in HF, serum potassium during dose escalation and periodically thereafter

2013 ACCF/AHA Heart Failure guideline recommendations: Within 1 to 2 weeks after initiation, reassess blood pressure (including postural blood pressure changes), renal function, and serum potassium; follow closely after dose changes. Patients with systolic blood pressure <80 mm Hg, low serum sodium, diabetes mellitus, and impaired renal function should be closely monitored (Yancy 2013)

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Use is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. in The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria (exchange transfusions or dialysis may be needed). These adverse events are generally associated with maternal use in the second and third trimesters.

Untreated chronic maternal hypertension is also associated with adverse events in the fetus, infant, and mother. The use of angiotensin II receptor blockers is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential (ACOG, 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, back pain, diarrhea, loss of strength and energy, headache, or flu-like symptoms. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling), severe dizziness, passing out, swelling of arms or legs, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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