Valsartan

Last updated

Valsartan
Valsartan skeletal.svg
Valsartan-from-xtal-3D-bs-17.png
Clinical data
Trade names Diovan, others
AHFS/Drugs.com Monograph
MedlinePlus a697015
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Angiotensin II receptor antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Protein binding 95%
Elimination half-life 6 hours
Excretion Kidney 30%, bile duct 70%
Identifiers
  • (S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.113.097 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H29N5O3
Molar mass 435.528 g·mol−1
3D model (JSmol)
  • CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)C(C(=O)O)C(C)C
  • InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1 Yes check.svgY
  • Key:ACWBQPMHZXGDFX-QFIPXVFZSA-N Yes check.svgY
   (verify)

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. [8] It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. [8] It is taken by mouth. [8]

Contents

Common side effects include feeling tired, dizziness, high blood potassium, diarrhea, and joint pain. [8] Other serious side effects may include kidney problems, low blood pressure, and angioedema. [8] Use in pregnancy may harm the baby and use when breastfeeding is not recommended. [9] It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II. [8]

Valsartan was patented in 1990, and came into medical use in 1996. [10] It is available as a generic medication. [11] In 2021, it was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions. [12] [13] Versions are available as the combinations valsartan/hydrochlorothiazide, [14] valsartan/amlodipine, [15] valsartan/amlodipine/hydrochlorothiazide, [16] valsartan/nebivolol, [17] and valsartan/sacubitril. [8] [18]

Medical uses

Valsartan is used to treat high blood pressure, heart failure, and to reduce death for people with left ventricular dysfunction after having a heart attack. [19] [7]

High blood pressure

Valsartan (and other ARBs) are an appropriate initial treatment option for most people with high blood pressure and no other coexisting conditions, as are ACE inhibitors, thiazide diuretics and calcium channel blockers. [20] If patients have coexisting diabetes or kidney disease, ARBs or ACE inhibitors may be considered over other classes of blood pressure medicines. [21] [22]

Heart failure

Valsartan has reduced rates of mortality and heart failure hospitalisations when used alone or in combination with beta-blockers in the treatment of heart failure. [23] Importantly, the combination of valsartan and ACE inhibitors has not shown morbidity or mortality benefits but rather increases mortality risk when added to combination beta-blocker and ACE-inhibitor therapy, and increases the risk of adverse events like hyperkalaemia, hypotension and renal failure. [23] [24] As shown in the PARADIGM-HF study, valsartan combined with sacubitril for the treatment of heart failure, significantly reduced all cause and cardiovascular mortality and hospitalisations due to heart failure. [25]

Diabetic kidney disease

In people with type 2 diabetes, antihypertensive therapy with valsartan decreases the rate of progression of albuminuria (albumin in urine), promotes regression to normoalbuminuria and may reduce the rate of progression to end-stage kidney disease. [26] [27] [28]

Contraindications

The packaging for valsartan includes a warning stating the drug should not be used with the renin inhibitor aliskiren in people with diabetes. It also states the safety of the drug in severe renal impairment has not been established. [7]

Valsartan includes a black box warning for fetal toxicity. [7] [9] Discontinuation of these agents is recommended immediately after detection of pregnancy and an alternative medication should be started. [7] Breastfeeding is not recommended. [7] [29] [30]

Side effects

Side effects depend on the reason the medication is being used.

Heart failure

Adverse effects are based on a comparison versus placebo in people with heart failure. [7] Most common side effects include dizziness (17% vs 9% ), low blood pressure (7% vs 2%), and diarrhea (5% vs 4%). [7] Less common side effects include joint pain, fatigue, and back pain (all 3% vs 2%). [7]

Hypertension

Clinical trials for valsartan treatment for hypertension versus placebo demonstrate side effects like viral infection (3% vs 2%), fatigue (2% vs 1%) and abdominal pain (2% vs 1%). Minor side effects that occurred at >1% but were similar to rates from the placebo group include: [7]

Kidney failure

People treated with ARBs including valsartan or diuretics are susceptible to conditions of developing low renal blood flow such as abnormal narrowing of blood vessel in kidney, hypertension, renal artery stenosis, heart failure, chronic kidney disease, severe congestive heart failure, or volume depletion whose renal function is in part dependent on the activity of the renin-angiotensin system like efferent arteriolar vasoconstriction done by angiotensin II are at high risk of deterioration of renal function comprising acute kidney failure, oliguria, worsening azotemia or heightened serum creatinine. [7] When blood flow to the kidneys is reduced, the kidney activates a series of response that triggers angiotensin release to constrict blood vessels and facilitate blood flow in the kidney. [31] So long as the nephron function degradation is being progressive or reaches clinically significant level, withhold or discontinue valsartan is warranted. [7] [32] [33] [34]

Interactions

The US prescribing information lists the following drug interactions for valsartan:

Food interaction

With the tablet, food decreases the valsartan tablet taker's exposure to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, evidenced by AUC change. [7]

Pharmacology

Mechanism of action

Valsartan blocks the actions of angiotensin II, which include constricting blood vessels and activating aldosterone, to reduce blood pressure. [36] The drug binds to angiotensin type I receptors (AT1), working as an antagonist. [37] This mechanism of action is different than that of the ACE inhibitor drugs, which block the conversion of angiotensin I to angiotensin II. As valsartan acts at the receptor, it can provide more complete angiotensin II antagonism since angiotensin II is generated by other enzymes as well as ACE. Also, valsartan does not affect the metabolism of bradykinin like ACE inhibitors do. [36]

Pharmacodynamics

Pharmacokinetics

The peak concentration of valsartan in plasma occurs 2 to 4 hours after dosing. [7] AUC and Cmax values of valsartan are observed to be approximately linearly dose-dependent over therapeutic dosing range. Owing to its relatively short elimination half life attribution, valsartan concentration in plasma does not accumulate in response to repeated dosing. [7]

Society and culture

Economics

In 2010, valsartan (trade name Diovan) achieved annual sales of $2.052 billion in the United States and $6.053 billion worldwide. [38] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012. [39] [40]

Combinations

Co-Diovan (valsartan and hydrochlorothiazide) Two boxes and a blister pack of Co-Diovan (Valsartan and hydrochlorothiazide), Singapore - 20150210.jpg
Co-Diovan (valsartan and hydrochlorothiazide)

Valsartan is combined with amlodipine or hydrochlorothiazide (HCTZ) (or both) into single-pill formulations for treating hypertension with multiple drugs. [8] [41] [42] [43] Valsartan is also available as the combination valsartan/sacubitril. [18] [44] [45] It is used to treat heart failure with reduced ejection fraction. [45] [46]

Recalls

In July 2018, the European Medicines Agency (EMA) recalled certain batches of valsartan and valsartan/hydrochlorothiazide film-coated tablets distributed in 22 countries in the European Union. [47] Zhejiang Huahai Pharmaceutical Co.  [ zh ] (ZHP) in Linhai, China manufactured the bulk ingredient contaminated by N-nitrosodimethylamine (NDMA), a carcinogen. [48] The active pharmaceutical ingredient was subsequently imported by a number of generic drugmakers, including Novartis, and marketed in Europe and Asia under their subsidiary Sandoz labeling, and in the UK by Dexcel Pharma Ltd and Accord Healthcare. [47]

Valsartan was recalled in Canada. [49] [50] Authorities believe the degree of contamination is negligible. [51] In July 2018, The National Agency of Drug and Food Control (NA-DFC or Badan POM Indonesia) announced voluntary recalls for two products containing valsartan produced by Actavis Indonesia and Dipa Pharmalab Intersains. [52] In July 2018, the US Food and Drug Administration (FDA) announced voluntary recalls of certain supplies of valsartan and valsartan/hydrochlorothiazide in the US distributed by Solco Healthcare LLC, Major Pharmaceuticals, and Teva Pharmaceutical Industries. [53] [48] Hong Kong's Department of Health initiated a similar recall. [54] In August 2018, the FDA published two lengthy, updated lists, classifying hundreds of specific US products containing valsartan into those included versus excluded from the recall. [55] [56] A week later, the FDA cited two more drugmakers, Zhejiang Tianyu Pharmaceuticals of China and Hetero Labs Limited of India, as additional sources of the contaminated valsartan ingredient. [57] [56]

In September 2018, the FDA announced that retesting of all valsartan supplies had found a second carcinogenic impurity, N-nitrosodiethylamine (NDEA), in the recalled products made by ZHP in China and marketed in the US under the Torrent Pharmaceuticals (India) brand. [58]

According to a 2018 Reuters analysis of national medicines agencies' records, more than 50 companies around the world have recalled valsartan mono-preparations or combination products manufactured from the tainted valsartan ingredient. The contamination has likely been present since 2012 when the manufacturing process was changed and approved by EDQM and FDA authorities. Based on inspections in late 2018, both agencies have suspended the Chinese and Indian manufacturers' certificates of suitability for the supply of valsartan in the EU and the US. [59]

In 2019, many more preparations of valsartan and its combinations were recalled due to the presence of the contaminant NDMA. [60] [61]

In August 2020, the European Medicines Agency (EMA) provided guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines and asked them to review all chemical and biological human medicines for the possible presence of nitrosamines and to test the products at risk. [62]

Shortages

Since July 2018, numerous recalls of losartan, valsartan and irbesartan drug products have caused marked shortages of these life saving medications in North America and Europe, particularly for valsartan. In March 2019, the FDA approved an additional generic version of Diovan™ to address the issue. [63] According to the agency, the shortage of valsartan was resolved in April 2020, [64] but the availability of the generic form remained unstable into July 2020. Pharmacies in the European Union were notified that the supply of the drug, particularly for higher dosage forms, would remain unstable well into December 2020. [65]

Research

In people with impaired glucose tolerance, valsartan may decrease the incidence of developing diabetes mellitus type 2. However, the absolute risk reduction is small (less than 1 percent per year) and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events (including death) was shown. [66]

In one study of people without diabetes, valsartan reduced the risk of developing diabetes mellitus over amlodipine, mainly for those with hypertension. [67]

A prospective study demonstrated a reduction in the incidence and progression of Alzheimer's disease and dementia. [68]

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Amlodipine</span> Medication against high blood pressure

Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD) and variant angina. It is taken orally.

<span class="mw-page-title-main">Enalapril</span> ACE inhibitor medication

Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furosemide. It is given by mouth or by injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to a day.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Irbesartan</span> Chemical compound

Irbesartan, sold under the brand name Avapro among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination irbesartan/hydrochlorothiazide.

<span class="mw-page-title-main">Lisinopril</span> Medication used to treat hypertension and heart failure

Lisinopril is a medication belonging to the drug class of angiotensin-converting enzyme (ACE) inhibitors and is used to treat hypertension, heart failure, and heart attacks. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken orally. Full effect may take up to four weeks to occur.

<span class="mw-page-title-main">Ramipril</span> ACE inhibitor medication

Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Candesartan</span> Angiotensin II receptor antagonist

Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure. Candesartan has a very low maintenance dose. Like Olmesartan, the metabolism of the drug is unusual as it is a cascading prodrug. Candesartan has good bioavailibility and is the most potent by weight of the AT-1 receptor antagonists.

<span class="mw-page-title-main">Telmisartan</span> Angiotensin II receptor antagonist

Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination telmisartan/hydrochlorothiazide, telmisartan/cilnidipine and telmisartan/amlodipine.

<span class="mw-page-title-main">Benazepril</span> Medication used to treat high blood pressure and heart failure

Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combinations benazepril/hydrochlorothiazide and benazepril/amlodipine.

<span class="mw-page-title-main">Losartan</span> Blood pressure medication

Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure (hypertension). It is in the angiotensin receptor blocker (ARB) family of medication, and is considered protective of the kidneys. Besides hypertension, it is also used in diabetic kidney disease, heart failure, and left ventricular enlargement. It comes as a tablet that is taken by mouth. It may be used alone or in addition to other blood pressure medication. Up to six weeks may be required for the full effects to occur.

<span class="mw-page-title-main">Olmesartan</span> Angiotensin II receptor antagonist

Olmesartan, sold under the brand name Benicar among others, is a medication used to treat high blood pressure (hypertension). It is taken orally. Versions are available as the combination olmesartan/hydrochlorothiazide and olmesartan/amlodipine.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

<span class="mw-page-title-main">Aliskiren</span> Medication

Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.

<span class="mw-page-title-main">Amlodipine/valsartan</span> Antihypertensive medication

Amlodipine/valsartan, sold under the brand name Exforge among others, is a blood pressure lowering combination drug. It contains amlodipine, as the besilate, a dihydropyridine-type calcium channel blocker, and valsartan, an angiotensin II receptor antagonist. This combination is usually well tolerated and effective for the reduction of blood pressure.

<span class="mw-page-title-main">Azilsartan</span> Chemical compound

Azilsartan, sold under the brand name Edarbi among others, is used for the treatment of hypertension. It is used as the prodrug azilsartan medoxomil, is an angiotensin II receptor antagonist, and was developed by Takeda.

<span class="mw-page-title-main">Valsartan/hydrochlorothiazide</span> Chemical compound

Valsartan/hydrochlorothiazide, sold under the brand name Diovan HCT among others, is a medication used to treat high blood pressure when valsartan is not sufficient. It is a combination of valsartan, an angiotensin receptor blocker with hydrochlorothiazide, a diuretic. It is taken by mouth.

<span class="mw-page-title-main">Sacubitril/valsartan</span> Combination medication

Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.

References

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  44. ↑ "Entresto- sacubitril and valsartan tablet, film coated". DailyMed. 1 September 2019. Retrieved 12 February 2020.
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