Valsartan

Valsartan, sold under the trade name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease.[3] It is a reasonable initial treatment for high blood pressure.[3] It is taken by mouth.[3] Versions are available as the combination valsartan/hydrochlorothiazide, valsartan/amlodipine, valsartan/amlodipine/hydrochlorothiazide, or valsartan/sacubitril.[3][4]

Valsartan
Clinical data
Trade namesDiovan, others
AHFS/Drugs.comMonograph
MedlinePlusa697015
License data
Pregnancy
category
  • AU: D [1]
  • US: N (Not classified yet) [1]
    Routes of
    administration    		By mouth
    Drug classAngiotensin II receptor antagonist
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability25%
    Protein binding95%
    Elimination half-life6 hours
    ExcretionKidney 30%, biliary 70%
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.113.097
    Chemical and physical data
    FormulaC24H29N5O3
    Molar mass435.528 g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include feeling tired, dizziness, high blood potassium, diarrhea, and joint pain.[3] Other serious side effects may include kidney problems, low blood pressure, and angioedema.[3] Use in pregnancy may harm the baby and use when breastfeeding is not recommended.[5] It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II.[3]

    Valsartan was patented in 1990, and came into medical use in 1996.[6] It is available as a generic medication.[7] In 2017, it was the 85th most commonly prescribed medication in the United States, with more than nine million prescriptions.[8][9]

    Medical uses

    Valsartan is used to treat high blood pressure, heart failure, and to reduce death for people with left ventricular dysfunction after having had a heart attack.[10][11]

    High blood pressure

    It is a reasonable initial treatment for high blood pressure as are ACE inhibitors, calcium-channel blockers, and thiazide diuretics.[3]

    Heart failure

    There is contradictory evidence with regard to treating people with heart failure with a combination of an angiotensin receptor blocker like valsartan and an angiotensin-converting enzyme inhibitor, with two major clinical trials showing a reduction in death, and two others showing no benefits, and more adverse effects including heart attacks, hypotension, and renal dysfunction.[10]

    Diabetic kidney disease

    In people with type 2 diabetes and high blood pressure or albumin in the urine, valsartan is used to slow the worsening and the development of end-stage kidney disease.[12]

    Contraindications

    The packaging for valsartan includes a warning stating the drug should not be used with the renin inhibitor aliskiren in people with diabetes mellitus. It also states the drug should not be used in people with kidney disease.[11]

    Valsartan falls in Food and Drug Administration (FDA) pregnancy category D and includes a black box warning for fetal toxicity.[11][5] Discontinuation of these agents is recommended immediately after detection of pregnancy and an alternative medication should be started.[11] The U.S. labeling makes no recommendation regarding continuation or discontinuation of valsartan for breast-feeding mothers.[11] The Canadian labeling does not recommend use by nursing women.[13]

    Side effects

    Rates of side effects depends on the reason the medication is used.

    Heart failure

    Rates of adverse effects are based on a comparison versus placebo in people with heart failure.[11] Most common side effects include dizziness (17% vs 9% ), low blood pressure (7% vs 2%), and diarrhea (5% vs 4%).[11] Less common side effects include joint pain, fatigue, and back pain (all 3% vs 2%).[11]

    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:[11]

    Kidney failure
    See also: Angiotensin II receptor blocker § Renal failure

    People treated with ARBs including valsartan or diuretics and 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.[11] 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.[14] So long as the nephron function degradation is being progressive or reaches clinically significant level, withhold or discontinue valsartan is warranted.[11][15][16][17]

    Interactions

    The U.S. prescribing information lists the following drug interactions for valsartan:

    • Other inhibitors of the renin-angiotensin system may increase the risks of low blood pressure, kidney problems, and hyperkalemia.
    • Potassium sparing diuretics, potassium supplements, salt substitutes containing potassium may increase the risk of hyperkalemia.
    • NSAIDs may increase the risk of kidney problems and may interfere with blood pressure-lowering effects.
    • Valsartan may increase the concentration of lithium.[11]
    • Valsartan and other angiotensin-related blood pressure medications may interact with the antibiotics co-trimoxazole or ciprofloxacin to increase risk of sudden death due to cardiac arrest.[18]

    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.[11]

    Pharmacology

    Mechanism of action

    Valsartan blocks the actions of angiotensin II, which include constricting blood vessels and activating aldosterone, to reduce blood pressure.[19] The drug binds to angiotensin type I receptors (AT1), working as an antagonist. 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.[19]

    Pharmacodynamics

    Pharmacokinetics

    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 doesn't accumulate in response to repeated dosing.[11]

    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.[20] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.[21][22]

    Combinations
    Further information: amlodipine/valsartan, valsartan/hydrochlorothiazide, valsartan/hydrochlorothiazide/amlodipine, and sacubitril/valsartan
    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.[3][23][24][25] Valsartan is also available as the combination valsartan/sacubitril.[4][26][27] It is used to treat heart failure with reduced ejection fraction.[27][28]

    Recalls

    See also: Ranitidine § impurities

    On 6 July 2018, the European Medicines Agency (EMA) recalled certain batches of valsartan and valsartan/hydrochlorothiazide film-coated tablets distributed in 22 countries in Europe, plus Canada.[29] Zhejiang Huahai Pharmaceutical Co. (ZHP) in Linhai, China manufactured the bulk ingredient contaminated by N-nitrosodimethylamine (NDMA), a carcinogen.[30] 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.[29] In Canada, the recall involves five companies and a class action suit has been initiated by a private law firm.[31][32] Authorities believe the degree of contamination is negligible, and advise those taking the drug to consult a doctor and not to cease taking the medication abruptly. On 12 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.[33] On 13 July 2018, the U.S. Food and Drug Administration (FDA) announced voluntary recalls of certain supplies of valsartan and valsartan/hydrochlorothiazide in the U.S. distributed by Solco Healthcare LLC, Major Pharmaceuticals, and Teva Pharmaceutical Industries.[34][30] Hong Kong's Department of Health initiated a similar recall.[35] On 2 August 2018, the FDA published two lengthy, updated lists, classifying hundreds of specific U.S. products containing valsartan into those included versus excluded from the recall.[36][37] 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.[38][37]

    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 U.S. under the Torrent Pharmaceuticals (India) brand.[39]

    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 U.S.[40]

    In 2019, many more preparations of valsartan and its combinations were recalled due to the presence of the contaminant NDMA.[41][42]

    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.[43]

    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.[44] According to the agency, the shortage of valsartan was resolved in 03/04/2020,[45] but the availability of the generic form remained unstable into July 2020. Pharmacies in Europe were notified that the supply of the drug, particularly for higher dosage forms, would remain unstable well into December 2020.[46]

    Research
    See also: Discovery and development of angiotensin receptor blockers

    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.[47]

    In one study of people without diabetes, valsartan reduced the risk of developing diabetes mellitus over amlodipine, mainly for those with hypertension.[48]

    A prospective study demonstrated a reduction in the incidence and progression of Alzheimer's disease and dementia.[49]

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    References
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    48. Kjeldsen SE, McInnes GT, Mancia G, Hua TA, Julius S, Weber MA, et al. (2008). "Progressive effects of valsartan compared with amlodipine in prevention of diabetes according to categories of diabetogenic risk in hypertensive patients: the VALUE trial". Blood Pressure. 17 (3): 170–7. doi:10.1080/08037050802169644. PMID 18608200.
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