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 inhibitoraliskiren 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]
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:
Other inhibitors of the renin-angiotensin system may increase the risks of low blood pressure, kidney problems, and hyperkalemia.
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 $2.052billion in the United States and $6.053billion worldwide.[38] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.[39][40]
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]
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]
^Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. (September 2001). "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy". The New England Journal of Medicine. 345 (12): 861–869.
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^Hollenberg NK, Parving HH, Viberti G, Remuzzi G, Ritter S, Zelenkofske S, et al. (September 2007). "Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus". Journal of Hypertension. 25 (9): 1921–1926.
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^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): 170–177.
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