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. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination valsartan/hydrochlorothiazide, valsartan/amlodipine, valsartan/amlodipine/hydrochlorothiazide, or valsartan/sacubitril.
Common side effects include feeling tired, dizziness, high blood potassium, diarrhea, and joint pain. Other serious side effects may include kidney problems, low blood pressure, and angioedema. Use in pregnancy may harm the baby and use when breastfeeding is not recommended. It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II.
Valsartan was patented in 1990, and came into medical use in 1996. It is available as a generic medication. In 2017, it was the 85th most commonly prescribed medication in the United States, with more than nine million prescriptions.

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.

High blood pressure

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

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.

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.

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

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. Most common side effects include dizziness, low blood pressure, and diarrhea. Less common side effects include joint pain, fatigue, and back pain.

Hypertension

Clinical trials for valsartan treatment for hypertension versus placebo demonstrate side effects like viral infection, fatigue and abdominal pain. Minor side effects that occurred at >1% but were similar to rates from the placebo group include:
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. 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. So long as the nephron function degradation is being progressive or reaches clinically significant level, withhold or discontinue valsartan is warranted.

Interactions

The U.S. prescribing information lists the following drug interactions for valsartan:
With the tablet, food decreases the valsartan tablet taker's exposure to valsartan by about 40% and peak plasma concentration by about 50%, evidenced by AUC change.

Pharmacology

Mechanism of action

Valsartan blocks the actions of angiotensin II, which include constricting blood vessels and activating aldosterone, to reduce blood pressure. The drug binds to angiotensin type I receptors, 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.

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.

Society and culture

Economics

In 2010, valsartan achieved annual sales of $2.052billion in the United States and $6.053billion worldwide. The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.

Combinations

Valsartan is combined with amlodipine or hydrochlorothiazide into single-pill formulations for treating hypertension with multiple drugs. Valsartan is also available as the combination valsartan/sacubitril. It is used to treat heart failure with reduced ejection fraction.

Recalls

On 6 July 2018, the European Medicines Agency recalled certain batches of valsartan and valsartan/hydrochlorothiazide film-coated tablets distributed in 22 countries in Europe, plus Canada. Zhejiang Huahai Pharmaceutical Co. in Linhai, China manufactured the bulk ingredient contaminated by N-nitrosodimethylamine, a carcinogen. 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. In Canada, the recall involves five companies and a class action suit has been initiated by a private law firm. 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 announced voluntary recalls for two products containing valsartan produced by Actavis Indonesia and Dipa Pharmalab Intersains. On 13 July 2018, the U.S. Food and Drug Administration 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. Hong Kong's Department of Health initiated a similar recall. 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. 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.
In September 2018, the FDA announced that retesting of all valsartan supplies had found a second carcinogenic impurity, N-nitrosodiethylamine, in the recalled products made by ZHP in China and marketed in the U.S. under the Torrent Pharmaceuticals brand.
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.
In 2019, many more preparations of valsartan and its combinations were recalled due to the presence of the contaminant NDMA.

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. According to the agency, the shortage of valsartan was resolved in 03/04/2020, 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.

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 and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events was shown.
In one study of people without diabetes, valsartan reduced the risk of developing diabetes mellitus over amlodipine, mainly for those with hypertension.
A prospective study demonstrated a reduction in the incidence and progression of Alzheimer's disease and dementia.