Angiotensin II receptor blocker

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Losartan, the first ARB Losartan structure.svg
Losartan, the first ARB

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, [1] also known as angiotensin receptor blockers, [2] [3] 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. [4]

Contents

Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. They selectively block the activation of the AT1 receptor, preventing the binding of angiotensin II compared to ACE inhibitors. [4]

ARBs and the similar-attributed ACE inhibitors are both indicated as the first-line antihypertensives in patients developing hypertension along with left-sided heart failure. [5] However, ARBs appear to produce less adverse effects compared to ACE inhibitors. [5]

Medical uses

Angiotensin II receptor blockers are used primarily for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy primarily because of persistent and/or dry cough. [6] They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy.[ citation needed ] More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, in particular candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type 2 diabetes,[ citation needed ] and may delay the progression of diabetic nephropathy.[ citation needed ] A 1998 double-blind study found "that lisinopril improved insulin sensitivity whereas losartan did not affect it." [7] Candesartan is used experimentally in preventive treatment of migraine. [8] [9] Lisinopril has been found less often effective than candesartan at preventing migraine. [10]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing effects at the maximal doses. [11] When used in clinical practice, the particular agent used may vary based on the degree of response required.

Some of these drugs have a uricosuric effect. [12] [13]

Angiotensin II, through AT1 receptor stimulation, is a major stress hormone and, because (ARBs) block these receptors, in addition to their eliciting anti-hypertensive effects, may be considered for the treatment of stress-related disorders. [14]

In 2008, they were reported to have a remarkable negative association with Alzheimer's disease (AD). A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found different types of commonly used antihypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35 to 40% less likely to develop AD than those using other antihypertensives. [15] [16]

A retrospective study of 1968 stroke patients revealed that prestroke treatment with ARB may be associated with both reduced stroke severity and better outcome. This finding agrees with experimental data that suggest that ARB's exert a cerebral protective effect. [17]

Adverse effects

This class of drugs is usually well tolerated. Common adverse drug reactions (ADRs) include: dizziness, headache, and/or hyperkalemia. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased hemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion. [18] A 2014 Cochrane systematic review based on randomized controlled trials reported that when comparing patients taking ACE inhibitors to patients taking ARBs, fewer ARB patients withdrew from the study due to adverse events compared to ACE inhibitor patients. [19]

While one of the main rationales for the use of this class is the avoidance of a persistent dry cough and/or angioedema associated with ACE inhibitor therapy, rarely they may still occur. In addition, there is also a small risk of cross-reactivity in patients having experienced angioedema with ACE inhibitor therapy. [18]

Myocardial infarction

The issue of whether angiotensin II receptor antagonists slightly increase the risk of myocardial infarction (MI or heart attack) is currently being investigated. Some studies suggest ARBs can increase the risk of MI. [20] However, other studies have found ARBs do not increase the risk of MI. [21] To date, with no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, further investigations are underway.[ needs update ]

Indeed, as a consequence of AT1 blockade, ARBs increase angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition, upregulated. However, recent data suggest AT2 receptor stimulation may be less beneficial than previously proposed, and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as eliciting proatherogenic and proinflammatory effects. [22] [23] [24]

Cancer

A study published in 2010 determined that "...meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation." [25] A later meta-analysis by the U.S. Food and Drug Administration (FDA) of 31 randomized controlled trials comparing ARBs to other treatment found no evidence of an increased risk of incident (new) cancer, cancer-related death, breast cancer, lung cancer, or prostate cancer in patients receiving ARBs. [26] In 2013, comparative effectiveness research from the United States Department of Veterans Affairs on the experience of more than a million veterans found no increased risks for either lung cancer [27] or prostate cancer. [28] The researchers concluded: "In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs." [27]

In May 2013, a senior regulator at the Food & Drug Administration, Medical Team Leader Thomas A. Marciniak, revealed publicly that contrary to the FDA's official conclusion that there was no increased cancer risk, after a patient-by-patient examination of the available FDA data he had concluded that there was a lung-cancer risk increase of about 24% in ARB patients, compared with patients taking a placebo or other drugs. One of the criticisms Marciniak made was that the earlier FDA meta-analysis did not count lung carcinomas as cancers. In ten of the eleven studies he examined, Marciniak said that there were more lung cancer cases in the ARB group than the control group. Ellis Unger, chief of the drug-evaluation division that includes Marciniak, was quoted as calling the complaints a "diversion," and saying in an interview, "We have no reason to tell the public anything new." In an article about the dispute, the Wall Street Journal interviewed three other doctors to get their views; one had "no doubt" ARBs increased cancer risk, one was concerned and wanted to see more data, and the third thought there was either no relationship or a hard to detect, low-frequency relationship. [29]

A 2016 meta-analysis including 148,334 patients found no significant differences in cancer incidence associated with ARB use. [30]

Kidney failure

Although ARBs have protective effects against developing kidney diseases for patients with diabetes and previous hypertension without administration of ARBs, [31] ARBs may worsen kidney functions such as reducing glomerular filtration rate associated with a rise of serum creatinine in patients with pre-existing proteinuria, renal artery stenosis, hypertensive nephrosclerosis, heart failure, polycystic kidney disease, chronic kidney disease, interstitial fibrosis, focal segmental glomerulosclerosis, or any conditions such as ARBs-treated but still clinically present hypertension that lead to abnormal narrowing of blood vessels to the kidney that interrupts oxygen and nutrient supply to the organ. [32] [33] [34] [35] [36] [37] [31] [ excessive citations ]

History

Structure

Losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan include the tetrazole group (a ring with four nitrogen and one carbon). Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.

Mechanism of action

These substances are AT1-receptor antagonists; that is, they block the activation of angiotensin II AT1 receptors. AT1 receptors are found in smooth muscle cells of vessels, cortical cells of the adrenal gland, and adrenergic nerve synapses. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.[ citation needed ]

The specific efficacy of each ARB within this class depends upon a combination of three pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Efficacy requires three key PD/PK areas at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter are at variance now.[ citation needed ]

Pressor inhibition

Pressor inhibition at trough level — this relates to the degree of blockade or inhibition of the blood pressure-raising ("pressor") effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure-lowering (BP) efficacy per se. The rates as listed in the U.S. Food and Drug Administration (FDA) Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows:

AT1 affinity vs AT2

The ratios of AT1 to AT2 in binding affinities of the specific ARBs are shown as follows. However, AT1 affinity vs AT2 is not a meaningful indicator of blood pressure response. [38]

Binding affinities Ki

Component

Nearly all ARBs contain biphenyltetrazole moiety except telmisartan and eprosartan. [40]

Active agent

Losartan carries a heterocycle imidazole while valsartan carries a nonplanar acylated amino acid. [40]

Pharmacokinetics comparison

Table 1: Comparison of ARB pharmacokinetics
DrugTrade name Biological half-life [hrs] Peak plasma concentration [Tmax] Protein binding [%] Bioavailability [%]Renal/hepatic clearance [%]Food effectDaily dosage [mg] Metabolism/transporter
Losartan Cozaar2 h1 hr [42] 98.7%33%10/90%Minimal50–100 Sensitive substrates: CYP2C9 and CYP3A4 [42]
EXP 3174 active metabolite of losartan-6–9 hrs3–4 hrs after oral losartan administration [42] 99.8%–50/50%––AUC reduced by phenytoin and rifampin by 63% [43] and 40% [42] respectively; specific CYP450 isozymes are unknown
Candesartan Atacand93–4 hrs [44] >99%15%60/40%No4–32 Moderate sensitive substrate: CYP2C9 [44]
Valsartan Diovan62–4 hrs [45] 95%25%30/70%Yes80–320Substrates: MRP2 and OATP1B1/SLCO1B1 [45]
Irbesartan Avapro11–151.5–2 hrs [46] 90–95%70%20/80%No150–300Minor substrates of CYP2C9 [46]
Telmisartan Micardis240.5–1 hr [47] >99%42–58%1/99%No40–80None known; >97% via biliary excretion [47]
Eprosartan Teveten51–2 hrs [48] 98%13%30/70%No400–800None known; >90% via renal and biliary excretion [48]
Olmesartan Benicar/Olmetec14–161–2 hrs [49] >99%29%40/60%No10–40Substrates of OATP1B1/SLCO1B1 [49]
Azilsartan Edarbi111.5–3 hrs [50] >99%60%55/42%No40–80Minor substrates of CYP2C9 [50]
Fimasartan Kanarb7–110.5–3 hrs after dosing. [51] >97%30–40%––30–120None known; primarily biliary excretion [52]
DrugTrade name Biological half-life [hrs] Peak plasma concentration [Tmax] Protein binding [%] Bioavailability [%]Renal/hepatic clearance [%]Food effectDaily dosage [mg] Metabolism/transporter

[53] [54] [55] [56] [57]

Research

Longevity

Knockout of the Agtr1a gene that encodes AT1 results in marked prolongation of the life-span of mice, by 26% compared to controls. The likely mechanism is reduction of oxidative damage (especially to mitochondria) and overexpression of renal prosurvival genes. The ARBs seem to have the same effect. [58] [59]

Fibrosis regression

ARBs, such as losartan, have been shown to curb or reduce muscular, [60] liver, [61] cardiac, [62] and kidney [63] fibrosis.

Dilated aortic root regression

A 2003 study using candesartan and valsartan demonstrated an ability to regress dilated aortic root size. [64]

Impurities

Nitrosamines

In June 2018, the US Food and Drug Administration (FDA) found traces of NDMA and NDEA impurities in the angiotensin II receptor blocker (ARB) drug products valsartan, losartan, and irbesartan. [65] [66] [67] [68] [69] The FDA stated "In June 2018, FDA was informed of the presence of an impurity, identified as N-Nitrosodimethylamine (NDMA), from one [70] API producer. Since then, FDA has determined that other types of nitrosamine compounds, e.g., N-Nitrosodiethylamine (NDEA), are present at unacceptable levels in APIs from multiple API producers of valsartan and other drugs in the ARB class." [71] In 2018, the FDA issued guidance to the industry on how to assess and control the impurities. [72]

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. [73]

In November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the EMA aligned recommendations for limiting nitrosamine impurities in sartan medicines with recommendations it issued for other classes of medicines. [74] The main change concerns the limits for nitrosamines, which previously applied to the active ingredients but now apply instead to the finished products (e.g. tablets). [74] These limits, based on internationally agreed standards (ICH M7(R1)), should ensure that the excess risk of cancer from nitrosamines in any sartan medicines is below 1 in 100,000 for a person taking the medicine for lifelong treatment. [74]

These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. [74] [75] Other sartan medicines which do not have this ring, such as azilsartan, eprosartan and telmisartan, were not included in this review but are covered by the subsequent review of other medicines. [74]

The FDA issued revised guidelines about nitrosamine impurities in September 2024. [76]

Azides

Losartan azide.svg
AZBT.svg
Losartan azide (left) and AZBT (right), two azido process impurities detected in sartans. Losartan azide occurs exclusively during manufacture of losartan, while AZBT can be found in several drugs in the class.

In April 2021, the European Directorate for the Quality of Medicines (EDQM) warned of the risk of contamination with non-nitrosamine impurities (specifically, azido compounds) in tetrazole-containing sartans. [77] In September 2021, the EDQM announced that investigations had revealed a novel azido contaminant which occurs only in losartan (losartan azide or losartan azido impurity) and which was found to be mutagenic on Ames testing. [78]

Later in 2021 and 2022, several cases of contamination with azido impurities were detected in losartan, irbesartan, and valsartan, prompting regulatory responses ranging from investigation to market withdrawals and precautionary recalls in Australia, [79] Brazil, [80] and Europe (including Switzerland). [81] [82]

Teva Pharmaceuticals announced that it would change its losartan manufacturing process to prevent future contamination with these impurities, [81] and the Indian API manufacturer IOL Chemicals and Pharmaceuticals applied for a patent on a new synthesis of losartan designed to be free of azido contaminants. [83]

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">Angiotensin</span> Group of peptide hormones in mammals

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

<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, angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.

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

Irbesartan, sold under the brand name Aprovel 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">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<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> Blood pressure lowering medication

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">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">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. 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. It is taken by mouth.

<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. It is available as a prodrug, olmesartan medoxomil.

<i>N</i>-Nitrosodimethylamine Chemical compound

N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN), is an organic compound with the formula (CH3)2NNO. It is one of the simplest members of a large class of nitrosamines. It is a volatile yellow oil. NDMA has attracted wide attention as being highly hepatotoxic and a known carcinogen in laboratory animals.

<i>N</i>-Nitrosodiethylamine Chemical compound

N-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has an amine or aromatic odor. It is used as gasoline and lubricant additive, antioxidant, and stabilizer for industry materials. When heated to decomposition, N-nitrosodiethylamine emits toxic fumes of nitrogen oxides. N-Nitrosodiethylamine affects DNA integrity, probably by alkylation, and is used in experimental research to induce liver tumorigenesis. It is carcinogenic and mutagenic. NDEA has also been found to perturb amino acid biosynthesis including arginine, as well as DNA damage repair and mitochondrial genome maintenance in yeast.

The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of antihypertensive drugs that act by blocking the effects of the hormone angiotensin II in the body, thereby lowering blood pressure. Their structure is similar to Ang II and they bind to Ang II receptors as inhibitors, e.g., [T24 from Rhys Healthcare].

Drug-induced angioedema is a known complication of the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists (ARBs), and Angiotensin-Neprilysin Inhibitor LCZ969. The angioedema appears to be dose dependent as it may resolve with decreased dose.

<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 among others, 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.

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

Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure. Through oral administration, fimasartan blocks angiotensin II receptor type 1 (AT1 receptors), reducing pro-hypertensive actions of angiotensin II, such as systemic vasoconstriction and water retention by the kidneys. Concurrent administration of fimasartan with diuretic hydrochlorothiazide has shown to be safe in clinical trials. Fimasartan was approved for use in South Korea on September 9, 2010, and is available under the brand name Kanarb through Boryung Pharmaceuticals, who are presently seeking worldwide partnership.

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

Forasartan, otherwise known as the compound SC-52458, is a nonpeptide angiotensin II receptor antagonist (ARB, AT1 receptor blocker).

References

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  42. 1 2 3 4 "LOSARTAN- losartan potassium tablet, film coated". DailyMed. 2018-12-26. Retrieved 2019-02-06. 12.3 Pharmacokinetics/ Absorption: Following oral administration, the systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (≈10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.
  43. ↑ Fischer, Tracy L.; Pieper, John A.; Graff, Donald W.; Rodgers, Jo E.; Fischer, Jeffrey D.; Parnell, Kimberly J.; Goldstein, Joyce A.; Greenwood, Robert; Patterson, J. Herbert (September 2002). "Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers". Clinical Pharmacology and Therapeutics. 72 (3): 238–246. doi:10.1067/mcp.2002.127945. ISSN   0009-9236. PMID   12235444. S2CID   28606328.
  44. 1 2 "CANDESARTAN - candesartan tablet". DailyMed. 2017-06-27. Retrieved 2019-02-06.
  45. 1 2 "VALSARTAN - valsartan tablet". DailyMed. 2017-12-07. Retrieved 2019-02-06.
  46. 1 2 "IRBESARTAN - irbesartan tablet". DailyMed. 2018-09-04. Retrieved 2019-02-06.
  47. 1 2 "TELMISARTAN - telmisartan tablet". DailyMed. 2018-11-01. Retrieved 2019-02-06.
  48. 1 2 "EPROSARTAN MESYLATE- eprosartan mesylate tablet, film coated". DailyMed. 2014-12-05. Retrieved 2019-02-06.
  49. 1 2 "OLMESARTAN MEDOXOMIL - olmesartan medoxomil tablet, film coated". DailyMed. 2017-05-04. Retrieved 2019-02-06.
  50. 1 2 "EDARBI- azilsartan kamedoxomil tablet". DailyMed. 2018-01-25. Retrieved 2019-02-06.
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  72. ↑ "M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk" (PDF). Food and Drug Administration (FDA). 30 August 2018. Retrieved 17 September 2019.
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