Valsartan

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

log Kow = 4.00 (average value)

5.8

White to practically white fine powder

Crystals from diisopropyl ether

soluble in ethanol, DMSO, and dimethyl formamide at 30 mg/mL

Soluble in ethanol and methanol

2.34e-02 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Blockers; ARBs

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

116-117 °C

116-117 °C

116 - 117 °C

4.73

pKa = 3.6

202 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

207.99 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H361 (82.8%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P273, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 99 reports by companies from 19 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl valsartan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Repr. 2 (82.8%)

Repr. 2 (100%)

Conditions for safe storage: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C Store with desiccant.

Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F). Protect from moisture.

Accidental Release Measures. Personal precautions: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Provide appropriate exhaust ventilation at places where dust is formed.

Hygiene measures: General industrial hygiene practice.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Skin and body protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Hand protection: Handle with gloves.

Eye protection; Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Concurrent use of valsartan and warfarin did not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin.

Concomitant use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes with valsartan may result in increased hyperkalemic effects and, in patients with heart failure, increases in serum creatinine concentration.

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Diovan. Monitor serum lithium levels during concomitant use.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS.

For more Interactions (Complete) data for VALSARTAN (11 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), estimated as 250(SRC), using a log Kow of 4.00(1) and a regression-derived equation(3) and an estimated Koc value of 2.3X10+4(SRC), determined from a structure estimation method(3) indicate that valsartan is expected to have moderate to no mobility in soil(SRC). The estimated pKa values of valsartan are 4.00 (tetrazole moiety) and 4.61 (carboxylic acid moiety)(4), indicating that this compound will exist in the zwitterion form in the environment. Valsartan breaks down to the anionic product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid in wastewater treatment(5), suggesting that the anionic form may dominate under environmental conditions(SRC). Anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(6). Volatilization from moist soil is not expected because the compound exists as an ion and ions do not volatilize. Valsartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.2X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2014).

AQUATIC FATE: Based on a classification scheme(1), estimated as 250(SRC), using a log Kow of 4.00(2) and a regression-derived equation(3) and an estimated Koc value of 2.3X10+4(SRC), determined from a structure estimation method(3), indicate that valsartan is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa values of 4.00 and 4.61(4) indicate valsartan will exist as a zwitterion. Valsartan breaks down to the anionic product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid in wastewater treatment(5), suggesting that the anionic form may dominate at pH values of 5 to 9(SRC). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2014).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl valsartan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

C09CA03

C - Cardiovascular system

QC - Cardiovascular system

Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. **Hypotension** Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. **Impaired Renal Function** Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. **Hyperkalemia** Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required.

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as [ramipril], [lisinopril], and [perindopril]) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor.

Valsartan, a nonpeptide tetrazole derivative, is an angiotensin II type 1 (AT1) receptor antagonist. Valsartan has pharmacologic actions similar to those of losartan; however, unlike losartan, valsartan is not a prodrug and its pharmacologic activity does not depend on hydrolysis in the liver. Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects, by selectively inhibiting access of angiotensin II to AT1 receptors within many tissues, including vascular smooth muscle and the adrenal gland. By comparison, angiotensin-converting enzyme (ACE, kininase II) inhibitors block the conversion of angiotensin I to angiotensin II; however, the blockade of angiotensin II production by ACE inhibitors is not complete since the vasopressor hormone can be formed via other enzymes that are not blocked by ACE inhibitors. Because valsartan, unlike ACE inhibitors, does not inhibit ACE, the drug does not interfere with response to bradykinins and substance P; a beneficial consequence is the absence of certain ACE inhibitor-induced adverse effects (e.g., cough), but possible renal and/or cardioprotective effects may be sacrificed. Valsartan also does not interfere with angiotensin II synthesis.

After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.

Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours.

... In an investigation of pharmacokinetics and pharmacodynamics in normotensive male volunteers, valsartan was rapidly absorbed with the maximal plasma concentration occurring 2-3 hr after oral administration. The elimination half-life was about 4-6 hr, valsartan was poorly metabolized, and most of the drug was excreted via feces. ...

Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.

Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although the only notable metabolite is 4-hydroxyvaleryl metabolite (4-OH valsartan), the responsible enzyme has not been clarified at present. The current in vitro studies were conducted to identify the cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan was metabolized to 4-OH valsartan by human liver microsomes and the Eadie-Hofstee plots were linear. The apparent Km and Vmax values for the formation of 4-OH valsartan were 41.9-55.8 microM and 27.2-216.9 pmol min(-1) mg(-1) protein, respectively. There was good correlation between the formation rates of 4-OH valsartan and diclofenac 4'-hydroxylase activities (representative CYP2C9 activity) of 11 individual microsomes (r = 0.889). No good correlation was observed between any of the other CYP enzyme marker activities (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A). Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan. For the specific CYP inhibitors or substrates examined (furafylline, diclofenac, S(+)-mephenytoin, quinidine and troleandomycin), only diclofenac inhibited the formation of 4-OH valsartan. These results showed that CYP2C9 is the only form responsible for 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible.

... Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. ...

Valsartan has known human metabolites that include 4-hydroxy-valsartan.

80M03YXJ7I

VALSARTAN

Mechanisms of Action [MoA] - Angiotensin 2 Receptor Antagonists

Established Pharmacologic Class [EPC] - Angiotensin 2 Receptor Blocker

Valsartan is an Angiotensin 2 Receptor Blocker. The mechanism of action of valsartan is as an Angiotensin 2 Receptor Antagonist.

VALSARTAN

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS.

After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.

The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.

Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. ... Following intravenous administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance).

Absolute bioavailability for the capsule formulation is approximately 25% (range, 10-35%). Food decreases the area under the plasma concentration-time curve (AUC) and peak plasma concentration by approximately 40 and 50%, respectively.

MEDICATION

Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents

Use (kg) in Switzerland (2009): >2500

Table: Valsartan Preparations [Table#7212]

Table: Valsartan Combination Preparations [Table#7213]