{{DrugProjectFormSinglePage |authorTag=Sheng Shi, M.D. [1], Rabin Bista, M.B.B.S. [2] |genericName=Valsartan |aOrAn=an |drugClass=Angiotensin 2 Receptor Blocker |indicationType=treatment |indication=hypertension, heart failure |hasBlackBoxWarning=Yes |adverseReactions=hypotension, dizziness, headache, raised serum blood urea nitrogen , raised serum creatinine , cough |blackBoxWarningTitle=WARNING: FETAL TOXICITY |blackBoxWarningBody=
|fdaLIADAdult=
|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Valsartan in adult patients.
|offLabelAdultNoGuideSupport=
|fdaLIADPed=
|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Valsartan in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Valsartan in pediatric patients. |contraindications=* Do not use in patients with known hypersensitivity to any component.
|warnings====Fetal Toxicity===
Pregnancy Category D
|clinicalTrials====Clinical Studies Experience===
Body as a Whole: Allergic reaction and asthenia
Cardiovascular: Palpitations
Dermatologic: Pruritus and rash
Digestive: Constipation, dry mouth, dyspepsia, and flatulence
Musculoskeletal: Back pain, muscle cramps, and myalgia
Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence
Respiratory: Dyspnea
Special Senses: Vertigo
Urogenital: Impotence
|postmarketing=* The following additional adverse reactions have been reported in post-marketing experience:
Digestive: Elevated liver enzymes and very rare reports of hepatitis
Renal: Impaired renal function, renal failure
Clinical Laboratory Tests: Hyperkalemia
Dermatologic: Alopecia
Blood and Lymphatic: There are very rare reports of thrombocytopenia
Vascular: Vasculitis
|drugInteractions=* No clinically significant pharmacokinetic interactions were observed when Diovan (valsartan) was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin,cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.
Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients. |FDAPregCat=D |useInPregnancyFDA=* Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnioscan be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
|useInNursing=* It is not known whether Diovan is excreted in human milk. Diovan was excreted in the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Diovan, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |useInPed=* The antihypertensive effects of Diovan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1-5 and 6-16 years of age. The pharmacokinetics of Diovan have been evaluated in pediatric patients 1 to 16 years of age. Diovan was generally well tolerated in children 6-16 years and the adverse experience profile was similar to that described for adults.
|useInGeri=* In the controlled clinical trials of valsartan, 1,214 (36.2%) hypertensive patients treated with valsartan were ≥65 years and 265 (7.9%) were ≥75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
|useInRenalImpair=* Safety and effectiveness of Diovan in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60-90 mL/min) or moderate (CrCl 30-60) renal impairment. |useInHepaticImpair=* No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease. |administration=* Oral |IVCompat=Oral |overdose=FDA Package Insert for Valsartan contains no information regarding drug overdose. |drugBox={{Drugbox2 | verifiedrevid = 470628341 | IUPAC_name = (S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid | image = Valsartan.png | image2 = Valsartan ball-and-stick.png
| tradename = Diovan | Drugs.com = Monograph | MedlinePlus = a697015 | licence_US = Valsartan | pregnancy_US = D | pregnancy_category = | legal_US = Rx-only | legal_status = | routes_of_administration = oral
| bioavailability = 25% | protein_bound = 95% | metabolism = | elimination_half-life = 6 hours | excretion = Renal 30%, biliary 70%
| CASNo_Ref = | CAS_number_Ref = | CAS_number = 137862-53-4 | ATC_prefix = C09 | ATC_suffix = CA03 | ATC_supplemental = | PubChem = 60846 | IUPHAR_ligand =3937 | DrugBank_Ref =
| DrugBank = DB00177
| ChemSpiderID_Ref = | ChemSpiderID = 54833 | UNII_Ref = | UNII = 80M03YXJ7I | KEGG_Ref = | KEGG = D00400 | ChEBI_Ref = | ChEBI = 9927 | ChEMBL_Ref = | ChEMBL = 1069
| C=24 | H=29 | N=5 | O=3 | molecular_weight = 435.519 g/mol | smiles = O=C(O)[C@@H](N(C(=O)CCCC)Cc3ccc(c1ccccc1c2nnnn2)cc3)C(C)C | InChI = 1/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1 | InChIKey = ACWBQPMHZXGDFX-QFIPXVFZBU | StdInChI_Ref = | StdInChI = 1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1 | StdInChIKey_Ref = | StdInChIKey = ACWBQPMHZXGDFX-QFIPXVFZSA-N }} |mechAction=* Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). angiotensinII is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Diovan (valsartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensinII by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
|structure=* iovan (valsartan) is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype.
|PD=Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.
|PK=* Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for Diovan is about 25% (range 10%-35%). The bioavailability of the suspension is 1.6 times greater than with the tablet. With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: 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.
Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Pediatric: In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.
Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.
Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease |nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility===
|clinicalStudies====Hypertension===
|howSupplied=* Valsartan is available as tablets containing valsartan, USP 40 mg, 80 mg, 160 mg, or 320 mg. All strengths are packaged in bottles as described below. 40 mg tablets are yellow colored, film-coated, oval-shaped tablets debossed with ' RX121' on one side and break line on the other side NDC 51660-140-03 Bottles of 10 NDC 51660-140-30 Bottles of 30 NDC 51660-140-05 Bottles of 500 80 mg tablets are yellowish brown colored, film-coated, oval-shaped tablets debossed with ' RX124' on one side and plain on the other side NDC 51660-141-03 Bottles of 10 NDC 51660-141-90 Bottles of 90 NDC 51660-141-05 Bottles of 500 160 mg tablets are pink colored, film-coated, oval-shaped tablets debossed with ' RX125' on one side and plain on the other side NDC 51660-142-03 Bottles of 10 NDC 51660-142-90 Bottles of 90 NDC 51660-142-05 Bottles of 500 320 mg tablets are brown colored, film-coated, oval-shaped tablets debossed with ' RX126' on one side and plain on the other side NDC 51660-143-03 Bottles of 10 NDC 51660-143-90 Bottles of 90 NDC 51660-143-05 Bottles of 500 |storage=* Store at 20 o - 25o C (68o - 77o F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in tight container (USP). |fdaPatientInfo=Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Distributed by: Ohm Laboratories Inc. North Brunswick, NJ 08902 USA March 2014 FDA-02 |alcohol=Alcohol-Valsartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=* Diovan |lookAlike=There is limited information about the Look-Alike Drug Names. }} {{#subobject:
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