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valsartan (Diovan)

* Several drug products containing valsartan found to contain N-nitrosodimethylamine, NDMA [11]. N-nitrosodiethylamine (NDEA) also found [11] (probable human carcinogens) July-Sept 2018. Mylan recalls all unexpired valsartan-containing products. [11] Tradname: Diovan. Generic Sept 2012 [9], March 2019 [12] Indications: - hypertension - heart failure - post-myocardial infarction [5] - diabetic nephropathy, nondiabetic proteinuric nephropathy [10] Contraindications: 1) pregnancy, trimesters 2 & 3, probably 1 as well 2) angioedema with ACE inhibitor 3) primary hyperaldosteronism 4) bilateral renal artery stenosis 5) biliary cirrhosis or biliary obstruction Dosage: 1) start 40 mg BID or 80 mg QD 2) titrate* to 160 mg BID as tolerated 3) CHF: start 20-40 mg BID; max 160 mg BID * antihypertensive effect enhanced by concurrent use of diuretic Tabs: 80, 160 mg. No dosage adjustment needed for creatinine clearance > 10 mL/min Use <= 80 mg/day if hepatic impairment Pharmacokinetics: 1) food delays & inhibits absorption up to 50% 2) bioavailability 23% 3) volume of distribution 17 L 4) peak serum levels reached 2 hours after oral dose 5) maximal effect observed 4-6 hours after oral dose 6) protein binding 94-97% 7) metabolized to an inactive metabolite {minor} 8) elimination 1/2 life 6 hours 9) 83% excreted unchanged in feces 10) 13% excreted unchange in urine 11) antihypertensive effects observed in 1-2 weeks 12) maximal effects observed in 4-6 weeks Monitor: - baseline & periodic electrolytes, urinalysis, renal function, liver function Adverse effects: 1) similar to placebo [4] 2) fewer adverse effects than ACE inhibitors 3) cardiovascular - edema, chest pain, tachycardia 4) central nervous system - headache, dizziness, drowsiness, ataxia, insomnia, fatigue, anxiety, nervousness 5) gastrointestinal - diarrhea, abdominal pain, nausea, abnormal taste, dyspepsia, heartburn 6) hematologic: anemia, neutropenia 7) musculoskeletal - arthralgia, muscle cramps, myalgia 8) renal: polyuria, increased serum creatinine 9) respiratory - cough (2.6%), upper respiratory tract infection, rhinitis, sinusitis, nasal congestion, pharyngitis 10) rash 11) increased liver function tests 12) decreased libido 13) serum K+ increases of > 20% in 4% of patients [4] Toxicity: 1) hypotension, tachycardia, bradycardia from vagal response 2) treatment is supportive Drug interactions: 1) increased mortality when used with ACE inhibitor & beta- blocker in patients with heart failure [3] 2) increased effect when used with cimetidine 3) decreased effect when used with phenobarbital, ketoconazole, troleandomycin 4) use caution with concurrent administration of K+ or K+-sparing diuretics Mechanism of action: 1) angiotensin II receptor antagonist a) directly inhibits AT2 receptors b) displaces angiotensin II from AT1 receptors c) antagonizes AT1-induced: 1] vasoconstriction 2] aldosterone release 3] catecholamine release 4] arginine vasopressin release 5] water intake 6] hypertrophic responses 2) angiotensin II receptor type 2 & 4-stimulating antihypertensive 3) more efficient antagonism of cardiovascular effects of angiotensin II than ACE inhibitors 4) improves survival after myocardial infarction [5] 5) valsartan clears beta-amyloid & improves spatial learning in a mouse model for Alzheimer's disease [7], (not a general feature of ARBs) Clinical trials: - Navigator study: - valsartan modestly lowers the incidence of diabetes (14%), but not cardiovascular events

Interactions

drug interactions drug adverse effects (more general classes) monitor with ARBs

Related

VALUE trial

General

angiotensin II receptor antagonist (ARB)

Properties

MISC-INFO: elimination route LIVER KIDNEY pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Prescriber's Letter 8(1):2 2001
  3. Journal Watch 22(1):2, 2002 Cohn et al N Engl J Med 345:1667, 2001
  4. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  5. Prescriber's Letter 10(12):67 2003
  6. Department of Veterans Affairs, VA National Formulary - non formulary drug request
  7. Wang J et al Valsartan lowers brain b-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease Journal of ClinicalInvestigation http://www.jci.org http://www.pubmedcentral.nih.gov/picrender.fcgi?doi=10.1172/JCI31547&blobtype=pdf PMID: 17965777
  8. Califf RM for the NAVIGATOR Study Group Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events N Engl J Med. 2010 Mar 29. PMID: 20228403 http://content.nejm.org/cgi/content/full/NEJMoa1001121
  9. Prescriber's Letter 19(4): 2012 CHART: Anticipated Availability of First-Time Generics Detail-Document#: 280401 (subscription needed) http://www.prescribersletter.com
  10. Deprecated Reference
  11. FDA News Release. July 13, 2018 FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613532.htm - FDA News Release. Sept 13, 2018 FDA provides update on its ongoing investigation into valsartan products; and reports on the finding of an additional impurity identified in one firm's s already recalled products. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620499.htm - Brooks M Mylan Expands Recall to All Unexpired Lots of Valsartan in the United States. Medscape - Dec 06, 2018. https://www.medscape.com/viewarticle/906158 - FDA Safety Alert. Jan 3, 2019 FDA updates on angiotensin II receptor blocker (ARB) recalls including valsartan, losartan and irbesartan. https://www.fda.gov/drugs/drugsafety/ucm613916.htm - List of recalled valsartan products https://www.fda.gov/downloads/Drugs/DrugSafety/UCM615703.pdf - List of valsartan products that have not been recalled https://www.fda.gov/downloads/Drugs/DrugSafety/UCM615704.pdf - FDA Safety Alert. March 1, 2019 AurobindoPharma USA, Inc. Initiates a Voluntary Nationwide Consumer Level Recall Expansion of 38 Lots of Amlodipine Valsartan Tablets USP and Valsartan Tablets, USP due to the detection of NDEA (N-Nitrosodiethylamine) Impurity. https://www.fda.gov/Safety/Recalls/ucm632442.htm
  12. FDA News Release. March 12, 2018 FDA approves a new generic valsartan. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633255.htm

Component-of

aliskiren/valsartan (Valturna) amlodipine/hydrochlorothiazide/valsartan amlodipine/valsartan (Exforge) hydrochlorothiazide/valsartan sacubitril/valsartan (Entresto)