valsartan (Diovan)
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Introduction
* 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
- pregnancy, trimesters 2 & 3, probably 1 as well
- angioedema with ACE inhibitor
- primary hyperaldosteronism
- bilateral renal artery stenosis
- biliary cirrhosis or biliary obstruction
Dosage
- start 40 mg BID or 80 mg QD
- titrate* to 160 mg BID as tolerated
- 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
- food delays & inhibits absorption up to 50%
- bioavailability 23%
- volume of distribution 17 L
- peak serum levels reached 2 hours after oral dose
- maximal effect observed 4-6 hours after oral dose
- protein binding 94-97%
- metabolized to an inactive metabolite {minor}
- elimination 1/2 life 6 hours
- 83% excreted unchanged in feces
- 13% excreted unchange in urine
- antihypertensive effects observed in 1-2 weeks
- maximal effects observed in 4-6 weeks
elimination via liver
elimination via kidney
Monitor
- baseline & periodic electrolytes, urinalysis, renal function, liver function
- monitor with ARBs
Adverse effects
- similar to placebo[4]
- fewer adverse effects than ACE inhibitors
- cardiovascular
- central nervous system
- gastrointestinal
- hematologic: anemia, neutropenia
- musculoskeletal
- renal: polyuria, increased serum creatinine
- respiratory
- rash
- increased liver function tests
- decreased libido
- serum K+ increases of > 20% in 4% of patients[4]
Toxicity:
- hypotension, tachycardia, bradycardia from vagal response
- treatment is supportive
- drug adverse effects of angiotensin II receptor antagonists
- drug adverse effects of renin-angiotensin-aldosterone system inhibitors (RAAS inhibitors)
- drug adverse effects of antihypertensive agents
Drug interactions
- increased mortality when used with ACE inhibitor & beta- blocker in patients with heart failure[3]
- increased effect when used with cimetidine
- decreased effect when used with phenobarbital, ketoconazole, troleandomycin
- use caution with concurrent administration of K+ or K+-sparing diuretics
- drug interaction(s) of calcineurin inhibitors with ARBs
- drug interaction(s) of calcium channel blockers with ARBs
- drug interaction(s) of renin-angiotensin-aldosterone inhibitors with trimethoprim-sulfamethoxazole
- drug interaction(s) of ARB with trimethoprim
- drug interaction(s) of angiotensin II receptor antagonists with aliskiren
- drug interaction(s) of ACE inhibitors with angiotensin II receptor antagonists
- drug interaction(s) of diuretics with angiotensin II receptor antagonists
- drug interaction(s) of NSAIDs with ARBs
- drug interaction(s) of NSAIDs, diuretics & angiotensin II receptor antagonists
- drug interaction(s) of NSAIDs & antihypertensives
Mechanism of action
- angiotensin II receptor antagonist
- directly inhibits AT2 receptors
- displaces angiotensin II from AT1 receptors
- antagonizes AT1-induced:
- vasoconstriction
- aldosterone release
- catecholamine release
- arginine vasopressin release
- water intake
- hypertrophic responses
- angiotensin II receptor type 2 & 4-stimulating antihypertensive
- more efficient antagonism of cardiovascular effects of angiotensin II than ACE inhibitors
- improves survival after myocardial infarction[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
More general terms
Additional terms
Component of
- nebivolol/valsartan
- sacubitril/valsartan (Entresto)
- hydrochlorothiazide/valsartan
- amlodipine/hydrochlorothiazide/valsartan
- aliskiren/valsartan (Valturna)
- amlodipine/valsartan (Exforge)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Prescriber's Letter 8(1):2 2001
- ↑ 3.0 3.1 Journal Watch 22(1):2, 2002 Cohn et al N Engl J Med 345:1667, 2001
- ↑ 4.0 4.1 4.2 Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ 5.0 5.1 5.2 Prescriber's Letter 10(12):67 2003
- ↑ Department of Veterans Affairs, VA National Formulary
non formulary drug request - ↑ 7.0 7.1 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: https://www.ncbi.nlm.nih.gov/pubmed/17965777
- ↑ 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20228403 <Internet> http://content.nejm.org/cgi/content/full/NEJMoa1001121
- ↑ 9.0 9.1 Prescriber's Letter 19(4): 2012 CHART: Anticipated Availability of First-Time Generics Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280401&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 10.0 10.1 Deprecated Reference
- ↑ 11.0 11.1 11.2 11.3 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 - ↑ 12.0 12.1 FDA News Release. March 12, 2018 FDA approves a new generic valsartan. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633255.htm