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losartan (Cozaar)

Tradename: Cozaar. (FDA-approved generic available) * Recall Jan 2019 is due to trace amounts of N-Nitrosodiethylamine (NDEA) in the losartan active pharmaceutical ingredient manufactured by Hetero Labs Limited & Torrent Pharmaceuticals [16] * Recall March 2019 is due to trace amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) in certain lots from Camber Pharmaceuticals * FDA is allowing manufacturers to temporarily sell losartan that has levels of N-Nitroso-N-methyl-4-amino butyric acid (NMBA), which is possibly carcinogenic, above the interim acceptable limit. [17] Indications: - hypertension - uricosuric effects; good choice for patients with gout [13] - stroke prevention* [4,5,7] - renal protection in patients with diabetes mellitus [6] - diabetic nephropathy [12] - nondiabetic proteinuric nephropathy - chronic heart failure - left ventricular systolic dysfunction - left ventricular diastolic dysfunction [12] Contraindications: 1) pregnancy, trimesters 2 & 3, probably 1 as well 2) angioedema with ACE inhibitor 3) renal artery stenosis ? [3] * more effective than atenolol for similar reductions in blood pressure Dosage: 1) start 50 mg PO QD; max 100 mg/day 2) CHF: 25-50 mg QD; max 50-100 mg/day 3) 150 mg QD may be more effective than 50 mg QD at a cost of increased risk of adverse effects [8] Tabs: 25, 50 mg. Pharmacokinetics: 1) well absorbed from GI tract 2) time to peak concentration 1 hour; 3 hours for active metabolite 3) plasma protein-binding 99% 4) volume of distribution 34 L; active metabolite 12 L 5) metabolized by cyt P450 2C9 & 3A4 to active metabolite - significant 1st pass metabolism 6) elimination 1/2 life 2 hours - active metabolite 1/2life is 6-9 hours Adverse effects: 1) well tolerated, adverse effects similar to placebo [3], 1-3% 2) no effect in clinical trials on electrolytes, serum uric acid, serum triglycerides, serum glucose, serum cholesterol - clinically minor effects on creatinine & BUN may be seen [3] 3) hyperkalemia, hypotension, & renal impairment (dose-dependent) 4) cardiovascular: - flushing - report of increased risk of heart failure with high dose losartan not confirmed [8,11] 5) CNS: anxiety, ataxia, dizziness, insomnia, depression, nervousness, somnolence, vertigo, abnormal dreams, panic disorder 6) dermatologic: rash, urticaria, pruritus, dermatitis, alopecia, erythema, photosensitivity, xerosis, angioedema (30 minutes-30 days of 1st dose) 7) gastrointestinal: diarrhea, constipation, dyspepsia, anorexia, vomiting, flatulence, xerostomia, gastritis, dysgeusia 8) genitourinary: nocturia, polyuria, impotence 9) hematologic: anemia, hemolysis 10) musculoskeletal: joint edema, muscle cramps, arthralgia, muscle weakness, arthritis, back pain, leg pain, myalgia 11) neurologic: tremors, paresthesia, peripheral neuropathy 12) ocular: burning eyes, blurred vision, conjunctivitis, decreased visual acuity 12) otic: tinnitus 13) respiratory: nasal congestion, cough, sinusitis, dyspnea, bronchitis, epistaxis, upper respiratory tract infection, rhinitis, lower airway congestion 14) dental pain [3] Drug interactions: 1) any drug which inhibits CYP2C9 or CYP3A4 can increase losartan levels 2) any drug which induces CYP2C9 or CYP3A4 can diminish losartan levels Mechanism of action: 1) angiotensin II receptor antagonist 2) angiotensin II receptor type 2 & 4-stimulating antihypertensive 3) may slow progression of atherosclerosis [4] 4) slows progression of albuminuria in patients with diabetes mellitus[6] 5) may provide protective effects against sarcopenia [14] 6) may enhance cognition in younger normotensive subjects [15] * also see angiotensin II receptor antagonist (ARB)

Interactions

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

Related

ELITE II Study hydrochlorothiazide/losartan; HCTZ/losartan (Hyzaar)

General

angiotensin II receptor antagonist (ARB)

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 2 HOURS 6 +/- 9 HOURS protein-binding 99% elimination by hemodialysis - 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 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  3. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  4. Prescriber's Letter 9(4):19 2002
  5. Journal Watch 22(10):76, 2002 Dahlof B et al, Lancet 359:995, 2002 Lindholm LH et al, Lancet 359:1004, 2002
  6. Prescriber's Letter 9(11):61 2002
  7. Prescriber's Letter 10(5):29 2003
  8. Konstam MA et al Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial The Lancet, Early Online Publication, 17 November 2009 PMID: 19922995 doi:10.1016/S0140-6736(09)61913-9 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61913-9/abstract - Krum H. Optimising management of chronic heart failure. Lancet 2009 Nov 17 http://dx.doi.org/10.1016/S0140-6736(09)61992-9
  9. FDA News Release April 7, 2010 FDA Approves First Generic Versions of Two Drugs for the Treatment of Hypertension http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm207791.htm
  10. Department of Veterans Affairs, VA National Formulary - restricted to patients who fail ACE inhibitor
  11. Svanstrom H et al Association of Treatment With Losartan vs Candesartan and Mortality Among Patients With Heart Failure Association of Treatment With Losartan vs Candesartan and Mortality Among Patients With Heart Failure JAMA. 2012;307(14):1506-1512 PMID: 22496265 http://jama.ama-assn.org/content/307/14/1506.short
  12. Deprecated Reference
  13. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  14. Burks TN1, Andres-Mateos E, Marx R et al Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Sci Transl Med. 2011 May 11;3(82):82ra37 PMID: 21562229
  15. Mechaeil R, Gard P, Jackson A, Rusted J. Cognitive enhancement following acute losartan in normotensive young adults. Psychopharmacology (Berl). 2011 Sep;217(1):51-60 PMID: 21484242
  16. 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 - FDA Safety Alert. Jan 3, 2019 Torrent Pharmaceuticals Limited Expands Voluntary Nationwide Recall of Losartan Potassium Tablets, USP. https://www.fda.gov/Safety/Recalls/ucm629261.htm - FDA News Release. March 1, 2019 FDA provides update on its ongoing investigation into ARB drug products; reports on finding of a new nitrosamine impurity in certain lots of losartan and product recall. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632425.htm - FDA Safety Alert. Feb 28, 2019 Camber Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25 mg, 50 mg and 100 mg Due to the Detection of Trace Amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) Impurity found in the Active Pharmaceutical Ingredient (API). https://www.fda.gov/Safety/Recalls/ucm632395.htm
  17. Young K, Sofair A, Chavey WE FDA Temporarily Allows Increased Levels of NMBA in Losartan Amid Recalls. Physician's First Watch, March 22, 2019 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org

Component-of

hydrochlorothiazide/losartan; HCTZ/losartan (Hyzaar)