Cozaar

Generic Name: Losartan Potassium
Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: 2 - Butyl - 4 - chloro - 1 - [[2′ - (1H - tetrazol - 5 - yl)[1,1′ - biphenyl] - 4 - yl] - methyl] - 1H - imidazole - 5 - methanol monopotassium salt
Molecular Formula: C₂₂H₂₃ClN₆O•K ½C₄H₄O₄
CAS Number: 124750-99-8

• 
  

  May cause fetal and neonatal morbidity and mortality if used during pregnancy.^{1 2 56 57} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  If pregnancy is detected, discontinue the drug as soon as possible.^{1 2 57}

  
  

Introduction

Angiotensin II receptor (AT₁) antagonist.^{1 2 5}

Uses for Cozaar

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents, including diuretics).^{1 2 5}

One of several preferred initial therapies in hypertensive patients with chronic kidney disease, diabetes mellitus, or heart failure.⁴⁹

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.⁴⁹

Prevention of Cardiovascular Morbidity and Mortality

Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy.^{1 2 53}

Evidence suggests that the benefit associated with such losartan-based antihypertensive therapy does not apply to black patients.^{1 20 53}

Preliminary evidence suggests that aspirin therapy at baseline in patients receiving losartan may reduce the risk of combined cardiovascular death, stroke, and AMI compared with aspirin therapy at baseline in patients receiving atenolol.⁵⁴

Diabetic Nephropathy

Management of diabetic nephropathy manifested by elevated S_cr and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes mellitus and hypertension.^{1 33}

A first-line agent in the treatment of diabetic nephropathy in such patients.^{28 29}

CHF

A second-line agent in the treatment of CHF†; should be used only in those intolerant of ACE inhibitors.

Cozaar Dosage and Administration

General

Hypertension

• 
  

  Losartan in fixed combination with hydrochlorothiazide should not be used for initial treatment of hypertension, except in severe hypertension when benefits of achieving prompt BP reduction are considered to outweigh risks of initiating combination therapy.²

  
  

Administration

Oral Administration

Administer losartan orally once or twice daily without regard to meals.^{1 2} Administer losartan as extemporaneously prepared oral suspension in patients unable to swallow tablets.¹ Administer losartan in fixed combination with hydrochlorothiazide once daily without regard to meals.²

Reconstitution

Preparation of extemporaneous suspension containing losartan potassium 2.5 mg/mL: Add 10 mL of purified water to a 240-mL polyethylene terephthalate (PET) bottle containing ten 50-mg tablets of losartan potassium; shake contents for ≥2 minutes.¹ Allow concentrated suspension to stand for 60 minutes following reconstitution, then shake for an additional minute.¹ Prepare a mixture containing equal parts (by volume) of syrup (Ora-Sweet) and suspending vehicle (Ora-Plus) separately.¹ Dilute the concentrated suspension of losartan potassium with 190 mL of the Ora-Sweet and Ora-Plus mixture; shake the container an additional minute to disperse ingredients.¹ Shake suspension before dispensing each dose.¹

Dosage

Available as losartan potassium; dosage expressed in terms of the salt.^{1 2}

Pediatric Patients

Hypertension

Oral

Children ≥6 years of age: Initially, 0.7 mg/kg (up to 50 mg) once daily.^{1 52} Adjust dosage until the desired BP goal is achieved⁵² (up to maximum dosage of 1.4 mg/kg or 100 mg daily).^{1 52}

Adults

Hypertension

Monotherapy

Oral

Initially, 50 mg once daily in adults without intravascular volume depletion.¹ Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.⁴⁹ In adults with depletion of intravascular volume, the usual initial dosage is 25 mg once daily.¹

Usual dosage: 25–100 mg daily, given in 1 dose or 2 divided doses; no additional therapeutic benefit with higher dosages.¹

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.¹

Combination Therapy

Oral

If BP is not adequately controlled by monotherapy with losartan potassium or hydrochlorothiazide (25 mg daily), if BP is controlled but hypokalemia is problematic at this hydrochlorothiazide dosage, or in those with severe hypertension in whom the potential benefit of achieving prompt BP control outweighs the potential risk of initiating therapy with the commercially available fixed combination, can use the fixed-combination tablets once daily (losartan potassium 50 mg and hydrochlorothiazide 12.5 mg; then losartan potassium 100 mg and hydrochlorothiazide 25 mg, if BP remains uncontrolled after about 3 weeks of therapy [or after 2–4 weeks of therapy in those with severe hypertension]).²

If BP is not adequately controlled by monotherapy with losartan potassium 100 mg daily, can switch to fixed-combination tablets once daily (losartan potassium 100 mg and hydrochlorothiazide 12.5 mg; then losartan potassium 100 mg and hydrochlorothiazide 25 mg [administered as 2 tablets of the fixed combination containing 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, or alternatively, as 1 tablet of the fixed combination containing 100 mg of losartan potassium and 25 mg of hydrochlorothiazide] if BP remains uncontrolled after about 3 weeks of therapy).²

Prevention of Cardiovascular Morbidity and Mortality

Oral

Initially, 50 mg once daily.¹ Adjust dosage based on BP response.^{1 2} If indicated, add hydrochlorothiazide 12.5 mg daily and/or increase dosage of losartan to 100 mg once daily.^{1 2} Subsequently, may increase hydrochlorothiazide dosage to 25 mg once daily.^{1 2} Alternatively, administer fixed combination of losartan potassium and hydrochlorothiazide at appropriate dosages.²

Diabetic Nephropathy

Oral

Initially, 50 mg once daily.¹ If BP is not adequately controlled, increase dosage to 100 mg once daily.¹

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Maximum 1.4 mg/kg or 100 mg daily.^{1 52}

Adults

Hypertension

Combination Therapy

Oral

Maximum 100 mg of losartan potassium and 25 mg of hydrochlorothiazide daily as the fixed combination.²

Special Populations

Hepatic Impairment

Manufacturer recommends initial dosage of 25 mg once daily in adults with a history of hepatic impairment.¹

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with hepatic impairment.²

Renal Impairment

No initial dosage adjustments recommended by manufacturer for adults with renal impairment, including those undergoing hemodialysis.¹ Use not recommended in pediatric patients with Cl_cr <30 mL/minute per 1.73 m².^{1 52}

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.²

Geriatric Patients

No initial dosage adjustments necessary.¹

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage (25 mg once daily).^{1 2}

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with intravascular volume depletion (e.g., patients receiving diuretics).²

Cautions for Cozaar

Contraindications

• 
  

  Known hypersensitivity to losartan or any ingredient in the formulation.^{1 2}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.^{1 2 5 6 7 8 9 10 11 12 13 14 15 16 57} (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.⁵⁷

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.^{56 57}

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.^{56 57} Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.^{11 13}

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics).^{1 2} (See Volume- and/or Salt-Depleted Patients under Dosage and Administration.)

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.^{120 121 123 126} However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.^{126 127 128 129} Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.¹²⁶

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible;^{1 2} not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.⁵⁸

General Precautions

Renal Effects

Possible oliguria, progressive azotemia and, rarely, acute renal failure and/or death in patients with severe CHF.^{1 2}

Increases in BUN and S_cr possible in patients with unilateral or bilateral renal artery stenosis.^{1 2}

Hyperkalemia

Possible hyperkalemia, particularly in patients with renal impairment with or without diabetes mellitus or in those receiving concomitant therapy with a potassium-sparing diuretic (e.g., amiloride, spironolactone, triamterene), and/or potassium supplements or salt substitutes containing potassium.¹

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.²

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).^{1 2} (See Boxed Warning.)

Lactation

Losartan and its active metabolite are distributed into milk in rats; not known whether distributed into human milk.^{1 2} Discontinue nursing or the drug.^{1 2}

Pediatric Use

Safety and efficacy not established in children <6 years of age or in pediatric patients with Cl_cr <30 mL/minute per 1.73 m².^{1 52}

Geriatric Use

No substantial differences in safety or efficacy of losartan monotherapy relative to younger adults, but increased sensitivity cannot be ruled out.¹

No apparent overall differences in efficacy with fixed combination containing losartan and hydrochlorothiazide in patients ≥65 years of age compared with younger adults.² Adverse effects more frequent in geriatric patients compared with younger patients; select dosage with caution.²

Hepatic Impairment

Systemic exposure to losartan and its active metabolite may be increased.¹ (See Absorption: Special Populations, under Pharmacokinetics.) Initial dosage adjustment recommended.¹ (See Hepatic Impairment under Dosage and Administration.)

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with hepatic impairment (tablet dosage exceeds recommended initial dosage).²

Renal Impairment

Deterioration of renal function may occur.^{1 37} (See Renal Effects under Cautions.)

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with Cl_cr <30 mL/minute.²

Blacks

BP reduction may be smaller in black patients compared with nonblack patients; use in combination with a diuretic.^{1 2}

No evidence that the benefits of therapy in reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to black patients.¹

Common Adverse Effects

Patients with hypertension: upper respiratory infection,^{1 2} dizziness,^{1 2} nasal congestion, back pain, leg pain, muscle cramp, sinusitis.

Patients with diabetic nephropathy: Urinary tract infection, diarrhea, anemia, asthenia/fatigue, hypoglycemia, chest pain, cough, bronchitis, diabetic vascular disease, influenza-like disease, cataracts, cellulitis, hyperkalemia, hypotension, muscular weakness, sinusitis, gastritis, hypoesthesia, infection, knee pain, and leg pain.¹

Interactions for Cozaar

Formation of active metabolite appears to be mediated by cytochrome P-450 microsomal isoenzyme 2C9 (CYP2C9).² CYP3A4 apparently contributes to formation of inactive metabolites.²

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 inhibitors: Possible inhibition of the formation of losartan’s active metabolite.^{1 2}

CYP3A4 inhibitors: Clinically important interactions unlikely (possible increased concentration of losartan, but no effects on formation of active metabolite observed).²

Specific Drugs

Drug	Interaction	Comment
Cimetidine	Pharmacokinetic interaction unlikely1 2
Digoxin	Pharmacokinetic interaction unlikely1 2
Diuretics, potassium-sparing (e.g., amiloride, spironolactone, triamterene)	Possible additive hyperkalemic effects1 2	Concomitant use not recommended1 2
Erythromycin	Clinically important pharmacokinetic interaction unlikely2
Fluconazole	Decreased plasma concentrations of losartan’s active metabolite and increased plasma losartan concentrations1 2
Hydrochlorothiazide	Pharmacokinetic interaction unlikely1 2 Additive hypotensive effects; used for therapeutic advantage in hypertension treatment1 2
Ketoconazole	Conversion of losartan to its active metabolite unaffected1 2
Lithium	Lithium excretion may be reduced.1 2	Carefully monitor serum lithium concentrations 1 2
NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors	Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients1 2 Possible decreased hypotensive effect1 2	Monitor renal function periodically1
Phenobarbital	Pharmacokinetic interaction unlikely1 2
Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) potassium supplements and potassium-containing salt substitutes	Increased serum potassium concentrations resulting in additive hyperkalemic effect1 2	Concomitant use not recommended1 2
Rifampin	Decreased plasma concentrations of losartan and its active metabolite1 2
Warfarin	Pharmacokinetic interaction unlikely1 2

Cozaar Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration but undergoes substantial first-pass metabolism.^{1 2}

Systemic bioavailability of losartan is about 33%.^{1 2} Bioavailability of the suspension formulation (see Oral Administration under Dosage and Administration) is similar to that of losartan tablets with respect to both the drug and its active metabolite.¹

Peak plasma concentrations of losartan and its active metabolite attained 1 and 3–4 hours, respectively, following oral administration.¹

Onset

Antihypertensive effect evident within 1 week, with maximum BP reduction after 3–6 weeks.¹

Food

Food slows absorption of losartan and decreases its peak plasma concentration but has minimal effect on AUC of losartan or its active metabolite.^{1 2}

Special Populations

In pediatric patients, pharmacokinetics of losartan and its active metabolite generally are similar to historical data in adults.¹

In patients with hepatic impairment, oral bioavailability is about 2 times higher than in those with normal hepatic function.¹

In patients with mild to moderate alcoholic cirrhosis, plasma concentration of losartan and its active metabolite were about 5 and 2 times those of healthy individuals, respectively.^{1 2}

In patients with mild (Cl_cr 50–74 mL/minute) or moderate (Cl_cr 30–49 mL/minute) renal impairment, plasma concentrations and AUC of losartan and its active metabolite are increased by 50–90%.²

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.^{1 2}

Crosses the blood-brain barrier poorly, if at all, in animals.^{1 2}

Distributed into milk in rats; not known whether distributed into human milk.^{1 2}

Plasma Protein Binding

Losartan and its active metabolite: >98%.^{1 2}

Elimination

Metabolism

Undergoes biotransformation through CYP2C9 to an active carboxylic acid metabolite that is responsible for most of the drug’s angiotensin II receptor antagonism.² CYP3A4 apparently contributes to formation of inactive metabolites.²

Elimination Route

Eliminated mainly in urine and feces (via bile).^{1 2}

Half-life

Terminal half-life of losartan and its active metabolite is approximately 2 and 6–9 hours, respectively.^{1 2}

Special Populations

In patients with mild to moderate alcoholic cirrhosis, total plasma clearance of losartan is about 50% lower than in those with normal hepatic function.¹

In patients with mild or moderate renal impairment, renal clearance of losartan and its active metabolite is decreased by 55–85%.² Neither losartan nor its active metabolite is removed by hemodialysis.^{1 2}

Stability

Storage

Oral

Extemporaneous Suspension

2.5-mg/mL preparation of losartan potassium tablets in a mixture of syrup (Ora-Sweet) and suspending vehicle (Ora-Plus) (see Oral Administration under Dosage and Administration): Up to 30 days at 2–8°C.¹

Tablets

Tight container at 25°C (may be exposed to 15–30°C).^{1 2} Protect from light.^{1 2}

Actions

• 
  

  Losartan (prodrug) has little pharmacologic activity until activated in the liver.^{1 2}

  
  


• 
  

  Losartan’s active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, noncompetitive inhibitor of the AT₁ receptor.^{1 2}

  
  


• 
  

  Blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.^{1 2}

  
  


• 
  

  Does not interfere with response to bradykinins.^{1 2}

  
  

• 
  

  Does not share the ACE inhibitor common adverse effect of dry cough.^{1 2}

  
  

Advice to Patients

• 
  

  Risks of use during pregnancy.^{1 2 56 57}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 2}

  
  

• 
  

  Importance of advising patients not to use potassium supplements or salt substitutes containing potassium without consulting their clinician.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).^{1 2}

  
  

• 
  

  Importance of informing patients of other important precautionary information.^{1 2} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Losartan Potassium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg	Cozaar	Merck
		50 mg	Cozaar	Merck
		100 mg	Cozaar	Merck

Losartan Potassium Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg with Hydrochlorothiazide 12.5 mg	Hyzaar	Merck
		100 mg with Hydrochlorothiazide 12.5 mg	Hyzaar	Merck
		100 mg with Hydrochlorothiazide 25 mg	Hyzaar	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 01/2012. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cozaar 25MG Tablets (MERCK SHARP &amp; DOHME): 30/$64.28 or 90/$188.69

Cozaar 50MG Tablets (MERCK SHARP &amp; DOHME): 30/$88.13 or 90/$234.32

Hyzaar 100-12.5MG Tablets (MERCK SHARP &amp; DOHME): 30/$130.66 or 90/$373.29

Hyzaar 100-25MG Tablets (MERCK SHARP &amp; DOHME): 30/$130.00 or 90/$385.98

Hyzaar 50-12.5MG Tablets (MERCK SHARP &amp; DOHME): 90/$279.99 or 180/$536.00

Losartan Potassium 100MG Tablets (APOTEX): 90/$259.97 or 270/$715.92

Losartan Potassium 25MG Tablets (APOTEX): 90/$125.99 or 270/$350.94

Losartan Potassium 50MG Tablets (TEVA PHARMACEUTICALS USA): 90/$176.99 or 270/$501.96

Losartan Potassium-HCTZ 100-12.5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$95.99 or 90/$265.96

Losartan Potassium-HCTZ 100-25MG Tablets (TEVA PHARMACEUTICALS USA): 30/$97.99 or 90/$268.98

Losartan Potassium-HCTZ 50-12.5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$69.99 or 90/$193.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2012, Selected Revisions December 23, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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2. Merck & Co., Inc. Hyzaar (losartan potassium-hydrochlorothiazide) tablets prescribing information. Whitehouse Station, NJ; 2008 Sep.

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32. Novartis. Diovan (valsartan) tablets prescribing information. East Hanover, NJ; 2002 Aug.

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34. Williams MA, Fleg JL, Ades PA et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥ 75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac rehabilitation, and Prevention. Circulation. 2002; 105:1735-43. [PubMed 11940556]

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36. Parving HH, Lehnert H, Bröchner-Mortensen J et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345:870-6. [IDIS 469608] [PubMed 11565519]

37. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-60. [IDIS 469606] [PubMed 11565517]

38. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. [IDIS 321612] [PubMed 8413456]

39. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. [PubMed 8413463]

40. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

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42. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994; 271:275-9. [IDIS 324307] [PubMed 8295285]

43. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1994; 330:937. [PubMed 8114873]

44. Kasiske VL, Kalil RSN, Ma JZ et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med. 1993; 118:129-138. [IDIS 308066] [PubMed 8416309]

45. Björck S, Mulec H, Johnsen SA et al. Renal protective effect of enalapril in diabetic nephropathy. BMJ. 1992; 304:339-43. [IDIS 291988] [PubMed 1540729]

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