Cozaar

>10%

Fatigue (14%)

Hypoglycemia (14%)

Anemia (14%)

Urinary tract infection (UTI) (13%)

Chest pain (12%)

Weakness (14%)

Diarrhea (2-15%)

Cough; incidence higher in previous cough related to angiotensin-converting enzyme (ACE) inhibitor therapy (3-11%)

1-10%

Upper respiratory tract infection (8%)

Hypotension (7%)

Dizziness (4%)

Cellulitis (7%)

Gastritis (5%)

Nausea (2%)

Frequency Not Defined

Angioedema

Edema/swelling

Hypotension in hypovolemic or diuretic-using patients

Asthenia

Headache

Malaise

Nausea

Abdominal pain

Hyperkalemia

Back pain

Worsening renal failure

Pregnancy category: D

Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces renal function and increases fetal and neonatal morbidity and death

Resulting oligohydramnios can 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 as soon as possible

Lactation: Unknown if excreted in milk; not recommended

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

COZAAR (losartan potassium) is an angiotensin II receptor blocker acting on the AT1 receptor subtype. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1Htetrazol- 5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt.

Its empirical formula is C22H22ClKN6O, and its structural formula is:

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

COZAAR is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide.

COZAAR 25 mg, 50 mg and 100 mg tablets contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively. COZAAR 25 mg, COZAAR 50 mg, and COZAAR 100 mg may also contain carnauba wax.

Cozaar is a prescription medicine used:

• alone or with other blood pressure medicines to lower high blood pressure (hypertension).
• to lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy.
• to slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor about all of your medical conditions including if you:

• are pregnant or planning to become pregnant. (See pregnancy warning.)
• are breastfeeding. It is not known if Cozaar passes into your breast milk.
• are vomiting a lot or having a lot of diarrhea.
• have liver problems.
• have kidney problems

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. 

Do not use Cozaar while you are pregnant (especially in your second or third trimester). Cozaar can harm your unborn baby. If you think you have become pregnant while using this medicine, tell your doctor right away. 

If you take too much Cozaar call your local Poison Control Center or seek emergency medical attention right away.

Angiotensin II receptor (AT1) antagonist (i.e., angiotensin II receptor blocker, ARB).1 2

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents, including diuretics).1 2 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.500 501 502 504 520 523 524 527 534 535 536 543

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

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 acute MI compared with aspirin therapy at baseline in patients receiving atenolol.54

Diabetic Nephropathy

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

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.38 39 41 42 43 520 535 536

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure†.524 528 800

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); 524 however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.701 702 703 800

Angiotensin II receptor antagonists may be used as an alternative for those patients in whom an ACE inhibitor or ARNI is inappropriate.524 800

No additional therapeutic benefit when angiotensin II receptor antagonist used in combination with an ACE inhibitor.a

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Formation of active metabolite appears to be mediated by 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

Storage

Oral

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

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

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using this medicine, tell your doctor right away.

Dizziness or lightheadedness may occur after the first dose of this medicine, especially if you have been taking a diuretic (water pill). Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Check with your doctor right away if you become sick while taking this medicine, especially if you have severe or continuing nausea, vomiting, or diarrhea that does not stop. These conditions may cause you to lose too much water and may lead to low blood pressure. You can also lose water by sweating, so drink plenty of water during exercise or in hot weather.

Ask your doctor before you use medicines, supplements, or salt substitutes that contain potassium.

Avoid alcoholic beverages until you have discussed their use with your doctor. Alcohol may make the low blood pressure effect worse or increase the possibility of dizziness or fainting.

Do not take other medicines unless they have been discussed with your doctor. This especially includes prescription or nonprescription (over-the-counter [OTC]) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, and herbal or vitamin supplements.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Keep taking Cozaar as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.
• A liquid (suspension) can be made if you cannot swallow pills. Talk with your doctor or pharmacist.
• If a liquid (suspension) is made, shake well before use.
• Measure liquid doses carefully. Use the measuring device that comes with this medicine. If there is none, ask the pharmacist for a device to measure Cozaar.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Hypertension

Adult Hypertension

The usual starting dose of Cozaar is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure [see Clinical Studies (14.1)]. A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

Pediatric Hypertension

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension [see Dosage and Administration (2.5)]. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3), Clinical Studies (14.1), and Warnings and Precautions (5.2)].

Cozaar is not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m2 [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of Cozaar once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Cozaar should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response [see Clinical Studies (14.2)].

Nephropathy in Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response [see Clinical Studies (14.3)].

Dosage Modifications in Patients with Hepatic Impairment

In patients with mild-to-moderate hepatic impairment the recommended starting dose of Cozaar is 25 mg once daily. Cozaar has not been studied in patients with severe hepatic impairment [see Use in Special Populations (8.8) and Clinical Pharmacology (12.3)].

Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg Cozaar tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™ and Ora-Sweet SF™. Add 190 mL of the 50/50 Ora-Plus™/Ora-Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

• Cozaar, 25 mg, are white, oval, film-coated tablets with code 951 on one side.
• Cozaar, 50 mg, are white, oval, film-coated tablets with code 952 on one side and scored on the other.
• Cozaar, 100 mg, are white, teardrop-shaped, film-coated tablets with code 960 on one side.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m2 basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day.

Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Cozaar is a white film-coated tablet supplied as follows:

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• a diuretic or "water pill";

• other blood pressure medications;

• lithium;

• celecoxib; or

• aspirin or other NSAIDs (nonsteroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with losartan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Losartan is an angiotensin II receptor antagonist. Losartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Losartan is used to treat high blood pressure (hypertension) in adults and children who are at least 6 years old. It is also used to lower the risk of stroke in certain people with heart disease.

Losartan is used to slow long-term kidney damage in people with type 2 diabetes who also have high blood pressure.

Losartan may also be used for purposes not listed in this medication guide.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of losartan.

Do not use potassium supplements or salt substitutes while you are taking losartan, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.