what time of day to take losartan potassium

What is Cozaar and how is it used?

Cozaar is a prescription medicine used to treat the symptoms of high blood pressure level (hypertension), lower the risk of stroke in sure people with heart disease and diabetic nerve hurting (neuropathy). Cozaar may be used alone or with other medications.

Cozaar belongs to a grade of drugs chosen Angiotensin Ii Receptor Antagonist (ARBs).

It is not known if Cozaar is safety and effective in children younger than half-dozen years of age.

What are the possible side furnishings of Cozaar?

Cozaar may cause serious side furnishings including:

• lightheadedness,
• pain or burning when you urinate,
• nausea,
• weakness,
• tingly feeling,
• breast pain,
• irregular heartbeats,
• loss of movements,
• little or no urination,
• rapid weight gain, and
• swelling in your hands, anxiety or ankles

Go medical help correct away, if yous have any of the symptoms listed above.

The most common side effects of Cozaar include:

• dizziness,
• back pain, and
• cold symptoms (stuffy nose, sneezing, sore pharynx)

Tell the doctor if you accept whatever side effect that bothers you or that does not become away.

These are not all the possible side effects of Cozaar. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. Yous may report side furnishings to FDA at one-800-FDA-1088.

Alarm

FETAL TOXICITY

When pregnancy is detected, discontinue COZAAR as presently as possible. Drugs that deed directly on the renin-angiotensin arrangement tin can crusade injury and death to the developing fetus [see WARNINGS AND PRECAUTIONS].

DESCRIPTION

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

Its empirical formula is C₂₂H₂₂ClKN_half-dozenO, and its structural formula is:

Losartan potassium is a white to fair free-flowing crystalline pulverisation 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 v-hydroxymethyl grouping on the imidazole ring results in the agile metabolite of losartan.

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

COZAAR 25 mg, l mg and 100 mg tablets contain potassium in the post-obit 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 as well contain carnauba wax.

INDICATIONS

Hypertension

COZAAR^® is indicated for the treatment of hypertension in adults and pediatric patients half dozen years of age and older, to lower blood force per unit area. Lowering blood pressure lowers the gamble of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan.

Control of high blood pressure should be part of comprehensive cardiovascular chance direction, including, every bit appropriate, lipid command, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will crave more 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Handling of Loftier Claret Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it tin be ended that it is blood pressure level reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also take been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at college blood pressures, and so that fifty-fifty modest reductions of severe hypertension tin can provide substantial do good. Relative risk reduction from blood pressure level reduction is like across populations with varying absolute hazard, so the absolute do good is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to do good from more aggressive treatment to a lower claret pressure goal.

Some antihypertensive drugs have smaller claret pressure level effects (as monotherapy) in Black patients, and many antihypertensive drugs have boosted approved indications and furnishings (e.g., on angina, middle failure, or diabetic kidney disease). These considerations may guide selection of therapy.

COZAAR may be administered with other antihypertensive agents.

Hypertensive Patients With Left Ventricular Hypertrophy

COZAAR is indicated to reduce the adventure of stroke in patients with hypertension and left ventricular hypertrophy, but at that place is show that this benefit does not employ to Black patients [see Utilise In Specific Populations and CLINICAL PHARMACOLOGY].

Nephropathy In Blazon 2 Diabetic Patients

COZAAR is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type ii diabetes and a history of hypertension. In this population, COZAAR reduces the charge per unit of progression of nephropathy every bit measured by the occurrence of doubling of serum creatinine or end phase renal affliction (demand for dialysis or renal transplantation) [see Clinical Studies].

QUESTION

Salt and sodium are the aforementioned. Encounter Answer

DOSAGE AND Administration

Hypertension

Developed Hypertension

The usual starting dose of COZAAR is l mg once daily. The dosage can be increased to a maximum dose of 100 mg in one case daily as needed to control claret force per unit area [see Clinical Studies]. 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 Preparation Of Intermission (For 200 mL Of A 2.five mg/mL Suspension)]. Dosage should be adapted according to blood force per unit area response. Doses higher up 1.4 mg per kg (or in backlog of 100 mg) daily have not been studied in pediatric patients [see CLINICAL PHARMACOLOGY , Clinical Studies, and WARNINGS AND PRECAUTIONS].

COZAAR is non 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 [run into Use In Specific Populations , CLINICAL PHARMACOLOGY, and Clinical Studies].

Hypertensive Patients With Left Ventricular Hypertrophy

The usual starting dose is l mg of COZAAR one time 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 level response [see Clinical Studies].

Nephropathy In Blazon 2 Diabetic Patients

The usual starting dose is fifty mg once daily. The dose should be increased to 100 mg once daily based on claret pressure response [come across Clinical Studies].

Dosage Modifications In Patients With Hepatic Harm

In patients with balmy-to-moderate hepatic impairment the recommended starting dose of COZAAR is 25 mg once daily. COZAAR has not been studied in patients with astringent hepatic impairment [see Utilize In Specific Populations and CLINICAL PHARMACOLOGY].

Training Of Suspension (For 200 mL Of A 2.5 mg/mL Intermission)

Add 10 mL of Purified Water USP to an viii ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing 10 50 mg COZAAR tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour so shake for 1 infinitesimal 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/fifty Ora-Plus™/Ora- Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for ane infinitesimal to disperse the ingredients. The suspension should exist refrigerated at 2-eight°C (36-46°F) and tin can be stored for upwards to 4 weeks. Milk shake the suspension prior to each use and render promptly to the refrigerator.

HOW SUPPLIED

Dosage Forms And Strengths

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

Storage And Handling

COZAAR is a white film-coated tablet supplied every bit follows:

Losartan	Shape	Engraving (contrary)	NDC 0006-xxxx-xx
			Bottle/thirty	Canteen/90
25 mg	oval	951	n/a	0951-54
l mg	oval	952 (scored)	0952-31	0952-54
100 mg	teardrop	960	0960-31	0960-54

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

Manufacturedn for: Merck Sharp & Dohme Corp.,a subsidiary of MERCK&CO.,INC.,Whitehouse Station, NJ 08889, Usa. Revised: October 2018

SIDE Furnishings

Clinical Trials Feel

Because clinical trials are conducted under widely varying weather condition, adverse reaction rates observed in the clinical trials of a drug cannot exist directly compared to rates in the clinical trials of another drug and may not reverberate the rates observed in exercise.

Hypertension

COZAAR has been evaluated for condom in more than 3300 developed patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one twelvemonth.

Treatment with COZAAR was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with COZAAR and 3.vii% of patients given placebo. In 4 clinical trials involving over 1000 patients on various doses (10-150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with COZAAR and more than commonly than placebo were: dizziness (3% vs. ii%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. ane%), and back hurting (2% vs. 1%).

The post-obit less mutual agin reactions take been reported:

Claret and lymphatic organisation disorders: Anemia.

Psychiatric disorders: Depression.

Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine.

Ear and labyrinth disorders: Vertigo, tinnitus.

Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA.

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Gastrointestinal disorders: Intestinal pain, constipation, nausea, vomiting.

Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Reproductive organization and breast disorders: Impotence.

General disorders and administration site conditions: Edema.

Cough

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a crusade of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-grouping, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan l mg, lisinopril 20 mg, or either placebo (one report, n=97) or 25 mg hydrochlorothiazide (n=135). The double-bullheaded treatment catamenia lasted up to 8 weeks. The incidence of coughing is shown in Table ane below.

Table ane:

Study one*	HCTZ	Losartan	Lisinopril
Coughing	25%	17%	69%
Study 2†	Placebo	Losartan	Lisinopril
Cough	35%	29%	62%
* Demographics = (89% Caucasian, 64% female) † Demographics = (90% Caucasian, 51% female)

These studies demonstrate that the incidence of coughing associated with losartan therapy, in a population that all had coughing associated with ACE-inhibitor therapy, is like to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Hypertensive Patients With Left Ventricular Hypertrophy

In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with COZAAR were similar to those reported previously for patients with hypertension.

Nephropathy In Blazon 2 Diabetic Patients

In the Reduction of Endpoints in NIDDM with the Angiotensin Ii Receptor Antagonist Losartan (RENAAL) written report involving 1513 patients treated with COZAAR or placebo, the overall incidences of reported adverse events were similar for the 2 groups. Discontinuations of COZAAR because of side effects were similar to placebo (19% for COZAAR, 24% for placebo). The adverse events, regardless of drug human relationship, reported with an incidence of ≥4% of patients treated with COZAAR and occurring with ≥2% difference in the losartan grouping vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary tract infection.

Postmarketing Feel

The following boosted adverse reactions have been reported in postmarketing experience with COZAAR. Because these reactions are reported voluntarily from a population of uncertain size, it is non always possible to estimate their frequency reliably or to plant a causal relationship to drug exposure:

Digestive: Hepatitis.

General Disorders and Administration Site Weather condition: Malaise.

Hematologic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the confront, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions take been reported.

Metabolic and Nutrition: Hyponatremia.

Musculoskeletal: Rhabdomyolysis.

Nervous system disorders: Dysgeusia.

Skin: Erythroderma.

SLIDESHOW

How to Lower Blood Pressure level: Do Tips See Slideshow

DRUG INTERACTIONS

Agents Increasing Serum Potassium

Coadministration of losartan with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-two Inhibitors (COX-ii Inhibitors)

In patients who are elderly, book-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin Ii receptor antagonists (including losartan) may event in deterioration of renal function, including possible acute renal failure. These effects are normally reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be adulterate past NSAIDs, including selective COX-2 inhibitors.

Dual Blockade Of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any boosted benefit compared to monotherapy for the combined endpoint of refuse in GFR, stop stage renal disease, or death, merely experienced an increased incidence of hyperkalemia and astute kidney injury compared with the monotherapy group.

In nigh patients no do good has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on COZAAR and other agents that affect the RAS.

Do not coadminister aliskiren with COZAAR in patients with diabetes. Avoid utilize of aliskiren with COZAAR in patients with renal impairment (GFR <60 mL/min).

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Fetal Toxicity

Employ of drugs that deed on the renin-angiotensin system during the 2d and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and decease. 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 COZAAR as soon as possible [meet Use In Specific Populations].

Hypotension In Volume- Or Common salt-Depleted Patients

In patients with an activated renin-angiotensin organisation, such as volume- or salt-depleted patients (e.g., those being treated with loftier doses of diuretics), symptomatic hypotension may occur after initiation of treatment with COZAAR. Correct volume or salt depletion prior to administration of COZAAR [come across DOSAGE AND ADMINISTRATION].

Renal Part Deterioration

Changes in renal part including astute renal failure tin be caused by drugs that inhibit the reninangiotensin system and by diuretics. Patients whose renal office may depend in office on the activity of the renin-angiotensin system (due east.k., patients with renal artery stenosis, chronic kidney illness, severe congestive heart failure, or volume depletion) may be at particular risk of developing astute renal failure on COZAAR. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant subtract in renal function on COZAAR [see DRUG INTERACTIONS and Utilize In Specific Populations].

Hyperkalemia

Monitor serum potassium periodically and treat accordingly. Dosage reduction or discontinuation of COZAAR may be required [run across Agin REACTIONS].

Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see DRUG INTERACTIONS].

Patient Counseling Data

Advise the patient to read the FDA-approved patient labeling (Patient Data).

Pregnancy

Advise female person patients of childbearing historic period nearly the consequences of exposure to COZAAR during pregnancy. Hash out treatment options with women planning to get pregnant. Tell patients to report pregnancies to their physicians as before long equally possible [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Potassium Supplements

Advise patients receiving COZAAR non to employ potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see DRUG INTERACTIONS].

Nonclinical Toxicology

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/twenty-four hours in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically agile metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a fifty kg homo given 100 mg per day.

Losartan potassium was negative in the microbial mutagenesis and 5-79 mammalian cell mutagenesis assays and in the in vitro alkaline metal elution and in vitro and in vivo chromosomal aberration assays. In add-on, the active metabolite showed no prove of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were non affected in studies with male rats given oral doses of losartan potassium upwardly to approximately 150 mg/kg/solar day. The assistants of toxic dosage levels in females (300/200 mg/kg/solar day) was associated with a pregnant (p<0.05) decrease in the number of corpora lutea/female person, implants/female, and live fetuses/female at C-section. At 100 mg/kg/solar day only a subtract in the number of corpora lutea/female person was observed. The relationship of these findings to drugtreatment is uncertain since at that place 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/twenty-four hour period 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).

Apply In Specific Populations

Pregnancy

Pregnancy Category D

Utilize of drugs that act on the renin-angiotensin organization during the second and tertiary trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and expiry. Resulting oligohydramnios tin exist associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal agin furnishings include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue losartan every bit soon every bit possible. These adverse outcomes are unremarkably associated with use of these drugs in the 2d and tertiary trimester of pregnancy. Near epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the beginning trimester have non distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no advisable alternative to therapy with drugs affecting the reninangiotensin system for a item patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to appraise the intra-amniotic environment. If oligohydramnios is observed, discontinue COZAAR, unless information technology is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, yet, that oligohydramnios may not appear until afterward the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to COZAAR for hypotension, oliguria, and hyperkalemia [see Pediatric Use].

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, bloodshed and renal toxicity. With the exception of neonatal weight proceeds (which was affected at doses as low every bit 10 mg/kg/day), doses associated with these furnishings exceeded 25 mg/kg/twenty-four hours (approximately 3 times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Meaning levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Nursing Mothers

It is not known whether losartan is excreted in human milk, simply significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for agin effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the female parent.

Pediatric Use

Neonates With A History Of In Utero Exposure To COZAAR

If oliguria or hypotension occurs, straight attention toward support of claret pressure and renal perfusion. Exchange transfusion or dialysis may be required every bit means of reversing hypotension and/or substituting for matted renal role.

Antihypertensive effects of COZAAR have been established in hypertensive pediatric patients aged half-dozen to xvi years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/one.73 m² [see DOSAGE AND Administration , CLINICAL PHARMACOLOGY , and Clinical Studies].

Geriatric Apply

Of the total number of patients receiving COZAAR in controlled clinical studies for hypertension, 391 patients (xix%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical written report for the reduction in the combined gamble of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or condom were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot exist ruled out.

Race

In the LIFE study, Blackness patients with hypertension and left ventricular hypertrophy treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Blackness patients treated with COZAAR (both cotreated with hydrochlorothiazide in the majority of patients). The primary endpoint was the starting time occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. In the subgroup of Blackness patients (north=533, 6% of the LIFE study patients), there were 29 main endpoints among 263 patients on atenolol (11%, 26 per grand patientyears) and 46 chief endpoints among 270 patients (17%, 42 per grand patient-years) on COZAAR. This finding could not be explained on the basis of differences in the populations other than race or on whatsoever imbalances between handling groups. In add-on, blood force per unit area reductions in both treatment groups were consistent betwixt Black and non-Blackness patients. Given the difficulty in interpreting subset differences in large trials, it cannot exist known whether the observed difference is the event of chance. Notwithstanding, the LIFE report provides no evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy employ to Black patients [meet Clinical Studies].

Renal Impairment

Patients with renal insufficiency have elevated plasma concentrations of losartan and its active metabolite compared to subjects with normal renal function. No dose adjustment is necessary in patients with renal impairment unless a patient with renal impairment is also volume depleted [run across DOSAGE AND Assistants , WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Hepatic Damage

The recommended starting dose of COZAAR is 25 mg in patients with balmy-to-moderate hepatic impairment. Following oral administration in patients with mild-to-moderate hepatic impairment, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and i.seven times those seen in salubrious volunteers. COZAAR has non been studied in patients with severe hepatic harm [meet DOSAGE AND Administration and CLINICAL PHARMACOLOGY].

Overdosage & Contraindications

OVERDOSE

Significant lethality was observed in mice and rats afterward oral assistants of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended homo dose on a mg/grand² basis.

Express information 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 agile metabolite can be removed by hemodialysis.

CONTRAINDICATIONS

COZAAR is contraindicated:

• In patients who are hypersensitive to whatever component of this production.
• For coadministration with aliskiren in patients with diabetes.

CLINICAL PHARMACOLOGY

Mechanism Of Activeness

Angiotensin Two [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase Ii)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its master agile metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin Two by selectively blocking the binding of angiotensin II to the AT_ane receptor found in many tissues, (east.g., vascular smooth muscle, adrenal gland). There is likewise an AT₂ receptor constitute in many tissues but information technology is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activeness at the AT₁ receptor, and both have much greater analogousness (well-nigh g-fold) for the AT_ane receptor than for the AT₂ receptor. In vitro binding studies signal that losartan is a reversible, competitive inhibitor of the AT₁ receptor. The active metabolite is ten to 40 times more strong by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT_ane receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase 2, the enzyme that converts angiotensin I to angiotensin 2 and degrades bradykinin), nor do they bind to or cake other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacodynamics

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect past about 85% at peak with 25-twoscore% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin Two causes a doubling to tripling in plasma renin activity and consequent ascension in angiotensin Two plasma concentration in hypertensive patients. Losartan does not bear upon the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations autumn following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.

The event of losartan is substantially present within 1 calendar week but in some studies the maximal upshot occurred in 3-half dozen weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for upwards to a year. There is no apparent rebound issue later on abrupt withdrawal of losartan. There was essentially no modify in boilerplate middle rate in losartan-treated patients in controlled trials.

Pharmacokinetics

Absorption

Following oral administration, losartan is well absorbed and undergoes substantial starting time-laissez passer metabolism. The systemic bioavailability of losartan is approximately 33%. Hateful superlative concentrations of losartan and its agile metabolite are reached in 1 60 minutes and in iii-iv hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (surface area nether the bend) of the metabolite is almost four times equally great as that of losartan. A repast slows absorption of losartan and decreases its Cmax but has only pocket-sized effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its agile metabolite are linear with oral losartan doses up to 200 mg and practise not change over fourth dimension.

Distribution

The book of distribution of losartan and the active metabolite is well-nigh 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of ane.3% and 0.2%, respectively. Plasma protein binding is abiding over the concentration range achieved with recommended doses. Studies in rats signal that losartan crosses the blood-brain bulwark poorly, if at all.

Metabolism

Losartan is an orally active amanuensis that undergoes substantial offset-pass metabolism past cytochrome P450 enzymes. Information technology is converted, in office, to an active carboxylic acid metabolite that is responsible for nearly of the angiotensin II receptor antagonism that follows losartan treatment. Near 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies signal that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

Elimination

Total plasma clearance of losartan and the agile metabolite is about 600 mL/min and l mL/min, respectively, with renal clearance of nearly 75 mL/min and 25 mL/min, respectively. The concluding one-half-life of losartan is well-nigh ii hours and of the metabolite is most half-dozen-ix hours. After unmarried doses of losartan administered orally, virtually 4% of the dose is excreted unchanged in the urine and about six% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Post-obit oral ^fourteenC-labeled losartan, near 35% of radioactive decay is recovered in the urine and about 60% in the feces. Post-obit an intravenous dose of ^xivC-labeled losartan, about 45% of radioactive decay is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

Special Populations

Pediatric

Pharmacokinetic parameters later multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to sixteen years are shown in Table 4 beneath. Pharmacokinetics of losartan and its active metabolite were generally like across the studied age groups and similar to historical pharmacokinetic information in adults. The chief pharmacokinetic parameters in adults and children are shown in the table below.

Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Historic period 6-sixteen Following Multiple Dosing

	Adults given fifty mg once daily for 7 days N=12		Historic period 6-16 given 0.7 mg/kg one time daily for 7 days Due north=25
	Parent	Active Metabolite	Parent	Active Metabolite
AUC0-24 (ng•60 minutes/mL)*	442 ± 173	1685 ± 452	368 ± 169	1866 ± 1076
CMAX (ng/mL)*	224 ± 82	212 ± 73	141 ± 88	222 ± 127
Tone/2 (h)†	2.one ± 0.70	vii.4 ± two.four	2.3 ± 0.8	5.half-dozen ± 1.ii
TPEAK (h)‡	0.9	three.five	2.0	4.ane
CLREN (mL/min)*	56 ± 23	20 ± 3	53 ± 33	17 ± eight
* Hateful ± standard departure † Harmonic mean and standard departure ‡ Median

The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are like in their bioavailability with respect to both losartan and the active metabolite [come across DOSAGE AND ADMINISTRATION].

Geriatric And Gender

Losartan pharmacokinetics accept been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the agile metabolite were similar in males and females. No dosage adjustment is necessary [encounter DOSAGE AND ADMINISTRATION].

Race

Pharmacokinetic differences due to race accept non been studied [meet Use In Specific Populations].

Renal Insufficiency

Following oral assistants, plasma concentrations and AUCs of losartan and its agile metabolite are increased by 50-ninety% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its agile metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis [see WARNINGS AND PRECAUTIONS and Employ In Specific Populations].

Hepatic Insufficiency

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its agile metabolite were, respectively, 5-times and about one.seven-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about l% lower and the oral bioavailability was well-nigh doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic harm. COZAAR has not been studied in patients with severe hepatic harm [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Drug Interactions

No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Nonetheless, rifampin has been shown to subtract the AUC of losartan and its active metabolite by thirty% and forty%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, simply increased the AUC of losartan past approximately 70% following multiple doses. Conversion of losartan to its active metabolite afterwards intravenous administration is non affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was non affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to agile metabolite have been shown to take a specific, rare defect in cytochrome P450 2C9. These information suggest that the conversion of losartan to its agile metabolite is mediated primarily past P450 2C9 and not P450 3A4.

Clinical Studies

Hypertension

Adult Hypertension

The antihypertensive effects of COZAAR were demonstrated principally in four placebo-controlled, 6- to 12- calendar week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic claret pressures of 95-115. The studies immune comparisons of two doses (50-100 mg/day) every bit one time-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. 3 additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The ten- and 25-mg doses produced some effect at tiptop (6 hours after dosing) only small-scale and inconsistent trough (24 60 minutes) responses. Doses of l, 100 and 150 mg once daily gave statistically pregnant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.v/three.5-vii.5 mmHg, with the 150-mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (half dozen hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-summit ratio for systolic and diastolic responses 50-95% and lx-90%, respectively.

Add-on of a low dose of hydrochlorothiazide (12.5 mg) to losartan l mg once daily resulted in placeboadjusted claret pressure level reductions of 15.v/nine.2 mmHg.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and nether 65, had generally similar responses. COZAAR was constructive in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

Pediatric Hypertension

The antihypertensive effect of losartan was studied in one trial enrolling 177 hypertensive pediatric patients aged half-dozen to 16 years former. Children who weighed <50 kg received 2.5, 25 or 50 mg of losartan daily and patients who weighed ≥fifty kg received v, fifty or 100 mg of losartan daily. Children in the lowest dose grouping were given losartan in a suspension formulation [see DOSAGE AND Assistants]. The majority of the children had hypertension associated with renal and urogenital affliction. The sitting diastolic blood pressure level (SiDBP) on entry into the study was higher than the 95^th percentile level for the patient's age, gender, and tiptop. At the end of three weeks, losartan reduced systolic and diastolic blood force per unit area, measured at trough, in a dose-dependent style. Overall, the two higher doses (25 to 50 mg in patients <50 kg; 50 to 100 mg in patients ≥50 kg) reduced diastolic blood pressure by v to 6 mmHg more than the lowest dose used (2.v mg in patients <50 kg; 5 mg in patients ≥50 kg). The lowest dose, corresponding to an boilerplate daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy. When patients were randomized to keep losartan at the two college doses or to placebo afterward 3 weeks of therapy, trough diastolic blood force per unit area rose in patients on placebo between five and seven mmHg more than than patients randomized to continuing losartan. When the low dose of losartan was randomly withdrawn, the ascension in trough diastolic blood pressure was the same in patients receiving placebo and in those standing losartan, again suggesting that the lowest dose did not take pregnant antihypertensive efficacy. Overall, no pregnant differences in the overall antihypertensive effect of losartan were detected when the patients were analyzed according to historic period (<, ≥12 years sometime) or gender. While blood pressure was reduced in all racial subgroups examined, likewise few non-White patients were enrolled to compare the dose-response of losartan in the non-White subgroup.

Hypertensive Patients With Left Ventricular Hypertrophy

The LIFE study was a multinational, double-blind study comparing COZAAR and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive in one case daily COZAAR fifty mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was non reached, hydrochlorothiazide (12.5 mg) was added get-go and, if needed, the dose of COZAAR or atenolol was then increased to 100 mg in one case daily. If necessary, other antihypertensive treatments (eastward.m., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, blastoff-blockers, or centrally acting agents, simply non ACE inhibitors, angiotensin 2 antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.

Of the randomized patients, 4963 (54%) were female person and 533 (half-dozen%) were Black. The hateful age was 67 with 5704 (62%) age ≥65. At baseline, 1195 (xiii%) had diabetes, 1326 (fourteen%) had isolated systolic hypertension, 1469 (xvi%) had coronary heart illness, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure level was 174/98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit earlier a chief endpoint, 77% of the group treated with COZAAR and 73% of the group treated with atenolol were yet taking study medication. Of the patients still taking study medication, the mean doses of COZAAR and atenolol were both about 80 mg/day, and xv% were taking atenolol or losartan every bit monotherapy, while 77% were likewise receiving hydrochlorothiazide (at a mean dose of 20 mg/mean solar day in each grouping). Blood pressure reduction measured at trough was like for both treatment groups but claret force per unit area was non measured at any other time of the day. At the end of study or at the final visit before a chief endpoint, the hateful blood pressures were 144.1/81.three mmHg for the grouping treated with COZAAR and 145.iv/lxxx.nine mmHg for the group treated with atenolol; the difference in systolic blood pressure (SBP) of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in diastolic blood force per unit area (DBP) was not significant (p=0.098).

The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Patients with nonfatal events remained in the trial, and so that there was also an examination of the first event of each type even if it was not the first event (eastward.g., a stroke following an initial myocardial infarction would exist counted in the analysis of stroke). Treatment with COZAAR resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group (meet Figure 1 and Table 3); this difference was primarily the result of an upshot on fatal and nonfatal stroke. Treatment with COZAAR reduced the risk of stroke by 25% relative to atenolol (p=0.001) (come across Figure 2 and Table 3).

Effigy 1: Kaplan-Meier estimates of the primary endpoint of fourth dimension to cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction in the groups treated with COZAAR and atenolol. The Risk Reduction is adjusted for baseline Framingham hazard score and level of electrocardiographic left ventricular hypertrophy.

Effigy 2: Kaplan-Meier estimates of the time to fatal/nonfatal stroke in the groups treated with COZAAR and atenolol. The Gamble Reduction is adjusted for baseline Framingham chance score and level of electrocardiographic left ventricular hypertrophy.

Table 3 shows the results for the primary composite endpoint and the individual endpoints. The main endpoint was the offset occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an ITT approach. The table shows the number of events for each component in two different ways. The Components of Chief Endpoint (every bit a showtime outcome) counts only the events that define the primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or not they were preceded past a different type of event.

Tabular array iii: Incidence of Main Endpoint Events

	COZAAR		Atenolol		Risk Reduction †	95% CI	p-Value
	N (%)	Charge per unit*	Due north (%)	Rate*
Principal Blended Endpoint	508 (11)	23.eight	588 (13)	27.9	13%	2% to 23%	0.021
Components of Main Composite Endpoint (as a first outcome)
Stroke (nonfatal)	209 (5)		286 (6)
Myocardial infarction (nonfatal)	174 (four)		168 (4)
Cardiovascular mortality	125 (3)		134 (iii)
Secondary Endpoints (whatsoever time in written report)
Stroke (fatal/nonfatal)	232 (5)	10.8	309 (7)	14.five	25%	11% to 37%	0.001
Myocardial infarction (fatal/nonfatal)	198 (4)	9.2	188 (4)	8.7	-vii%	-13% to 12%	0.491
Cardiovascular bloodshed	204 (4)	nine.2	234 (v)	10.6	11%	-vii% to 27%	0.206
Due to CHD	125 (3)	5.vi	124 (3)	5.6	-3%	-32% to xx%	0.839
Due to Stroke	forty (1)	one.8	62 (1)	two.8	35%	4% to 67%	0.032
Other‡	39 (1)	i.8	48 (1)	2.two	16%	-28% to 45%	0.411
* Charge per unit per 1000 patient-years of follow-up † Adapted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy ‡ Death due to heart failure, not-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other than stroke or coronary heart disease

Although the LIFE study favored COZAAR over atenolol with respect to the primary endpoint (p=0.021), this result is from a unmarried written report and, therefore, is less compelling than the difference between COZAAR and placebo. Although not measured directly, the divergence betwixt COZAAR and placebo is compelling because there is bear witness that atenolol is itself effective (vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.

Other clinical endpoints of the LIFE report were: total mortality, hospitalization for heart failure or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac abort. There were no pregnant differences in the rates of these endpoints between the COZAAR and atenolol groups.

For the master endpoint and stroke, the effects of COZAAR in patient subgroups defined by age, gender, race and presence or absenteeism of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD) are shown in Effigy 3 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or adventure effects.

Figure 3: Primary Endpoint Events^† within Demographic Subgroups

Nephropathy In Blazon 2 Diabetic Patients

The RENAAL study was a randomized, placebo-controlled, double-bullheaded, multicenter study conducted worldwide in 1513 patients with type two diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/dL in females or males ≤lx kg and i.five to 3.0 mg/dL in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g]).

Patients were randomized to receive COZAAR 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin 2 antagonists. After ane month, investigators were instructed to titrate study drug to 100 mg in one case daily if the trough blood pressure goal (140/90 mmHg) was not achieved. Overall, 72% of patients received the 100-mg daily dose more than 50% of the time they were on study drug. Because the study was designed to attain equal claret pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel blockers, blastoff- or beta-blockers, and centrally interim agents) could be added as needed in both groups. Patients were followed for a mean elapsing of 3.4 years.

The study population was diverse with regard to race (Asian 16.7%, Black 15.two%, Hispanic 18.3%, White 48.6%). Overall, 63.2% of the patients were men, and 66.4% were under the age of 65 years. Nearly all of the patients (96.vi%) had a history of hypertension, and the patients entered the trial with a mean serum creatinine of i.9 mg/dL and mean proteinuria (urinary albumin/creatinine) of 1808 mg/one thousand at baseline.

The primary endpoint of the study was the time to beginning occurrence of any ane of the following events: doubling of serum creatinine, stop-stage renal disease (ESRD) (need for dialysis or transplantation), or decease. Treatment with COZAAR resulted in a 16% risk reduction in this endpoint (come across Figure four and Table 4). Handling with COZAAR also reduced the occurrence of sustained doubling of serum creatinine past 25% and ESRD by 29% every bit separate endpoints, just had no effect on overall mortality (encounter Tabular array iv).

The mean baseline blood pressures were 152/82 mmHg for COZAAR plus conventional antihypertensive therapy and 153/82 mmHg for placebo plus conventional antihypertensive therapy. At the end of the study, the mean claret pressures were 143/76 mmHg for the grouping treated with COZAAR and 146/77 mmHg for the group treated with placebo.

Effigy 4: Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, cease stage renal disease (demand for dialysis or transplantation) or death.

Tabular array 4: Incidence of Main Endpoint Events

	Incidence		Risk Reduction	95% C.I.	p- Value
	Losartan	Placebo
Master Blended Endpoint	43.5%	47.1%	16.1%	two.3% to 27.nine%	0.022
Doubling of Serum Creatinine, ESRD and Death Occurring as a Beginning Event
Doubling of Serum Creatinine	21.6%	26.0%
ESRD	eight.5%	viii.5%
Death	13.four%	12.6%
Overall Incidence of Doubling of Serum Creatinine, ESRD and Death
Doubling of Serum Creatinine	21.6%	26.0%	25.3%	vii.8% to 39.4%	0.006
ESRD	19.half dozen%	25.5%	28.half-dozen%	11.5% to 42.4%	0.002
Death	21.0%	20.3%	-1.seven%	-26.9% to xviii.6%	0.884

The secondary endpoints of the report were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular expiry). Compared with placebo, COZAAR significantly reduced proteinuria by an average of 34%, an effect that was axiomatic inside three months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, every bit measured by the reciprocal of the serum creatinine concentration. There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality.

The favorable effects of COZAAR were seen in patients too taking other anti-hypertensive medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not allowed), oral hypoglycemic agents and lipid-lowering agents.

For the primary endpoint and ESRD, the furnishings of COZAAR in patient subgroups divers by historic period, gender and race are shown in Tabular array 5 below. Subgroup analyses can be difficult to interpret and information technology is not known whether these correspond truthful differences or gamble effects.

Table 5: Efficacy Outcomes inside Demographic Subgroups

	No. of Patients	Principal Composite Endpoint			ESRD
		COZAAR Issue Rate %	Placebo Event Rate %	Hazard Ratio (95% CI)	COZAAR Event Rate %	Placebo Event Charge per unit %	Hazard Ratio (95% CI)
Overall Results	1513	43.5	47.1	0.84 (0.72, 0.98)	19.6	25.v	0.71 (0.58, 0.89)
Historic period
<65 years	1005	44.1	49.0	0.78 (0.65, 0.94)	21.one	28.5	0.67 (0.52, 0.86)
≥65 years	508	42.3	43.v	0.98 (0.75, i.28)	16.5	19.6	0.85 (0.56, 1.28)
Gender
Female	557	47.8	54.1	0.76 (0.60, 0.96)	22.8	32.viii	0.lx (0.44, 0.83)
Male	956	forty.nine	43.iii	0.89 (0.73, 1.09)	17.5	21.5	0.81 (0.60, 1.08)
Race
Asian	252	41.9	54.viii	0.66 (0.45, 0.95)	18.eight	27.iv	0.63 (0.37, 1.07)
Black	230	forty.0	39.0	0.98 (0.65, 1.l)	17.half dozen	21.0	0.83 (0.46, i.52)
Hispanic	277	55.0	54.0	ane.00 (0.73, 1.38)	thirty.0	28.5	1.02 (0.66, 1.59)
White	735	forty.5	43.2	0.81 (0.65, one.01)	xvi.2	23.9	0.60 (0.43, 0.83)

PATIENT INFORMATION

COZAAR^®
(CO-zar)
(losartan potassium tablets) 25 mg, 50 mg, 100 mg

Read the Patient Information that comes with COZAAR^® before you showtime taking information technology and each time you get a refill. In that location may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment.

What is the most important data I should know about COZAAR?

• COZAAR can cause harm or decease to an unborn baby.
• Talk to your md about other ways to lower your claret pressure level if you program to go pregnant.
• If you get significant while taking COZAAR, tell your doc right away.

What is COZAAR?

COZAAR is a prescription medicine called an angiotensin receptor blocker (ARB). Information technology is used:

• lonely or with other blood force per unit area medicines to lower high blood force per unit area (hypertension).
• to lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy. COZAAR may not help Black patients with this problem.
• to tiresome the worsening of diabetic kidney affliction (nephropathy) in patients with type two diabetes who accept or had high blood force per unit area.

COZAAR has not been studied in children less than 6 years old or in children with certain kidney problems.

High Claret Pressure (hypertension). Blood pressure is the force in your blood vessels when your eye beats and when your eye rests. You take high blood pressure level when the strength is also much. COZAAR can help your blood vessels relax and then your blood pressure is lower.

Left Ventricular Hypertrophy (LVH) is an enlargement of the walls of the left chamber of the heart (the middle's main pumping chamber). LVH can happen from several things. High blood pressure is the well-nigh common cause of LVH.

Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults. If you take diabetic nephropathy it means that your kidneys do not work properly because of impairment from the diabetes.

Who should non take COZAAR?

• Practise non have COZAAR if you are allergic to any of the ingredients in COZAAR. See the end of this leaflet for a complete list of ingredients in COZAAR.
• Do not take COZAAR if you have diabetes and are taking a medicine called aliskiren to reduce claret pressure.

What should I tell my doctor earlier taking COZAAR?

Tell your doctor almost all of your medical atmospheric condition including if you:

• are pregnant or planning to become pregnant. See "What is the about important data I should know nigh COZAAR?"
• are breastfeeding. It is not known if COZAAR passes into your breast milk. You should choose either to take COZAAR or breastfeed, only non both.
• are vomiting a lot or having a lot of diarrhea
• have liver issues
• take kidney problems

Tell your doc about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. COZAAR and certain other medicines may collaborate with each other. Especially tell your doctor if you are taking:

• potassium supplements
• table salt substitutes containing potassium
• other medicines that may increase serum potassium
• water pills (diuretics)
• lithium (a medicine used to treat a sure kind of low)
• medicines used to care for pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-ii inhibitors
• other medicines to reduce blood pressure

How should I have COZAAR?

• Take COZAAR exactly as prescribed by your physician. Your dr. may change your dose if needed.
• COZAAR can be taken with or without nutrient.
• If y'all miss a dose, take it every bit soon as you lot remember. If information technology is shut to your next dose, practice not take the missed dose. Only accept the side by side dose at your regular fourth dimension.
• If you lot take too much COZAAR, call your doctor or Toxicant Control Centre, or go to the nearest hospital emergency room right abroad.

What are the possible side effects of COZAAR?

COZAAR may cause the post-obit side effects that may be serious:

• Injury or death of unborn babies. See "What is the well-nigh important information I should know about COZAAR?"
• Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue. Get emergency medical help correct away and end taking COZAAR.
• Depression blood pressure (hypotension). Low blood pressure may cause you lot to feel faint or dizzy. Lie downwards if you feel faint or lightheaded. Phone call your physician right away.
• For people who already accept kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.
• Loftier blood levels of potassium

The most common side furnishings of COZAAR in people with loftier blood pressure are:

• "colds" (upper respiratory infection)
• dizziness
• stuffy olfactory organ
• back pain

The most mutual side effects of COZAAR in people with type 2 diabetes with diabetic kidney disease are:

• diarrhea
• tiredness
• low blood sugar
• chest hurting
• loftier blood potassium
• low blood pressure level

Tell your medico if you get any side result that bothers you or that won't get away.

This is not a complete list of side furnishings. For a complete list, inquire your physician or pharmacist.

How do I store COZAAR?

• Store COZAAR tablets at 59°F to 86°F (xv°C to 30°C).
• Go on COZAAR in a tightly airtight container that protects the medicine from calorie-free.
• Go along COZAAR and all medicines out of the reach of children.

General data about COZAAR

Medicines are sometimes prescribed for conditions that are non mentioned in patient information leaflets. Do not utilize COZAAR for a condition for which it was not prescribed. Do not requite COZAAR to other people, even if they have the same symptoms that you take. It may harm them.

This leaflet summarizes the near important information about COZAAR. If you would like more information, talk with your doctor. Yous can ask your pharmacist or doctor for information nearly COZAAR that is written for health professionals.

What are the ingredients in COZAAR?

Agile ingredients: losartan potassium

Inactive ingredients:

microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. COZAAR 25 mg, COZAAR l mg, and COZAAR 100 mg may also incorporate carnauba wax.

From

Heart Wellness Resources

Report Issues to the Food and Drug Administration

You are encouraged to written report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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